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201. Body mass index and breast cancer survival

Author: Guo, Q. (Qi), Burgess, S. (Stephen), Turman, C. (Constance), Bolla, M.K. (Manjeet K.), Wang, Q. (Qin), Lush, M. (Michael), Abraham, J. (Jean), Aittomäki, K. (Kristiina), Andrulis, I.L. (Irene), Apicella, C. (Carmel), Arndt, V. (Volker), Barrdahl, M. (Myrto), Benítez, J. (Javier), Berg, C.D. (Christine), Blomqvist, C. (Carl), Bojesen, S.E. (Stig), Bonnani, B. (Bernardo), Brand, J.S. (Judith S.), Brenner, H. (Hermann), Broeks, A. (Annegien), Burwinkel, B. (Barbara), Caldas, C. (Carlos), Campa, D. (Daniele), Canzian, F. (Federico), Chang-Claude, J. (Jenny), Chanock, S.J. (Stephen), Chin, S.-F. (Suet-Feung), Couch, F.J. (Fergus J.), Cox, A. (Angela), Cross, S.S. (Simon), Cybulski, C. (Cezary), Czene, K. (Kamila), Darabi, H. (Hatef), Devilee, P. (Peter), Diver, W.R. (Ryan), Dunning, A.M. (Alison), Earl, H. (Helena), Eccles, D.M. (Diana M.), Ekici, A.B. (Arif B.), Eriksson, M. (Mats), Evans, D.G. (D Gareth), Fasching, P.A. (Peter), Figueroa, J.D. (Jonine), Flesch-Janys, D. (Dieter), Flyger, H. (Henrik), Gapstur, S.M. (Susan M.), Gaudet, M.M. (Mia M.), Giles, G.G. (Graham G.), Glendon, G. (Gord), Grip, M. (Mervi), Gronwald, J. (Jacek), Haeberle, L. (Lothar), Haiman, C.A. (Christopher), Hall, P. (Per), Hamann, U. (Ute), Hankinson, S.E. (Susan), Hartikainen, J.M. (Jaana M.), Hein, A. (Alexander), Hiller, L. (Louise), Hogervorst, F.B. (Frans B.), Holleczek, B. (B.), Hooning, M.J. (Maartje), Hoover, R.N. (Robert), Humphreys, K. (Keith), Hunter, D. (David), Hüsing, A. (Anika), Jakubowska, A. (Anna), Jukkola-Vuorinen, A. (Arja), Kaaks, R. (Rudolf), Kabisch, M. (Maria), Kataja, V. (Vesa), Knight, J.A. (Julia), Koppert, L.B. (Linetta), Kosma, V-M. (Veli-Matti), Kristensen, V.N. (Vessela N.), Lambrechts, D. (Diether), Le Marchand, L. (Loic), Li, J. (Jingmei), Lindblom, A. (Annika), Lindström, S. (Sara), Lissowska, J. (Jolanta), Lubinski, J. (Jan), Machiela, M.J. (Mitchell J.), Mannermaa, A. (Arto), Manoukian, S. (Siranoush), Margolin, S. (Sara), Marme, F. (Federik), Martens, J.W.M. (John), McLean, C.A. (Catriona Ann), Menéndez, P. (Primitiva), Milne, R.L. (Roger), Mulligan, A.-M. (Anna-Marie), Muranen, T.A. (Taru A.), Nevanlinna, H. (Heli), Neven, P. (Patrick), Nielsen, S.F. (Sune F.), Nordestgaard, B.G. (Børge), Olson, J.E. (Janet), Perez, J.I.A. (Jose Ignacio Arias), Peterlongo, P. (Paolo), Phillips, K.-A. (Kelly-Anne), Poole, C.J. (Christopher J.), Pykäs, K. (Katri), Radice, P. (Paolo), Rahman, N. (Nazneen), Rud̈iger, T. (Thomas), Rudolph, A. (Anja), Sawyer, E.J. (Elinor), Schumacher, F.R. (Fredrick R), Seibold, P. (Petra), Seynaeve, C.M. (Caroline), Shah, M. (Mitul), Smeets, A. (Ann), Southey, M.C. (Melissa C.), Tollenaar, R.A.E.M. (Rob), Tomlinson, I.P. (Ian), Tsimiklis, H. (Helen), Ulmer, H.U. (Hans), Vachon, C. (Celine), Ouweland, A.M.W. (Ans) van den, Veer, L.J. (Laura) van 't, Wildiers, H. (Hans), Willett, W.C. (Walter C.), Winqvist, R. (Robert), Zamora, M.P. (Pilar), Chenevix-Trench, G. (Georgia), Dörk, T. (Thilo), Easton, D.F. (Douglas), García-Closas, M. (Montserrat), Kraft, P. (Peter), Hopper, J.L. (John), Zheng, W. (Wei), Schmidt, M.K. (Marjanka), Pharoah, P.D.P. (Paul), Guo, Q. (Qi), Burgess, S. (Stephen), Turman, C. (Constance), Bolla, M.K. (Manjeet K.), Wang, Q. (Qin), Lush, M. (Michael), Abraham, J. (Jean), Aittomäki, K. (Kristiina), Andrulis, I.L. (Irene), Apicella, C. (Carmel), Arndt, V. (Volker), Barrdahl, M. (Myrto), Benítez, J. (Javier), Berg, C.D. (Christine), Blomqvist, C. (Carl), Bojesen, S.E. (Stig), Bonnani, B. (Bernardo), Brand, J.S. (Judith S.), Brenner, H. (Hermann), Broeks, A. (Annegien), Burwinkel, B. (Barbara), Caldas, C. (Carlos), Campa, D. (Daniele), Canzian, F. (Federico), Chang-Claude, J. (Jenny), Chanock, S.J. (Stephen), Chin, S.-F. (Suet-Feung), Couch, F.J. (Fergus J.), Cox, A. (Angela), Cross, S.S. (Simon), Cybulski, C. (Cezary), Czene, K. (Kamila), Darabi, H. (Hatef), Devilee, P. (Peter), Diver, W.R. (Ryan), Dunning, A.M. (Alison), Earl, H. (Helena), Eccles, D.M. (Diana M.), Ekici, A.B. (Arif B.), Eriksson, M. (Mats), Evans, D.G. (D Gareth), Fasching, P.A. (Peter), Figueroa, J.D. (Jonine), Flesch-Janys, D. (Dieter), Flyger, H. (Henrik), Gapstur, S.M. (Susan M.), Gaudet, M.M. (Mia M.), Giles, G.G. (Graham G.), Glendon, G. (Gord), Grip, M. (Mervi), Gronwald, J. (Jacek), Haeberle, L. (Lothar), Haiman, C.A. (Christopher), Hall, P. (Per), Hamann, U. (Ute), Hankinson, S.E. (Susan), Hartikainen, J.M. (Jaana M.), Hein, A. (Alexander), Hiller, L. (Louise), Hogervorst, F.B. (Frans B.), Holleczek, B. (B.), Hooning, M.J. (Maartje), Hoover, R.N. (Robert), Humphreys, K. (Keith), Hunter, D. (David), Hüsing, A. (Anika), Jakubowska, A. (Anna), Jukkola-Vuorinen, A. (Arja), Kaaks, R. (Rudolf), Kabisch, M. (Maria), Kataja, V. (Vesa), Knight, J.A. (Julia), Koppert, L.B. (Linetta), Kosma, V-M. (Veli-Matti), Kristensen, V.N. (Vessela N.), Lambrechts, D. (Diether), Le Marchand, L. (Loic), Li, J. (Jingmei), Lindblom, A. (Annika), Lindström, S. (Sara), Lissowska, J. (Jolanta), Lubinski, J. (Jan), Machiela, M.J. (Mitchell J.), Mannermaa, A. (Arto), Manoukian, S. (Siranoush), Margolin, S. (Sara), Marme, F. (Federik), Martens, J.W.M. (John), McLean, C.A. (Catriona Ann), Menéndez, P. (Primitiva), Milne, R.L. (Roger), Mulligan, A.-M. (Anna-Marie), Muranen, T.A. (Taru A.), Nevanlinna, H. (Heli), Neven, P. (Patrick), Nielsen, S.F. (Sune F.), Nordestgaard, B.G. (Børge), Olson, J.E. (Janet), Perez, J.I.A. (Jose Ignacio Arias), Peterlongo, P. (Paolo), Phillips, K.-A. (Kelly-Anne), Poole, C.J. (Christopher J.), Pykäs, K. (Katri), Radice, P. (Paolo), Rahman, N. (Nazneen), Rud̈iger, T. (Thomas), Rudolph, A. (Anja), Sawyer, E.J. (Elinor), Schumacher, F.R. (Fredrick R), Seibold, P. (Petra), Seynaeve, C.M. (Caroline), Shah, M. (Mitul), Smeets, A. (Ann), Southey, M.C. (Melissa C.), Tollenaar, R.A.E.M. (Rob), Tomlinson, I.P. (Ian), Tsimiklis, H. (Helen), Ulmer, H.U. (Hans), Vachon, C. (Celine), Ouweland, A.M.W. (Ans) van den, Veer, L.J. (Laura) van 't, Wildiers, H. (Hans), Willett, W.C. (Walter C.), Winqvist, R. (Robert), Zamora, M.P. (Pilar), Chenevix-Trench, G. (Georgia), Dörk, T. (Thilo), Easton, D.F. (Douglas), García-Closas, M. (Montserrat), Kraft, P. (Peter), Hopper, J.L. (John), Zheng, W. (Wei), Schmidt, M.K. (Marjanka), and Pharoah, P.D.P. (Paul)
Abstract: __Background:__ There is increasing evidence that elevated body mass index (BMI) is associated with reduced survival for women with breast cancer. However, the underlying reasons remain unclear. We conducted a Mendelian randomization analysis to investigate a possible causal role of BMI in survival from breast cancer. __Methods:__ We used individual-level data from six large breast cancer case-cohorts including a total of 36 210 individuals (2475 events) of European ancestry. We created a BMI genetic risk score (GRS) based on genotypes at 94 known BMI-associated genetic variants. Association between the BMI genetic score and breast cancer survival was analysed by Cox regression for each study separately. Study-specific hazard ratios were pooled using fixed-effect meta-analysis. __Results:__
Published: 2017
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202. Reproductive profiles and risk of breast cancer subtypes

Author: Brouckaert, O. (Olivier), Rudolph, A. (Anja), Laenen, A. (Annouschka), Keeman, J.N., Bolla, M.K. (Manjeet K.), Wang, Q. (Qin), Soubry, A. (Adelheid), Wildiers, H. (Hans), Andrulis, I.L. (Irene), Arndt, V. (Volker), Beckmann, M.W. (Matthias), Benítez, J. (Javier), Blomqvist, C. (Carl), Bojesen, S.E. (Stig), Brauch, H. (Hiltrud), Brennan, P. (Paul), Brenner, H. (Hermann), Chenevix-Trench, G. (Georgia), Choi, J.-Y. (Ji-Yeob), Cornelissen, S. (Sten), Couch, F.J. (Fergus J.), Cox, A. (Angela), Cross, S.S. (Simon S.), Czene, K. (Kamila), Eriksson, M. (Mats), Fasching, P.A. (Peter), Figueroa, J.D. (Jonine), Flyger, H. (Henrik), Giles, G.G. (Graham G.), González-Neira, A. (Anna), Guénel, P. (Pascal), Hall, P. (Per), Hollestelle, A. (Antoinette), Hopper, J.L. (John), Ito, H. (Hidemi), Jones, M. (Michael), Kang, D. (Daehee), Knight, J.A. (Julia), Kosma, V-M. (Veli-Matti), Li, J. (Jingmei), Lindblom, A. (Annika), Lilyquist, J. (Jenna), Lophatananon, A. (Artitaya), Mannermaa, A. (Arto), Manoukian, S. (Siranoush), Margolin, S. (Sara), Matsuo, K. (Keitaro), Muir, K.R. (K.), Nevanlinna, H. (Heli), Peterlongo, P. (Paolo), Pykäs, K. (Katri), Saajrang, S. (Suleeporn), Seynaeve, C.M. (Caroline), Shen, C.-Y. (Chen-Yang), Shu, X.-O. (Xiao-Ou), Southey, M.C. (Melissa C.), Swerdlow, A.J. (Anthony ), Teo, S.H. (Soo Hwang), Tollenaar, R.A.E.M. (Rob), Truong, T. (Thérèse), Tseng, C.-C. (Chiu-Chen), van den Broek, A.J. (Alexandra J.), Deurzen, C.H.M. (Carolien) van, Winqvist, R. (Robert), Wu, A.H. (Anna), Yip, C.H. (Cheng Har), Yu, J.-C. (Jyh-Cherng), Zheng, W. (Wei), Milne, R.L. (Roger), Pharoah, P.D.P. (Paul), Easton, D.F. (Douglas), Schmidt, M.K. (Marjanka), García-Closas, M. (Montserrat), Chang-Claude, J. (Jenny), Lambrechts, D. (Diether), Neven, P. (Patrick), Brouckaert, O. (Olivier), Rudolph, A. (Anja), Laenen, A. (Annouschka), Keeman, J.N., Bolla, M.K. (Manjeet K.), Wang, Q. (Qin), Soubry, A. (Adelheid), Wildiers, H. (Hans), Andrulis, I.L. (Irene), Arndt, V. (Volker), Beckmann, M.W. (Matthias), Benítez, J. (Javier), Blomqvist, C. (Carl), Bojesen, S.E. (Stig), Brauch, H. (Hiltrud), Brennan, P. (Paul), Brenner, H. (Hermann), Chenevix-Trench, G. (Georgia), Choi, J.-Y. (Ji-Yeob), Cornelissen, S. (Sten), Couch, F.J. (Fergus J.), Cox, A. (Angela), Cross, S.S. (Simon S.), Czene, K. (Kamila), Eriksson, M. (Mats), Fasching, P.A. (Peter), Figueroa, J.D. (Jonine), Flyger, H. (Henrik), Giles, G.G. (Graham G.), González-Neira, A. (Anna), Guénel, P. (Pascal), Hall, P. (Per), Hollestelle, A. (Antoinette), Hopper, J.L. (John), Ito, H. (Hidemi), Jones, M. (Michael), Kang, D. (Daehee), Knight, J.A. (Julia), Kosma, V-M. (Veli-Matti), Li, J. (Jingmei), Lindblom, A. (Annika), Lilyquist, J. (Jenna), Lophatananon, A. (Artitaya), Mannermaa, A. (Arto), Manoukian, S. (Siranoush), Margolin, S. (Sara), Matsuo, K. (Keitaro), Muir, K.R. (K.), Nevanlinna, H. (Heli), Peterlongo, P. (Paolo), Pykäs, K. (Katri), Saajrang, S. (Suleeporn), Seynaeve, C.M. (Caroline), Shen, C.-Y. (Chen-Yang), Shu, X.-O. (Xiao-Ou), Southey, M.C. (Melissa C.), Swerdlow, A.J. (Anthony ), Teo, S.H. (Soo Hwang), Tollenaar, R.A.E.M. (Rob), Truong, T. (Thérèse), Tseng, C.-C. (Chiu-Chen), van den Broek, A.J. (Alexandra J.), Deurzen, C.H.M. (Carolien) van, Winqvist, R. (Robert), Wu, A.H. (Anna), Yip, C.H. (Cheng Har), Yu, J.-C. (Jyh-Cherng), Zheng, W. (Wei), Milne, R.L. (Roger), Pharoah, P.D.P. (Paul), Easton, D.F. (Douglas), Schmidt, M.K. (Marjanka), García-Closas, M. (Montserrat), Chang-Claude, J. (Jenny), Lambrechts, D. (Diether), and Neven, P. (Patrick)
Abstract: __Background:__ Previous studies have shown that reproductive factors are differentially associated with breast cancer (BC) risk by subtypes. The aim of this study was to investigate associations between reproductive factors and BC subtypes, and whether these vary by age at diagnosis. __Methods:__ We used pooled data on tumor markers (estrogen and progesterone receptor, human epidermal growth factor receptor-2 (HER2)) and reproductive risk factors (parity, age at first full-time pregnancy (FFTP) and age at menarche) from 28,095 patients with invasive BC from 34 studies participating in the Breast Cancer Association Consortium (BCAC). In a case-only analysis, we used logistic regression to assess associations between reproductive factors and BC subtype compared to luminal A tumors as a reference. The interaction between age and parity in BC subtype risk was also tested, across all ages and, because age was modeled non-linearly, specifically at ages 35, 55 and 75 years. __Results:__ Parous women were more likely to be diagnosed with triple negative BC (TNBC) than with luminal A BC, irrespective of age. Parous women were also more likely to be diagnosed with luminal and non-luminal HER2-like BCs and this effect was slightly more pronounced at an early age. For instance, women diagnosed at age 35 were 1.48 more likely to have luminal HER2-like BC than luminal A BC, while this association was not significant at age 75. While age at menarche was not significantly associated with BC subtype, increasing age at FFTP was non-linearly associated with TNBC relative to luminal A BC. An age at FFTP of 25 versus 20 years lowered the risk for TNBC, but this effect was not apparent at a later FFTP. __Conclusions:__ Our main findings suggest that parity is associated with TNBC across all ages at BC diagnosis, whereas the association with luminal HER2-like BC was present only for early onset BC.
Published: 2017
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203. TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer

Author: Fagerholm, R. (Rainer), Khan, S. (Sofia), Schmidt, M.K. (Marjanka), García-Closas, M. (Montserrat), Heikkilä, P. (Päivi), Saarela, J. (Jani), Beesley, J. (Jonathan), Jamshidi, M. (Maral), Aittomäki, K. (Kristiina), Liu, J. (Jianjun), Ali, H.R. (Hamid Raza), Andrulis, I.L. (Irene), Beckmann, M.W. (Matthias), Behrens, T.W. (Timothy), Blows, F.M. (Fiona M.), Brenner, H. (Hermann), Chang-Claude, J. (Jenny), Couch, F.J. (Fergus), Czene, K. (Kamila), Fasching, P.A. (Peter), Figueroa, J.D. (Jonine), Floris, O.A.M., Glendon, G. (Gord), Guo, Q. (Qi), Hll, P. (Per), Hallberg, E. (Emily), Hamann, U. (Ute), Holleczek, B. (B.), Hooning, M.J. (Maartje), Hopper, J.L. (John), Jager, A. (Agnes), Kabisch, M. (Maria), Keeman, J.N., Kosma, V-M. (Veli-Matti), Lambrechts, D. (Diether), Lindblom, A. (Annika), Mannermaa, A. (Arto), Margolin, S. (Sara), Provenzano, E. (Elena), Shah, M. (Mitul), Southey, M.C. (Melissa), Dennis, J. (Joe), Lush, M. (Michael), Michailidou, K. (Kyriaki), Wang, Q. (Qin), Bolla, M.K. (Manjeet K.), Dunning, A.M. (Alison), Easton, D.F. (Douglas), Pharoah, P.D.P. (Paul), Chenevix-Trench, G. (Georgia), Blomqvist, C. (Carl), Nevanlinna, H. (Heli), Fagerholm, R. (Rainer), Khan, S. (Sofia), Schmidt, M.K. (Marjanka), García-Closas, M. (Montserrat), Heikkilä, P. (Päivi), Saarela, J. (Jani), Beesley, J. (Jonathan), Jamshidi, M. (Maral), Aittomäki, K. (Kristiina), Liu, J. (Jianjun), Ali, H.R. (Hamid Raza), Andrulis, I.L. (Irene), Beckmann, M.W. (Matthias), Behrens, T.W. (Timothy), Blows, F.M. (Fiona M.), Brenner, H. (Hermann), Chang-Claude, J. (Jenny), Couch, F.J. (Fergus), Czene, K. (Kamila), Fasching, P.A. (Peter), Figueroa, J.D. (Jonine), Floris, O.A.M., Glendon, G. (Gord), Guo, Q. (Qi), Hll, P. (Per), Hallberg, E. (Emily), Hamann, U. (Ute), Holleczek, B. (B.), Hooning, M.J. (Maartje), Hopper, J.L. (John), Jager, A. (Agnes), Kabisch, M. (Maria), Keeman, J.N., Kosma, V-M. (Veli-Matti), Lambrechts, D. (Diether), Lindblom, A. (Annika), Mannermaa, A. (Arto), Margolin, S. (Sara), Provenzano, E. (Elena), Shah, M. (Mitul), Southey, M.C. (Melissa), Dennis, J. (Joe), Lush, M. (Michael), Michailidou, K. (Kyriaki), Wang, Q. (Qin), Bolla, M.K. (Manjeet K.), Dunning, A.M. (Alison), Easton, D.F. (Douglas), Pharoah, P.D.P. (Paul), Chenevix-Trench, G. (Georgia), Blomqvist, C. (Carl), and Nevanlinna, H. (Heli)
Abstract: TP53 overexpression is indicative of somatic TP53 mutations and associates with aggressive tumors and poor prognosis in breast cancer. We utilized a twostage SNP association study to detect variants associated with breast cancer survival in a TP53-dependent manner. Initially, a genome-wide study (n = 575 cases) was conducted to discover candidate SNPs for genotyping and validation in the Breast Cancer Association Consortium (BCAC). The SNPs were then tested for interaction with tumor TP53 status (n = 4,610) and anthracycline treatment (n = 17,828). For SNPs interacting with anthracycline treatment, siRNA knockdown experiments were carried out to validate candidate genes. In the test for interaction between SNP genotype and TP53 status, we identified one locus, represented by rs10916264 (p(interaction) = 3.44 × 10-5; FDR-adjusted p = 0.0011) in estrogen receptor (ER) positive cases. The rs10916264 AA genotype associated with worse survival among cases with ER-positive, TP53-positive tumors (hazard ratio [HR] 2.36, 95% confidence interval [C.I] 1.45-3.82). This is a cis-eQTL locus for FBXO28 and TP53BP2; expression levels of these genes were associated with patient survival specifically in ER-positive, TP53-mutated tumors. Additionally, the SNP rs798755 was associated with survival in interaction with anthracycline treatment (p(interaction) = 9.57 × 10-5, FDR-adjusted p = 0.0130). RNAi-based depletion of a predicted regulatory target gene, FAM53A, indicated that this gene can modulate doxorubicin sensitivity in breast cancer cell lines. If confirmed in independent data sets, these results may be of clinical relevance in the development of prognostic and predictive marker panels for breast cancer.
Published: 2017
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204. Reproductive profiles and risk of breast cancer subtypes: a multi-center case-only study

Author: Brouckaert, O, Rudolph, A, Laenen, A, Keeman, R, Bolla, MK, Wang, Q, Soubry, A, Wildiers, H, Andrulis, IL, Arndt, V, Beckmann, MW, Benitez, J, Blomqvist, C, Bojesen, SE, Brauch, H, Brennan, P, Brenner, H, Chenevix-Trench, G, Choi, J-Y, Cornelissen, S, Couch, FJ, Cox, A, Cross, SS, Czene, K, Eriksson, M, Fasching, PA, Figueroa, J, Flyger, H, Giles, GG, Gonzalez-Neira, A, Guenel, P, Hall, P, Hollestelle, A, Hopper, JL, Ito, H, Jones, M, Kang, D, Knight, JA, Kosma, V-M, Li, J, Lindblom, A, Lilyquist, J, Lophatananon, A, Mannermaa, A, Manoukian, S, Margolin, S, Matsuo, K, Muir, K, Nevanlinna, H, Peterlongo, P, Pylkas, K, Saajrang, S, Seynaeve, C, Shen, C-Y, Shu, X-O, Southey, MC, Swerdlow, A, Teo, S-H, Tollenaar, RAEM, Truong, T, Tseng, C-C, van den Broek, AJ, van Deurzen, CHM, Winqvist, R, Wu, AH, Yip, CH, Yu, J-C, Zheng, W, Milne, RL, Pharoah, PDP, Easton, DF, Schmidt, MK, Garcia-Closas, M, Chang-Claude, J, Lambrechts, D, Neven, P, Brouckaert, O, Rudolph, A, Laenen, A, Keeman, R, Bolla, MK, Wang, Q, Soubry, A, Wildiers, H, Andrulis, IL, Arndt, V, Beckmann, MW, Benitez, J, Blomqvist, C, Bojesen, SE, Brauch, H, Brennan, P, Brenner, H, Chenevix-Trench, G, Choi, J-Y, Cornelissen, S, Couch, FJ, Cox, A, Cross, SS, Czene, K, Eriksson, M, Fasching, PA, Figueroa, J, Flyger, H, Giles, GG, Gonzalez-Neira, A, Guenel, P, Hall, P, Hollestelle, A, Hopper, JL, Ito, H, Jones, M, Kang, D, Knight, JA, Kosma, V-M, Li, J, Lindblom, A, Lilyquist, J, Lophatananon, A, Mannermaa, A, Manoukian, S, Margolin, S, Matsuo, K, Muir, K, Nevanlinna, H, Peterlongo, P, Pylkas, K, Saajrang, S, Seynaeve, C, Shen, C-Y, Shu, X-O, Southey, MC, Swerdlow, A, Teo, S-H, Tollenaar, RAEM, Truong, T, Tseng, C-C, van den Broek, AJ, van Deurzen, CHM, Winqvist, R, Wu, AH, Yip, CH, Yu, J-C, Zheng, W, Milne, RL, Pharoah, PDP, Easton, DF, Schmidt, MK, Garcia-Closas, M, Chang-Claude, J, Lambrechts, D, and Neven, P
Abstract: BACKGROUND: Previous studies have shown that reproductive factors are differentially associated with breast cancer (BC) risk by subtypes. The aim of this study was to investigate associations between reproductive factors and BC subtypes, and whether these vary by age at diagnosis. METHODS: We used pooled data on tumor markers (estrogen and progesterone receptor, human epidermal growth factor receptor-2 (HER2)) and reproductive risk factors (parity, age at first full-time pregnancy (FFTP) and age at menarche) from 28,095 patients with invasive BC from 34 studies participating in the Breast Cancer Association Consortium (BCAC). In a case-only analysis, we used logistic regression to assess associations between reproductive factors and BC subtype compared to luminal A tumors as a reference. The interaction between age and parity in BC subtype risk was also tested, across all ages and, because age was modeled non-linearly, specifically at ages 35, 55 and 75 years. RESULTS: Parous women were more likely to be diagnosed with triple negative BC (TNBC) than with luminal A BC, irrespective of age (OR for parity = 1.38, 95% CI 1.16-1.65, p = 0.0004; p for interaction with age = 0.076). Parous women were also more likely to be diagnosed with luminal and non-luminal HER2-like BCs and this effect was slightly more pronounced at an early age (p for interaction with age = 0.037 and 0.030, respectively). For instance, women diagnosed at age 35 were 1.48 (CI 1.01-2.16) more likely to have luminal HER2-like BC than luminal A BC, while this association was not significant at age 75 (OR = 0.72, CI 0.45-1.14). While age at menarche was not significantly associated with BC subtype, increasing age at FFTP was non-linearly associated with TNBC relative to luminal A BC. An age at FFTP of 25 versus 20 years lowered the risk for TNBC (OR = 0.78, CI 0.70-0.88, p < 0.0001), but this effect was not apparent at a later FFTP. CONCLUSIONS: Our main findings suggest that parity is associated with TN
Published: 2017

205. TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer

Author: Fagerholm, R, Khan, S, Schmidt, MK, Garcia-Closas, M, Heikkila, P, Saarela, J, Beesley, J, Jamshidi, M, Aittomaki, K, Liu, J, Ali, HR, Andrulis, IL, Beckmann, MW, Behrens, S, Blows, FM, Brenner, H, Chang-Claude, J, Couch, FJ, Czene, K, Fasching, PA, Figueroa, J, Floris, G, Glendon, G, Guo, Q, Hall, P, Hallberg, E, Hamann, U, Holleczek, B, Hooning, MJ, Hopper, JL, Jager, A, Kabisch, M, Keeman, R, Kosma, V-M, Lambrechts, D, Lindblom, A, Mannermaa, A, Margolin, S, Provenzano, E, Shah, M, Southey, MC, Dennis, J, Lush, M, Michailidou, K, Wang, Q, Bolla, MK, Dunning, AM, Easton, DF, Pharoah, PDP, Chenevix-Trench, G, Blomqvist, C, Nevanlinna, H, Fagerholm, R, Khan, S, Schmidt, MK, Garcia-Closas, M, Heikkila, P, Saarela, J, Beesley, J, Jamshidi, M, Aittomaki, K, Liu, J, Ali, HR, Andrulis, IL, Beckmann, MW, Behrens, S, Blows, FM, Brenner, H, Chang-Claude, J, Couch, FJ, Czene, K, Fasching, PA, Figueroa, J, Floris, G, Glendon, G, Guo, Q, Hall, P, Hallberg, E, Hamann, U, Holleczek, B, Hooning, MJ, Hopper, JL, Jager, A, Kabisch, M, Keeman, R, Kosma, V-M, Lambrechts, D, Lindblom, A, Mannermaa, A, Margolin, S, Provenzano, E, Shah, M, Southey, MC, Dennis, J, Lush, M, Michailidou, K, Wang, Q, Bolla, MK, Dunning, AM, Easton, DF, Pharoah, PDP, Chenevix-Trench, G, Blomqvist, C, and Nevanlinna, H
Abstract: TP53 overexpression is indicative of somatic TP53 mutations and associates with aggressive tumors and poor prognosis in breast cancer. We utilized a two-stage SNP association study to detect variants associated with breast cancer survival in a TP53-dependent manner. Initially, a genome-wide study (n = 575 cases) was conducted to discover candidate SNPs for genotyping and validation in the Breast Cancer Association Consortium (BCAC). The SNPs were then tested for interaction with tumor TP53 status (n = 4,610) and anthracycline treatment (n = 17,828). For SNPs interacting with anthracycline treatment, siRNA knockdown experiments were carried out to validate candidate genes.In the test for interaction between SNP genotype and TP53 status, we identified one locus, represented by rs10916264 (p(interaction) = 3.44 × 10-5; FDR-adjusted p = 0.0011) in estrogen receptor (ER) positive cases. The rs10916264 AA genotype associated with worse survival among cases with ER-positive, TP53-positive tumors (hazard ratio [HR] 2.36, 95% confidence interval [C.I] 1.45 - 3.82). This is a cis-eQTL locus for FBXO28 and TP53BP2; expression levels of these genes were associated with patient survival specifically in ER-positive, TP53-mutated tumors. Additionally, the SNP rs798755 was associated with survival in interaction with anthracycline treatment (p(interaction) = 9.57 × 10-5, FDR-adjusted p = 0.0130). RNAi-based depletion of a predicted regulatory target gene, FAM53A, indicated that this gene can modulate doxorubicin sensitivity in breast cancer cell lines.If confirmed in independent data sets, these results may be of clinical relevance in the development of prognostic and predictive marker panels for breast cancer.
Published: 2017

206. Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3

Author: Hamdi, Y, Soucy, P, Kuchenbaeker, KB, Pastinen, T, Droit, A, Lemacon, A, Adlard, J, Aittomaki, K, Andrulis, IL, Arason, A, Arnold, N, Arun, BK, Azzollini, J, Bane, A, Barjhoux, L, Barrowdale, D, Benitez, J, Berthet, P, Blok, MJ, Bobolis, K, Bonadona, V, Bonanni, B, Bradbury, AR, Brewer, C, Buecher, B, Buys, SS, Caligo, MA, Chiquette, J, Chung, WK, Claes, KBM, Daly, MB, Damiola, F, Davidson, R, De la Hoya, M, De Leeneer, K, Diez, O, Ding, YC, Dolcetti, R, Domchek, SM, Dorfling, CM, Eccles, D, Eeles, R, Einbeigi, Z, Ejlertsen, B, Engel, C, Evans, DG, Feliubadalo, L, Foretova, L, Fostira, F, Foulkes, WD, Fountzilas, G, Friedman, E, Frost, D, Ganschow, P, Ganz, PA, Garber, J, Gayther, SA, Gerdes, A-M, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gronwald, J, Hahnen, E, Hamann, U, Hansen, TVO, Hart, S, Hays, JL, Hogervorst, FBL, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jakubowska, A, James, P, Janavicius, R, Jensen, UB, John, EM, Joseph, V, Just, W, Kaczmarek, K, Karlan, BY, Kets, CM, Kirk, J, Kriege, M, Laitman, Y, Laurent, M, Lazaro, C, Leslie, G, Lester, J, Lesueur, F, Liljegren, A, Loman, N, Loud, JT, Manoukian, S, Mariani, M, Mazoyer, S, McGuffog, L, Meijers-Heijboer, HEJ, Meindl, A, Miller, A, Montagna, M, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nussbaum, RL, Olah, E, Olopade, OI, Ong, K-R, Oosterwijk, JC, Osorio, A, Papi, L, Park, SK, Pedersen, IS, Peissel, B, Segura, PP, Peterlongo, P, Phelan, CM, Radice, P, Rantala, J, Rappaport-Fuerhauser, C, Rennert, G, Richardson, A, Robson, M, Rodriguez, GC, Rookus, MA, Schmutzler, RK, Sevenet, N, Shah, PD, Singer, CF, Slavin, TP, Snape, K, Sokolowska, J, Sonderstrup, IMH, Southey, M, Spurdle, AB, Stadler, Z, Stoppa-Lyonnet, D, Sukiennicki, G, Sutter, C, Tan, Y, Tea, M-K, Teixeira, MR, Teule, A, Teo, S-H, Terry, MB, Thomassen, M, Tihomirova, L, Tischkowitz, M, Tognazzo, S, Toland, AE, Tung, N, van den Ouweland, AMW, van der Luijt, RB, van Engelen, K, van Rensburg, EJ, Varon-Mateeva, R, Wappenschmidt, B, Wijnen, JT, Rebbeck, T, Chenevix-Trench, G, Offit, K, Couch, FJ, Nord, S, Easton, DF, Antoniou, AC, Simard, J, Hamdi, Y, Soucy, P, Kuchenbaeker, KB, Pastinen, T, Droit, A, Lemacon, A, Adlard, J, Aittomaki, K, Andrulis, IL, Arason, A, Arnold, N, Arun, BK, Azzollini, J, Bane, A, Barjhoux, L, Barrowdale, D, Benitez, J, Berthet, P, Blok, MJ, Bobolis, K, Bonadona, V, Bonanni, B, Bradbury, AR, Brewer, C, Buecher, B, Buys, SS, Caligo, MA, Chiquette, J, Chung, WK, Claes, KBM, Daly, MB, Damiola, F, Davidson, R, De la Hoya, M, De Leeneer, K, Diez, O, Ding, YC, Dolcetti, R, Domchek, SM, Dorfling, CM, Eccles, D, Eeles, R, Einbeigi, Z, Ejlertsen, B, Engel, C, Evans, DG, Feliubadalo, L, Foretova, L, Fostira, F, Foulkes, WD, Fountzilas, G, Friedman, E, Frost, D, Ganschow, P, Ganz, PA, Garber, J, Gayther, SA, Gerdes, A-M, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gronwald, J, Hahnen, E, Hamann, U, Hansen, TVO, Hart, S, Hays, JL, Hogervorst, FBL, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jakubowska, A, James, P, Janavicius, R, Jensen, UB, John, EM, Joseph, V, Just, W, Kaczmarek, K, Karlan, BY, Kets, CM, Kirk, J, Kriege, M, Laitman, Y, Laurent, M, Lazaro, C, Leslie, G, Lester, J, Lesueur, F, Liljegren, A, Loman, N, Loud, JT, Manoukian, S, Mariani, M, Mazoyer, S, McGuffog, L, Meijers-Heijboer, HEJ, Meindl, A, Miller, A, Montagna, M, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nussbaum, RL, Olah, E, Olopade, OI, Ong, K-R, Oosterwijk, JC, Osorio, A, Papi, L, Park, SK, Pedersen, IS, Peissel, B, Segura, PP, Peterlongo, P, Phelan, CM, Radice, P, Rantala, J, Rappaport-Fuerhauser, C, Rennert, G, Richardson, A, Robson, M, Rodriguez, GC, Rookus, MA, Schmutzler, RK, Sevenet, N, Shah, PD, Singer, CF, Slavin, TP, Snape, K, Sokolowska, J, Sonderstrup, IMH, Southey, M, Spurdle, AB, Stadler, Z, Stoppa-Lyonnet, D, Sukiennicki, G, Sutter, C, Tan, Y, Tea, M-K, Teixeira, MR, Teule, A, Teo, S-H, Terry, MB, Thomassen, M, Tihomirova, L, Tischkowitz, M, Tognazzo, S, Toland, AE, Tung, N, van den Ouweland, AMW, van der Luijt, RB, van Engelen, K, van Rensburg, EJ, Varon-Mateeva, R, Wappenschmidt, B, Wijnen, JT, Rebbeck, T, Chenevix-Trench, G, Offit, K, Couch, FJ, Nord, S, Easton, DF, Antoniou, AC, and Simard, J
Abstract: PURPOSE: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. METHODS: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. RESULTS: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10-6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. CONCLUSION: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.
Published: 2017

207. Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores

Author: Lecarpentier, J, Silvestri, V, Kuchenbaecker, KB, Barrowdale, D, Dennis, J, McGuffog, L, Soucy, P, Leslie, G, Rizzolo, P, Navazio, AS, Valentini, V, Zelli, V, Lee, A, Al Olama, AA, Tyrer, JP, Southey, M, John, EM, Conner, TA, Goldgar, DE, Buys, SS, Janavicius, R, Steele, L, Ding, YC, Neuhausen, SL, Hansen, TVO, Osorio, A, Weitzel, JN, Toss, A, Medici, V, Cortesi, L, Zanna, I, Palli, D, Radice, P, Manoukian, S, Peissel, B, Azzollini, J, Viel, A, Cini, G, Damante, G, Tommasi, S, Peterlongo, P, Fostira, F, Hamann, U, Evans, DG, Henderson, A, Brewer, C, Eccles, D, Cook, J, Ong, K-R, Walker, L, Side, LE, Porteous, ME, Davidson, R, Hodgson, S, Frost, D, Adlard, J, Izatt, L, Eeles, R, Ellis, S, Tischkowitz, M, Godwin, AK, Meindl, A, Gehrig, A, Dworniczak, B, Sutter, C, Engel, C, Niederacher, D, Steinemann, D, Hahnen, E, Hauke, J, Rhiem, K, Kast, K, Arnold, N, Ditsch, N, Wang-Gohrke, S, Wappenschmidt, B, Wand, D, Lasset, C, Stoppa-Lyonnet, D, Belotti, M, Damiola, F, Barjhoux, L, Mazoyer, S, Van Heetvelde, M, Poppe, B, De Leeneer, K, Claes, KBM, de la Hoya, M, Garcia-Barberan, V, Caldes, T, Perez Segura, P, Kiiski, JI, Aittomaeki, K, Khan, S, Nevanlinna, H, van Asperen, CJ, Vaszko, T, Kasler, M, Olah, E, Balmana, J, Gutierrez-Enriquez, S, Diez, O, Teule, A, Izquierdo, A, Darder, E, Brunet, J, Del Valle, J, Feliubadalo, L, Pujana, MA, Lazaro, C, Arason, A, Agnarsson, BA, Johannsson, OT, Barkardottir, RB, Alducci, E, Tognazzo, S, Montagna, M, Teixeira, MR, Pinto, P, Spurdle, AB, Holland, H, Lee, JW, Lee, MH, Lee, J, Kim, S-W, Kang, E, Kim, Z, Sharma, P, Rebbeck, TR, Vijai, J, Robson, M, Lincoln, A, Musinsky, J, Gaddam, P, Tan, YY, Berger, A, Singer, CF, Loud, JT, Greene, MH, Mulligan, AM, Glendon, G, Andrulis, IL, Toland, AE, Senter, L, Bojesen, A, Nielsen, HR, Skytte, A-B, Sunde, L, Jensen, UB, Pedersen, IS, Krogh, L, Kruse, TA, Caligo, MA, Yoon, S-Y, Teo, S-H, von Wachenfeldt, A, Huo, D, Nielsen, SM, Olopade, OI, Nathanson, KL, Domchek, SM, Lorenchick, C, Jankowitz, RC, Campbell, I, James, P, Mitchell, G, Orr, N, Park, SK, Thomassen, M, Offit, K, Couch, FJ, Simard, J, Easton, DF, Chenevix-Trench, G, Schmutzler, RK, Antoniou, AC, Ottini, L, Lecarpentier, J, Silvestri, V, Kuchenbaecker, KB, Barrowdale, D, Dennis, J, McGuffog, L, Soucy, P, Leslie, G, Rizzolo, P, Navazio, AS, Valentini, V, Zelli, V, Lee, A, Al Olama, AA, Tyrer, JP, Southey, M, John, EM, Conner, TA, Goldgar, DE, Buys, SS, Janavicius, R, Steele, L, Ding, YC, Neuhausen, SL, Hansen, TVO, Osorio, A, Weitzel, JN, Toss, A, Medici, V, Cortesi, L, Zanna, I, Palli, D, Radice, P, Manoukian, S, Peissel, B, Azzollini, J, Viel, A, Cini, G, Damante, G, Tommasi, S, Peterlongo, P, Fostira, F, Hamann, U, Evans, DG, Henderson, A, Brewer, C, Eccles, D, Cook, J, Ong, K-R, Walker, L, Side, LE, Porteous, ME, Davidson, R, Hodgson, S, Frost, D, Adlard, J, Izatt, L, Eeles, R, Ellis, S, Tischkowitz, M, Godwin, AK, Meindl, A, Gehrig, A, Dworniczak, B, Sutter, C, Engel, C, Niederacher, D, Steinemann, D, Hahnen, E, Hauke, J, Rhiem, K, Kast, K, Arnold, N, Ditsch, N, Wang-Gohrke, S, Wappenschmidt, B, Wand, D, Lasset, C, Stoppa-Lyonnet, D, Belotti, M, Damiola, F, Barjhoux, L, Mazoyer, S, Van Heetvelde, M, Poppe, B, De Leeneer, K, Claes, KBM, de la Hoya, M, Garcia-Barberan, V, Caldes, T, Perez Segura, P, Kiiski, JI, Aittomaeki, K, Khan, S, Nevanlinna, H, van Asperen, CJ, Vaszko, T, Kasler, M, Olah, E, Balmana, J, Gutierrez-Enriquez, S, Diez, O, Teule, A, Izquierdo, A, Darder, E, Brunet, J, Del Valle, J, Feliubadalo, L, Pujana, MA, Lazaro, C, Arason, A, Agnarsson, BA, Johannsson, OT, Barkardottir, RB, Alducci, E, Tognazzo, S, Montagna, M, Teixeira, MR, Pinto, P, Spurdle, AB, Holland, H, Lee, JW, Lee, MH, Lee, J, Kim, S-W, Kang, E, Kim, Z, Sharma, P, Rebbeck, TR, Vijai, J, Robson, M, Lincoln, A, Musinsky, J, Gaddam, P, Tan, YY, Berger, A, Singer, CF, Loud, JT, Greene, MH, Mulligan, AM, Glendon, G, Andrulis, IL, Toland, AE, Senter, L, Bojesen, A, Nielsen, HR, Skytte, A-B, Sunde, L, Jensen, UB, Pedersen, IS, Krogh, L, Kruse, TA, Caligo, MA, Yoon, S-Y, Teo, S-H, von Wachenfeldt, A, Huo, D, Nielsen, SM, Olopade, OI, Nathanson, KL, Domchek, SM, Lorenchick, C, Jankowitz, RC, Campbell, I, James, P, Mitchell, G, Orr, N, Park, SK, Thomassen, M, Offit, K, Couch, FJ, Simard, J, Easton, DF, Chenevix-Trench, G, Schmutzler, RK, Antoniou, AC, and Ottini, L
Abstract: Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10-6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10-9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.
Published: 2017

208. Breast cancer risk prediction using a polygenic risk score in the familial setting: a prospective study from the Breast Cancer Family Registry and kConFab

Author: Li, H, Feng, B, Miron, A, Chen, X, Beesley, J, Bimeh, E, Barrowdale, D, John, EM, Daly, MB, Andrulis, IL, Buys, SS, Kraft, P, Thorne, H, Chenevix-Trench, G, Southey, MC, Antoniou, AC, James, PA, Terry, MB, Phillips, K-A, Hopper, JL, Mitchell, G, Goldgar, DE, Li, H, Feng, B, Miron, A, Chen, X, Beesley, J, Bimeh, E, Barrowdale, D, John, EM, Daly, MB, Andrulis, IL, Buys, SS, Kraft, P, Thorne, H, Chenevix-Trench, G, Southey, MC, Antoniou, AC, James, PA, Terry, MB, Phillips, K-A, Hopper, JL, Mitchell, G, and Goldgar, DE
Abstract: PURPOSE: This study examined the utility of sets of single-nucleotide polymorphisms (SNPs) in familial but non-BRCA-associated breast cancer (BC). METHODS: We derived a polygenic risk score (PRS) based on 24 known BC risk SNPs for 4,365 women from the Breast Cancer Family Registry and Kathleen Cuningham Consortium Foundation for Research into Familial Breast Cancer familial BC cohorts. We compared scores for women based on cancer status at baseline; 2,599 women unaffected at enrollment were followed-up for an average of 7.4 years. Cox proportional hazards regression was used to analyze the association of PRS with BC risk. The BOADICEA risk prediction algorithm was used to measure risk based on family history alone. RESULTS: The mean PRS at baseline was 2.25 (SD, 0.35) for affected women and was 2.17 (SD, 0.35) for unaffected women from combined cohorts (P < 10-6). During follow-up, 205 BC cases occurred. The hazard ratios for continuous PRS (per SD) and upper versus lower quintiles were 1.38 (95% confidence interval: 1.22-1.56) and 3.18 (95% confidence interval: 1.84-5.23) respectively. Based on their PRS-based predicted risk, management for up to 23% of women could be altered. CONCLUSION: Including BC-associated SNPs in risk assessment can provide more accurate risk prediction than family history alone and can influence recommendations for cancer screening and prevention modalities for high-risk women.Genet Med 19 1, 30-35.
Published: 2017

209. rs2735383, located at a microRNA binding site in the 3'UTR of NBS1, is not associated with breast cancer risk

Author: Liu, J, Lončar, I, Collée, JM, Bolla, MK, Dennis, J, Michailidou, K, Wang, Q, Andrulis, IL, Barile, M, Beckmann, MW, Behrens, S, Benitez, J, Blomqvist, C, Boeckx, B, Bogdanova, NV, Bojesen, SE, Brauch, H, Brennan, P, Brenner, H, Broeks, A, Burwinkel, B, Chang-Claude, J, Chen, ST, Chenevix-Trench, G, Cheng, CY, Choi, JY, Couch, FJ, Cox, A, Cross, SS, Cuk, K, Czene, K, Dörk, T, Dos-Santos-Silva, I, Fasching, PA, Figueroa, J, Flyger, H, García-Closas, M, Giles, GG, Glendon, G, Goldberg, MS, González-Neira, A, Guénel, P, Haiman, CA, Hamann, U, Hart, SN, Hartman, M, Hatse, S, Hopper, JL, Ito, H, Jakubowska, A, Kabisch, M, Kang, D, Kosma, VM, Kristensen, VN, Le Marchand, L, Lee, E, Li, J, Lophatananon, A, Jan Lubinski, Mannermaa, A, Matsuo, K, Milne, RL, NBCS Collaborators, Neuhausen, SL, Nevanlinna, H, Orr, N, Perez, JI, Peto, J, Putti, TC, Pylkäs, K, Radice, P, Sangrajrang, S, Sawyer, EJ, Schmidt, MK, Schneeweiss, A, Shen, CY, Shrubsole, MJ, Shu, XO, Simard, J, Southey, MC, Swerdlow, A, Teo, SH, Tessier, DC, Thanasitthichai, S, Tomlinson, I, Torres, D, Truong, T, Tseng, CC, Vachon, C, Winqvist, R, Wu, AH, Yannoukakos, D, Zheng, W, Hall, P, Dunning, AM, Easton, DF, Hooning, MJ, van den Ouweland, AM, Martens, JW, Hollestelle, A, Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository
Subjects: BRCA2 Protein, Binding Sites, Genotype, BRCA1 Protein, Nuclear Proteins, Breast Neoplasms, Cell Cycle Proteins, Polymorphism, Single Nucleotide, MicroRNAs, Risk Factors, Odds Ratio, Humans, Female, Genetic Predisposition to Disease, 3' Untranslated Regions, Alleles
Abstract: NBS1, also known as NBN, plays an important role in maintaining genomic stability. Interestingly, rs2735383 G > C, located in a microRNA binding site in the 3'-untranslated region (UTR) of NBS1, was shown to be associated with increased susceptibility to lung and colorectal cancer. However, the relation between rs2735383 and susceptibility to breast cancer is not yet clear. Therefore, we genotyped rs2735383 in 1,170 familial non-BRCA1/2 breast cancer cases and 1,077 controls using PCR-based restriction fragment length polymorphism (RFLP-PCR) analysis, but found no association between rs2735383CC and breast cancer risk (OR = 1.214, 95% CI = 0.936-1.574, P = 0.144). Because we could not exclude a small effect size due to a limited sample size, we further analyzed imputed rs2735383 genotypes (r$^{2}$ > 0.999) of 47,640 breast cancer cases and 46,656 controls from the Breast Cancer Association Consortium (BCAC). However, rs2735383CC was not associated with overall breast cancer risk in European (OR = 1.014, 95% CI = 0.969-1.060, P = 0.556) nor in Asian women (OR = 0.998, 95% CI = 0.905-1.100, P = 0.961). Subgroup analyses by age, age at menarche, age at menopause, menopausal status, number of pregnancies, breast feeding, family history and receptor status also did not reveal a significant association. This study therefore does not support the involvement of the genotype at NBS1 rs2735383 in breast cancer susceptibility.
Published: 2016

210. Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation

Author: Ghoussaini, M., French, J.D., Michailidou, K., Nord, S., Beesley, J., Canisus, S., Hillman, K.M., Kaufmann, S., Sivakumaran, H., Marjaneh, M.M., Lee, J.S., Dennis, J., Bolla, M.K., Wang, Q., Dicks, E., Milne, R.L., Hopper, J.L., Southey, M.C., Schmidt, M.K., Broeks, A., Muir, K., Lophatananon, A., Fasching, P.A., Beckmann, M.W., Fletcher, O., Johnson, N., Sawyer, E.J., Tomlinson, I., Burwinkel, B., Marme, F., Guenel, P., Truong, T., Bojesen, S.E., Flyger, H., Benitez, J., Gonzalez-Neira, A., Alonso, R., Pita, G., Neuhausen, S.L., Anton-Culver, H., Brenner, H., Arndt, V., Meindl, A., Schmutzler, R.K., Brauch, H., Hamann, U., Tessier, D.C., Vincent, D., Nevanlinna, H., Khan, S., Matsuo, K., Ito, H., Dork, T., Bogdanova, N.V., Lindblom, A., Margolin, S., Mannermaa, A., Kosma, V.M., Wu, A.H., Berg, D. van den, Lambrechts, D., Floris, G., Chang-Claude, J., Rudolph, A., Radice, P., Barile, M., Couch, F.J., Hallberg, E., Giles, G.G., Haiman, C.A., Marchand, L. le, Goldberg, M.S., Teo, S.H., Yip, C.H., Borresen-Dale, A.L., Zheng, W., Cai, Q.Y., Winqvist, R., Pylkas, K., Andrulis, I.L., Devilee, P., Tollenaar, R.A.E.M., Garcia-Closas, M., Figueroa, J., Hall, P., Czene, K., Brand, J.S., Darabi, H., Eriksson, M., Hooning, M.J., Koppert, L.B., Li, J.M., Shu, X.O., Zheng, Y., Cox, A., Cross, S.S., Shah, M., Rhenius, V., Choi, J.Y., Kang, D., Hartman, M., Chia, K.S., Kabisch, M., Torres, D., Luccarini, C., Conroy, D.M., Jakubowska, A., Lubinski, J., Sangrajrang, S., Brennan, P., Olswold, C., Slager, S., Shen, C.Y., Hou, M.F., Swerdlow, A., Schoemaker, M.J., Simard, J., Pharoah, P.D.P., Kristensen, V., Chenevix-Trench, G., Easton, D.F., Dunning, A.M., Edwards, S.L., kConFab AOCS, NBCS Collaborators, Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Dicks, Ed [0000-0002-0617-0401], Rhenius, Valerie [0000-0003-4215-3235], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Dunning, Alison [0000-0001-6651-7166], and Apollo - University of Cambridge Repository
Subjects: Quantitative Trait Loci, Breast Neoplasms, Polymorphism, Single Nucleotide, Enhancer Elements, Genetic, Haplotypes, Receptors, Estrogen, Case-Control Studies, Cell Line, Tumor, Chromosomes, Human, Pair 5, Humans, Genetic Predisposition to Disease, Receptor, Fibroblast Growth Factor, Type 2, Promoter Regions, Genetic, Fibroblast Growth Factor 10, Alleles
Abstract: Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER+) breast cancer (per-g allele OR ER+ = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10-30). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER-) breast cancer (lead SNP rs6864776: per-a allele OR ER- = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10-12), and a single signal 3 SNP (rs200229088: per-t allele OR ER+ = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10-05). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.
Published: 2016

211. Evidence that the 5p12 variant rs10941679 confers susceptibility to estrogen receptor positive breast cancer through FGF10 and MRPS30 regulation

Author: Ghoussaini, M, French, J.D., Michailidou, K., Nord, S., Beesley, J., Canisus, S., Hillman, K.M., Kaufmann, S., Sivakumaran, H., Marjaneh, M.M., Lee, J.S., Dennis, J., Bolla, M.K., Wang, Q., Dicks, E., Milne, R.L., Hopper, J.L., Southey, M.C., Schmidt, M.K., Broeks, A., Muir, K., Lophatananon, A, Fasching, P.A., Beckmann, M.W., Fletcher, O., Johnson, N., Sawyer, E.J., Tomlinson, I., Burwinkel, B., Marme, F., Guenel, P., Truong, T., Bojesen, S.E., Flyger, H., Benitez, J., González-Neira, A., Alonson, M.R., Pita, G., Neuhausen, S.L., Anton-Culver, H., Brenner, H., Arndt, V., Meindl, A., Schmutzler, R.K., Brauch, H., Hamann, U., Tessier, D.C., Vincent, D., Nevanlinna, H., Khan, S., Matsuo, K., Ito, H., Dörk, T., Bogdanova, N.V., Lindblom, A., Margolin, S., Mannermaa, A., Kosma, V-M., kConFab/AOCS Investigators, Wu, A.H., Van Den Berg, D., Lambrechts, D., Floris, G., Chang-Claude, J., Rudolph, A., Radice, P., Barile, M., Couch, F.J., Hallberg, E., Giles, G.G., Haiman, C.A., Le Marchand, L., Goldberg, M.S., Teo, S.H., Yip, C.H., Borresen-Dale, A-L., NBCS Collaborators, Zheng, W., Cai, Q., Winqvist, R., Pylkäs, K., Andrulis, I.L., Devilee, P., Tollenaar, R.A.E.M., García-Closas, M., Figueroa, J., Hall, P., Czene, K, Brand, J.S., Darabi, H, Eriksson, M., Hooning, M.J., Koppert, L.B., Jingmei, L., Shu, X-O., Zheng, Y., Cox, A, Cross, S.S., Shah, M., Rhenius, V., Choi, J-Y., Kang, D., Hartman, M., Chia, K.S., Kabisch, M., Torres, D., Luccarini, C., Conroy, D.M, Jakubowska, A., Libinski, J., Sangrajrang, S., Brennan, P., Olswold, C., Slager, S., Shen, C-Y., Hou, M-F., Swerdlow, A., Schoemaker, M.J., Simard, J., Pharoah, P.D.P, Kristensen, V., Chenevix-Trench, G., Easton, D.F., Dunning, A.M., and Edwards, S.L.
Abstract: Genome-wide association studies (GWAS) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine-mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). Using data for 3,365 genotyped and imputed single nucleotide polymorphisms (SNPs) across a 1Mb (positions 44394495-45364167; NCBI build 37) panel we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen receptor-positive (ER+) breast cancer (per-g allele OR ER+=1.15; 95% CI 1.13-1.18; P=8.35x10-30). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER-) breast cancer (lead SNP rs6864776: per-a allele OR ER-=1.10; 95% CI 1.05-1.14; P-conditional=1.44E-12); and a single signal 3 SNP (rs200229088: per-t allele OR ER+=1.12; 95% CI 1.09-1.15; P-conditional=1.12E-05). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is over-expressed in ~10% of human breast cancers, while MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.
Published: 2016

212. Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer

Author: Shi, J.J., Zhang, Y.F., Zheng, W., Michailidou, K., Ghoussaini, M., Bolla, M.K., Wang, Q., Dennis, J., Lush, M., Milne, R.L., Shu, X.O., Beesley, J., Kar, S., Andrulis, I.L., Anton-Culver, H., Arndt, V., Beckmann, M.W., Zhao, Z.G., Guo, X.Y., Benitez, J., Beeghly-Fadiel, A., Blot, W., Bogdanova, N.V., Bojesen, S.E., Brauch, H., Brenner, H., Brinton, L., Broeks, A., Bruening, T., Burwinkel, B., Cai, H., Canisius, S., Chang-Claude, J., Choi, J.Y., Couch, F.J., Cox, A., Cross, S.S., Czene, K., Darabi, H., Devilee, P., Droit, A., Dork, T., Fasching, P.A., Fletcher, O., Flyger, H., Fostira, F., Gaborieau, V., Garcia-Closas, M., Giles, G.G., Grip, M., Guenel, P., Haiman, C.A., Hamann, U., Hartman, M., Miao, H., Hollestelle, A., Hopper, J.L., Hsiung, C.N., Investigators, K., Ito, H., Jakubowska, A., Johnson, N., Torres, D., Kabisch, M., Kang, D., Khan, S., Knight, J.A., Kosma, V.M., Lambrechts, D., Li, J.M., Lindblom, A., Lophatananon, A., Lubinski, J., Mannermaa, A., Manoukian, S., Marchand, L. le, Margolin, S., Marme, F., Matsuo, K., McLean, C., Meindl, A., Muir, K., Neuhausen, S.L., Nevanlinna, H., Nord, S., Borresen-Dale, A.L., Olson, J.E., Orr, N., Ouweland, A.M.W. van den, Peterlongo, P., Putti, T.C., Rudolph, A., Sangrajrang, S., Sawyer, E.J., Schmidt, M.K., Schmutzler, R.K., Shen, C.Y., Hou, M.F., Shrubsole, M.J., Southey, M.C., Swerdlow, A., Teo, S.H., Thienpont, B., Toland, A.E., Tollenaar, R.A.E.M., Tomlinson, I., Truong, T., Tseng, C.C., Wen, W.Q., Winqvist, R., Wu, A.H., Yip, C.H., Zamora, P.M., Zheng, Y., Floris, G., Cheng, C.Y., Hooning, M.J., Martens, J.W.M., Seynaeve, C., Kristensen, V.N., Hall, P., Pharoah, P.D.P., Simard, J., Chenevix-Trench, G., Dunning, A.M., Antoniou, A.C., Easton, D.F., Cai, Q.Y., Long, J.R., Ghoussaini, Maya [0000-0002-2415-2143], Wang, Jean [0000-0002-9139-0627], Dennis, Joe [0000-0003-4591-1214], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Antoniou, Antonis [0000-0001-9223-3116], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository
Subjects: breast cancer, fine-mapping, single nucleotide polymorphism, 8q24, genetic susceptibility
Abstract: Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine-mapping study across 2.06 Mb (chr8:127,561,724-129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93-0.97, conditional p = 5.8 × 10(-6) ), rs7815245 (OR = 0.94, 95% CI = 0.91-0.96, conditional p = 1.1 × 10(-6) ) and rs2033101 (OR = 1.05, 95% CI = 1.02-1.07, conditional p = 1.1 × 10(-4) ) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r(2) = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry.
Published: 2016

213. Fine-mapping of the 1p11.2 breast cancer susceptibility locus

Author: Horne, HN, Chung, CC, Zhang, H, Yu, K, Prokunina-Olsson, L, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Hopper, JL, Southey, MC, Schmidt, MK, Broeks, A, Muir, K, Lophatananon, A, Fasching, PA, Beckmann, MW, Fletcher, O, Johnson, N, Sawyer, EJ, Tomlinson, I, Burwinkel, B, Marme, F, Guénel, P, Truong, T, Bojesen, SE, Flyger, H, Benitez, J, González-Neira, A, Anton-Culver, H, Neuhausen, SL, Brenner, H, Arndt, V, Meindl, A, Schmutzler, RK, Brauch, H, Hamann, U, Nevanlinna, H, Khan, S, Matsuo, K, Iwata, H, Dörk, T, Bogdanova, NV, Lindblom, A, Margolin, S, Mannermaa, A, Kosma, VM, Chenevix-Trench, G, Wu, AH, Ven Den Berg, D, Smeets, A, Zhao, H, Chang-Claude, J, Rudolph, A, Radice, P, Barile, M, Couch, FJ, Vachon, C, Giles, GG, Milne, RL, Haiman, CA, Marchand, LL, Goldberg, MS, Teo, SH, Taib, NAM, Kristensen, V, and Borresen-Dale, AL
Abstract: The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2:120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Perallelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P
Published: 2016

214. Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent

Author: Guo, Y, Warren Andersen, S, Shu, XO, Michailidou, K, Bolla, MK, Wang, Q, Garcia-Closas, M, Milne, RL, Schmidt, MK, Chang-Claude, J, Dunning, A, Bojesen, SE, Ahsan, H, Aittomäki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bogdanova, NV, Bonanni, B, Børresen-Dale, AL, Brand, J, Brauch, H, Brenner, H, Brüning, T, Burwinkel, B, Casey, G, Chenevix-Trench, G, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Dörk, T, Dumont, M, Fasching, PA, Figueroa, J, Flesch-Janys, D, Fletcher, O, Flyger, H, Fostira, F, Gammon, M, Giles, GG, Guénel, P, Haiman, CA, Hamann, U, Hooning, MJ, Hopper, JL, Jakubowska, A, Jasmine, F, Jenkins, M, John, EM, Johnson, N, Jones, ME, Kabisch, M, Kibriya, M, Knight, JA, Koppert, LB, Kosma, VM, Kristensen, V, Le Marchand, L, Lee, E, Li, J, Lindblom, A, Luben, R, Lubinski, J, Malone, KE, Mannermaa, A, Margolin, S, Marme, F, McLean, C, and Meijers-Heijboer, H
Abstract: © 2016 Guo et al. Background: Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors. Methods: We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases = 46,325, controls = 42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively. Results: In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR] = 0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56–0.75, p = 3.32 × 10−10). The associations were similar for both premenopausal (OR = 0.44, 95% CI:0.31–0.62, p = 9.91 × 10−8) and postmenopausal breast cancer (OR = 0.57, 95% CI: 0.46–0.71, p = 1.88 × 10−8). This association was replicated in the data from the DRIVE consortium (OR = 0.72, 95% CI: 0.60–0.84, p = 1.64 × 10−7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk. Conclusions: BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.
Published: 2016

215. Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk

Author: Lin, W.Y., Camp, N.J., Ghoussaini, M., Beesley, J., Michailidou, K., Hopper, J.L., Apicella, C., Southey, M.C., Stone, J., Schmidt, M.K., Broeks, A., Van't Veer, L.J., Rutgers, E.J.T., Muir, K., Lophatananon, A., Stewart-Brown, S., Siriwanarangsan, P., Fasching, P.A., Haeberle, L., Ekici, A.B., Beckmann, M.W., Peto, J., Dos-Santos-Silva, I., Fletcher, O., Johnson, N., Bolla, M.K., Wang, Q., Dennis, J., Sawyer, E.J., Cheng, T., Tomlinson, I., Kerin, M.J., Miller, N., Marme, F., Surowy, H.M., Burwinkel, B., Guenel, P., Truong, T., Menegaux, F., Mulot, C., Bojesen, S.E., Nordestgaard, B.G., Nielsen, S.F., Flyger, H., Benitez, J., Zamora, M.P., Perez, J.I.A., Menendez, P., Gonzalez-Neira, A., Pita, G., Alonso, M.R., Alvarez, N., Herrera, D., Anton-Culver, H., Brenner, H., Dieffenbach, A.K., Arndt, V., Stegmaier, C., Meindl, A., Lichtner, P., Schmutzler, R.K., Muller-Myhsok, B., Brauch, H., Bruning, T., Ko, Y.D., Tessier, D.C., Vincent, D., Bacot, F., Nevanlinna, H., Aittomaki, K., Blomqvist, C., Khan, S., Matsuo, K., Ito, H., Iwata, H., Horio, A., Bogdanova, N.V., Antonenkova, N.N., Dork, T., Lindblom, A., Margolin, S., Mannermaa, A., Kataja, V., Kosma, V.M., Hartikainen, J.M., Wu, A.H., Tseng, C.C., Berg, D. van den, Stram, D.O., Neven, P., Wauters, E., Wildiers, H., Lambrechts, D., Chang-Claude, J., Rudolph, A., Seibold, P., Flesch-Janys, D., Radice, P., Peterlongo, P., Manoukian, S., Bonanni, B., Couch, F.J., Wang, X.S., Vachon, C., Purrington, K., Giles, G.G., Milne, R.L., Mclean, C., Haiman, C.A., Henderson, B.E., Schumacher, F., Marchand, L. le, Simard, J., Goldberg, M.S., Labreche, F., Dumont, M., Teo, S.H., Yip, C.H., Hassan, N., Vithana, E.N., Kristensen, V., Zheng, W., Deming-Halverson, S., Shrubsole, M.J., Long, J.R., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Kauppila, S., Andrulis, I.L., Knight, J.A., Glendon, G., Tchatchou, S., Devilee, P., Tollenaar, R.A.E.M., Seynaeve, C., Asperen, C.J. van, Garcia-Closas, M., Figueroa, J., Lissowska, J., Brinton, L., Czene, K., Darabi, H., Eriksson, M., Brand, J.S., Hooning, M.J., Hollestelle, A., Ouweland, A.M.W. van den, Jager, A., Li, J.M., Liu, J.J., Humphreys, K., Shu, X.O., Lu, W., Gao, Y.T., Cai, H., Cross, S.S., Reed, M.W.R., Blot, W., Signorello, L.B., Cai, Q.Y., Pharoah, P.D.P., Perkins, B., Shah, M., Blows, F.M., Kang, D., Yoo, K.Y., Noh, D.Y., Hartman, M., Miao, H., Chia, K.S., Putti, T.C., Hamann, U., Luccarini, C., Baynes, C., Ahmed, S., Maranian, M., Healey, C.S., Jakubowska, A., Lubinski, J., Jaworska-Bieniek, K., Durda, K., Sangrajrang, S., Gaborieau, V., Brennan, P., Mckay, J., Slager, S., Toland, A.E., Yannoukakos, D., Shen, C.Y., Hsiung, C.N., Wu, P.E., Ding, S.L., Ashworth, A., Jones, M., Orr, N., Swerdlow, A.J., Tsimiklis, H., Makalic, E., Schmidt, D.F., Bui, Q.M., Chanock, S.J., Hunter, D.J., Hein, R., Dahmen, N., Beckmann, L., Aaltonen, K., Muranen, T.A., Heikkinen, T., Irwanto, A., Rahman, N., Turnbull, C.A., Waisfisz, Q., Meijers-Heijboer, H.E.J., Adank, M.A., Luijt, R.B. van der, Hall, P., Chenevix-Trench, G., Dunning, A., Easton, D.F., Cox, A., GENICA Network, kConFab Investigators, Australian Ovarian Canc Study Grp, Breast Ovarian Canc Susceptibility, Clinical Genetics, Obstetrics & Gynecology, Medical Oncology, Cardiothoracic Surgery, Cancer Center Amsterdam, Amsterdam Reproduction & Development (AR&D), Human Genetics, Human genetics, CCA - Oncogenesis, Ghoussaini, Maya [0000-0002-2415-2143], Wang, Jean [0000-0002-9139-0627], Dennis, Joe [0000-0003-4591-1214], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository
Subjects: Genotyping Techniques, Research Support, U.S. Gov't, P.H.S, CASP8 and FADD-Like Apoptosis Regulating Protein, Genome-wide association study, P.H.S, Medical and Health Sciences, Breast and Ovarian Cancer Susceptibility (BOCS) Study, Medizinische Fakultät, Genetics(clinical), Non-U.S. Gov't, Genetics (clinical), Genetics, Genetics & Heredity, variants, Caspase 8, Research Support, Non-U.S. Gov't, Association Studies Articles, General Medicine, Biological Sciences, ddc, Chromosomes, Human, Pair 2, kConFab Investigators, Female, GENICA Network, Australian Ovarian Cancer Study Group, European Continental Ancestry Group, Non-P.H.S, Single-nucleotide polymorphism, Breast Neoplasms, Biology, Research Support, Polymorphism, Single Nucleotide, White People, N.I.H, Breast cancer, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, medicine, Journal Article, Humans, Genetic Predisposition to Disease, ddc:610, gene, Genotyping, Molecular Biology, Genetic association, disease, Extramural, Proteins, Odds ratio, medicine.disease, susceptibility loci, Minor allele frequency, Case-Control Studies, genome-wide association, enhancers, U.S. Gov't, casp8, Research Support, U.S. Gov't, Non-P.H.S, Genome-Wide Association Study
Abstract: Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regressionmodels adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 × 10-5. Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P=3 × 10-6), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 × 10-9. Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8might be the target gene, suggesting amechanism involving apoptosis.
Published: 2016

216. Genetic predisposition to ductal carcinoma in situ of the breast

Author: Petridis, C., Brook, M.N., Shah, V., Kohut, K., Gorman, P., Caneppele, M., Levi, D., Papouli, E., Orr, N., Cox, A., Cross, S.S., dos-Santos-Silva, I., Peto, J., Swerdlow, A., Schoemaker, M.J., Bolla, M.K., Wang, Q., Dennis, J., Michailidou, K., Benitez, J., Gonzalez-Neira, A., Tessier, D.C., Vincent, D., Li, J.M., Figueroa, J., Kristensen, V., Borresen-Dale, A.L., Soucy, P., Simard, J., Milne, R.L., Giles, G.G., Margolin, S., Lindblom, A., Bruning, T., Brauch, H., Southey, M.C., Hopper, J.L., Dork, T., Bogdanova, N.V., Kabisch, M., Hamann, U., Schmutzler, R.K., Meindl, A., Brenner, H., Arndt, V., Winqvist, R., Pylkas, K., Fasching, P.A., Beckmann, M.W., Lubinski, J., Jakubowska, A., Mulligan, A.M., Andrulis, I.L., Tollenaar, R.A.E.M., Devilee, P., Marchand, L. le, Haiman, C.A., Mannermaa, A., Kosma, V.M., Radice, P., Peterlongo, P., Marme, F., Burwinkel, B., Deurzen, C.H.M. van, Hollestelle, A., Miller, N., Kerin, M.J., Lambrechts, D., Floris, G., Wesseling, J., Flyger, H., Bojesen, S.E., Yao, S., Ambrosone, C.B., Chenevix-Trench, G., Truong, T., Guenel, P., Rudolph, A., Chang-Claude, J., Nevanlinna, H., Blomqvist, C., Czene, K., Brand, J.S., Olson, J.E., Couch, F.J., Dunning, A.M., Hall, P., Easton, D.F., Pharoah, P.D.P., Pinder, S.E., Schmidt, M.K., Tomlinson, I., Roylance, R., Garcia-Closas, M., Sawyer, E.J., Pathology, Medical Oncology, Department of Obstetrics and Gynecology, Clinicum, and Department of Oncology
Subjects: 3122 Cancers, Breast Neoplasms, cancer risk, 610 Medical sciences Medicine, SDG 3 - Good Health and Well-being, Medizinische Fakultät, Humans, Genetic Predisposition to Disease, Neoplasm Invasiveness, ddc:610, risk-factors, skin and connective tissue diseases, neoplasms, Medicine(all), grade, variants, Genetic predisposition, Common variants, Carcinoma, Ductal, Breast, Ductal carcinoma in situ, susceptibility loci, Association study, body regions, dcis, Carcinoma, Intraductal, Noninfiltrating, genome-wide association, Carcinoma in Situ, metaanalysis, Research Article
Abstract: Background Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer. It is often associated with invasive ductal carcinoma (IDC), and is considered to be a non-obligate precursor of IDC. It is not clear to what extent these two forms of cancer share low-risk susceptibility loci, or whether there are differences in the strength of association for shared loci. Methods To identify genetic polymorphisms that predispose to DCIS, we pooled data from 38 studies comprising 5,067 cases of DCIS, 24,584 cases of IDC and 37,467 controls, all genotyped using the iCOGS chip. Results Most (67 %) of the 76 known breast cancer predisposition loci showed an association with DCIS in the same direction as previously reported for invasive breast cancer. Case-only analysis showed no evidence for differences between associations for IDC and DCIS after considering multiple testing. Analysis by estrogen receptor (ER) status confirmed that loci associated with ER positive IDC were also associated with ER positive DCIS. Analysis of DCIS by grade suggested that two independent SNPs at 11q13.3 near CCND1 were specific to low/intermediate grade DCIS (rs75915166, rs554219). These associations with grade remained after adjusting for ER status and were also found in IDC. We found no novel DCIS-specific loci at a genome wide significance level of P
Published: 2016

217. BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Author: Meeks, H.D., Song, H.L., Michailidou, K., Bolla, M.K., Dennis, J., Wang, Q., Barrowdale, D., Frost, D., McGuffog, L., Ellis, S., Feng, B.J., Buys, S.S., Hopper, J.L., Southey, M.C., Tesoriero, A., James, P.A., Bruinsma, F., Campbell, I.G., Broeks, A., Schmidt, M.K., Hogervorst, F.B.L., Beckman, M.W., Fasching, P.A., Fletcher, O., Johnson, N., Sawyer, E.J., Riboli, E., Banerjee, S., Menon, U., Tomlinson, I., Burwinkel, B., Hamann, U., Marme, F., Rudolph, A., Janavicius, R., Tihomirova, L., Tung, N., Garber, J., Cramer, D., Terry, K.L., Poole, E.M., Tworoger, S.S., Dorfling, C.M., Rensburg, E.J. van, Godwin, A.K., Guenel, P., Truong, T., Stoppa-Lyonnet, D., Damiola, F., Mazoyer, S., Sinilnikova, O.M., Isaacs, C., Maugard, C., Bojesen, S.E., Flyger, H., Gerdes, A.M., Hansen, T.V.O., Jensen, A., Kjaer, S.K., Hogdall, C., Hogdall, E., Pedersen, I.S., Thomassen, M., Benitez, J., Gonzalez-Neira, A., Osorio, A., Hoya, M. de la, Segura, P.P., Diez, O., Lazaro, C., Brunet, J., Anton-Culver, H., Eunjung, L., John, E.M., Neuhausen, S.L., Ding, Y.C., Castillo, D., Weitzel, J.N., Ganz, P.A., Nussbaum, R.L., Chan, S.B., Karlan, B.Y., Lester, J., Wu, A., Gayther, S., Ramus, S.J., Sieh, W., Whittermore, A.S., Monteiro, A.N.A., Phelan, C.M., Terry, M.B., Piedmonte, M., Offit, K., Robson, M., Levine, D., Moysich, K.B., Cannioto, R., Olson, S.H., Daly, M.B., Nathanson, K.L., Domchek, S.M., Lu, K.H., Liang, D., Hildebrant, M.A.T., Ness, R., Modugno, F., Pearce, L., Goodman, M.T., Thompson, P.J., Brenner, H., Butterbach, K., Meindl, A., Hahnen, E., Wappenschmidt, B., Brauch, H., Bruning, T., Blomqvist, C., Khan, S., Nevanlinna, H., Pelttari, L.M., Aittomaki, K., Butzow, R., Bogdanova, N.V., Dork, T., Lindblom, A., Margolin, S., Rantala, J., Kosma, V.M., Mannermaa, A., Lambrechts, D., Neven, P., Claes, K.B.M., Maerken, T. van, Chang-Claude, J., Flesch-Janys, D., Heitz, F., Varon-Mateeva, R., Peterlongo, P., Radice, P., Viel, A., Barile, M., Peissel, B., Manoukian, S., Montagna, M., Oliani, C., Peixoto, A., Teixeira, M.R., Collavoli, A., Hallberg, E., Olson, J.E., Goode, E.L., Hart, S.N., Shimelis, H., Cunningham, J.M., Giles, G.G., Milne, R.L., Healey, S., Tucker, K., Haiman, C.A., Henderson, B.E., Goldberg, M.S., Tischkowitz, M., Simard, J., Soucy, P., Eccles, D.M., N. le, Borresen-Dale, A.L., Kristensen, V., Salvesen, H.B., Bjorge, L., Bandera, E.V., Risch, H., Zheng, W., Beeghly-Fadiel, A., Cai, H., Pylkas, K., Tollenaar, R.A.E.M., Ouweland, A.M.W. van der, Andrulis, I.L., Knight, J.A., Narod, S., Devilee, P., Winqvist, R., Figueroa, J., Greene, M.H., Mai, P.L., Loud, J.T., Garcia-Closas, M., Schoemaker, M.J., Czene, K., Darabi, H., McNeish, I., Siddiquil, N., Glasspool, R., Kwong, A., Park, S.K., Teo, S.H., Yoon, S.Y., Matsuo, K., Hosono, S., Woo, Y.L., Gao, Y.T., Foretova, L., Singer, C.F., Rappaport-Feurhauser, C., Friedman, E., Laitman, Y., Rennert, G., Imyanitov, E.N., Hulick, P.J., Olopade, O.I., Senter, L., Olah, E., Doherty, J.A., Schildkraut, J., Koppert, L.B., Kiemeney, L.A., Massuger, L.F.A.G., Cook, L.S., Pejovic, T., Li, J.M., Borg, A., Ofverholm, A., Rossing, M.A., Wentzensen, N., Henriksson, K., Cox, A., Cross, S.S., Pasini, B.J., Shah, M., Kabisch, M., Torres, D., Jakubowska, A., Lubinski, J., Gronwald, J., Agnarsson, B.A., Kupryjanczyk, J., Moes-Sosnowska, J., Fostira, F., Konstantopoulou, I., Slager, S., Jones, M., Antoniou, A.C., Berchuck, A., Swerdlow, A., Chenevix-Trench, G., Dunning, A.M., Pharoah, P.D.P., Hall, P., Easton, D.F., Couch, F.J., Spurdle, A.B., Goldgar, D.E., EMBRACE, kConFab Investigators, Australia Ovarian Canc Study Grp, HEBON, GEMO Study Collaborators, OCGN, PRostate Canc Assoc Grp, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Clinical Genetics, Obstetrics & Gynecology, Surgery, and [ 1 ] Univ Utah, Huntsman Canc Inst, Canc Control & Populat Sci, Salt Lake City, UT USA [ 2 ] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England [ 3 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England [ 4 ] Univ Utah, Sch Med, Huntsman Canc Inst, Dept Dermatol, 2000 Circle Hope Dr, Salt Lake City, UT 84112 USA [ 5 ] Univ Utah, Sch Med, Dept Med, Huntsman Canc Inst, Salt Lake City, UT USA [ 6 ] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia [ 7 ] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia [ 8 ] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Parkville, Vic 3052, Australia [ 9 ] KConFab Kathleen Cuningham Consortium Res Familia, Peter MacCallum Canc Ctr, Melbourne, Vic, Australia [ 10 ] Peter MacCallum Canc Ctr, Familial Canc Ctr, Melbourne, Vic, Australia [ 11 ] Univ Melbourne, Dept Oncol, Melbourne, Vic, Australia [ 12 ] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia [ 13 ] Univ Melbourne, Peter MacCallum Canc Ctr, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3052, Australia [ 14 ] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld, Australia [ 15 ] Peter MacCallum Canc Inst, East Melbourne, Vic, Australia [ 16 ] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands [ 17 ] Netherlands Canc Inst, Family Canc Clin, Amsterdam, Netherlands [ 18 ] Netherlands Canc Inst, Hereditary Breast & Ovarian Canc Res Grp Netherla, Coordinating Ctr, Amsterdam, Netherlands [ 19 ] Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Dept Gynaecol & Ostetr, D-91054 Erlangen, Germany [ 20 ] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA [ 21 ] Inst Canc Res, Div Breast Canc Res, London SW3 6JB, England [ 22 ] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England [ 23 ] Guys Hosp, Kings Coll London, Div Canc Studies, Res Oncol, London SE1 9RT, England [ 24 ] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England [ 25 ] Royal Marsden NHS Fdn Trust, London, England [ 26 ] Univ Coll London Elizabeth Garrett Anderson EGA, Inst Womens Hlth, Womens Canc, London, England [ 27 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England [ 28 ] Univ Oxford, Oxford Biomed Res Ctr, Oxford, England [ 29 ] German Canc Res Ctr, Div Mol Genet Epidemiol, Heidelberg, Germany [ 30 ] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany [ 31 ] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany [ 32 ] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany [ 33 ] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany [ 34 ] State Res Inst Ctr Innovat Med, Vilnius, Lithuania [ 35 ] Latvian Biomed Res & Study Ctr, Riga, Latvia [ 36 ] Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA [ 37 ] Dana Farber Canc Inst, Canc Risk & Prevent Clin, Boston, MA 02115 USA [ 38 ] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, 75 Francis St, Boston, MA 02115 USA [ 39 ] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA [ 40 ] Harvard Univ, Sch Med, Boston, MA 02115 USA [ 41 ] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 665 Huntington Ave, Boston, MA 02115 USA [ 42 ] Univ Pretoria, Dept Genet, ZA-0002 Pretoria, South Africa [ 43 ] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA [ 44 ] Natl Inst Hlth & Med Res, Ctr Res Epidemiol & Populat Hlth CESP, Environm Epidemiol Canc, INSERM,U1018, Villejuif, France [ 45 ] Univ Paris Sud, Villejuif, France [ 46 ] UNICANCER Genet Grp, GEMO Study Natl Canc Genet Network, Paris, France [ 47 ] Inst Curie, Dept Tumour Biol, Paris, France [ 48 ] INSERM, U830, Inst Curie, Paris, France [ 49 ] Univ Paris 05, Sorbonne Paris Cite, Paris, France [ 50 ] Univ Lyon, Ctr Rech Cancerol Lyon, INSERM,U1052, CNRS UMR 5286, Lyon, France [ 51 ] Hosp Civils Pyon, Ctr Leon Berard, Unite Mixte Genet Constitutionelle Canc Frequents, Lyon, France [ 52 ] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA [ 53 ] Hop Univ Strasbourg, CHRU Nouvel, Lab Diagnost Genet, Hop Civil, Strasbourg, France [ 54 ] Hop Univ Strasbourg, CHRU Nouvel, Serv Oncohematol, Hop Civil, Strasbourg, France [ 55 ] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark [ 56 ] Copenhagen Univ Hosp, Dept Clin Biochem, Herlev Hosp, Herlev, Denmark [ 57 ] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, Herlev, Denmark [ 58 ] Copenhagen Univ Hosp, Rigshosp, Dept Clin Genet, Copenhagen, Denmark [ 59 ] Copenhagen Univ Hosp, Rigshosp, Ctr Genom Med, Copenhagen, Denmark [ 60 ] Danish Canc Soc, Dept Virus Lifestyle & Genes, Res Ctr, Copenhagen, Denmark [ 61 ] Univ Copenhagen, Rigshosp, Dept Gynecol, DK-2100 Copenhagen, Denmark [ 62 ] Univ Copenhagen, Herlev Hosp, Dept Pathol, Mol Unit, Copenhagen, Denmark [ 63 ] Aalborg Univ Hosp, Dept Biochem, Sect Mol Diagnost, Aalborg, Denmark [ 64 ] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark [ 65 ] Spanish Natl Canc Ctr CNIO, Human Canc Genet Program, Human Genet Grp, Madrid, Spain [ 66 ] Spanish Natl Canc Ctr CNIO, Human Canc Genet Program, Human Genotyping Unit CEGEN, Madrid, Spain [ 67 ] Biomed Network Rare Dis CIBERER, Madrid, Spain [ 68 ] IdISSC Inst Invest Sanitaria Hosp Clin San Carlos, Hosp Clin San Carlos, Mol Oncol Lab, Madrid, Spain [ 69 ] IdISSC, Hosp Clin San Carlos, Dept Oncol, Madrid, Spain [ 70 ] Univ Hosp Vall dHebron, VHIO, Oncogenet Grp, Barcelona, Spain [ 71 ] Univ Autonoma Barcelona, E-08193 Barcelona, Spain [ 72 ] Catalan Inst Oncol, IDIBELL Bellvitge Biomed Res Inst, Hereditary Canc Program, Mol Diagnost Unit, Barcelona, Spain [ 73 ] Catalan Inst Oncol, IDIBGI Inst Invest Biomed Girona, Hereditary Canc Program, Genet Counseling Unit, Girona, Spain [ 74 ] Univ Calif Irvine, Sch Med, Dept Epidemiol, Irvine, CA 92717 USA [ 75 ] Univ So Calif, Keck Sch Med, Dept Prevent Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA [ 76 ] Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA USA [ 77 ] Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA [ 78 ] City Hope Clin Canc Genet Community Res Network, Clin Canc Genet, Duarte, CA USA [ 79 ] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Sch Med, Div Canc Prevent & Control Res, Los Angeles, CA 90024 USA [ 80 ] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Sch Publ Hlth, Div Canc Prevent & Control Res, Los Angeles, CA 90024 USA [ 81 ] Univ Calif San Francisco, Dept Med & Genet, San Francisco, CA 94143 USA [ 82 ] Univ Calif San Francisco, Helen Diller Family Canc Ctr, Canc Risk Program, San Francisco, CA 94143 USA [ 83 ] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA [ 84 ] Stanford Univ, Dept Hlth Res & Policy Epidemiol, Stanford, CA USA [ 85 ] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Tampa, FL 33682 USA [ 86 ] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA [ 87 ] Roswell Pk Ctr Inst, NRG Oncol Stat & Data Management Ctr, Buffalo, NY USA [ 88 ] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA [ 89 ] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, 1275 York Ave, New York, NY 10021 USA [ 90 ] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA [ 91 ] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, 1275 York Ave, New York, NY 10021 USA [ 92 ] Fox Chase Canc Ctr, Dept Clin Genet, 7701 Burholme Ave, Philadelphia, PA 19111 USA [ 93 ] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Basser Ctr, Philadelphia, PA 19104 USA [ 94 ] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA [ 95 ] Texas So Univ, Coll Pharm & Hlth Sci, Houston, TX 77004 USA [ 96 ] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA [ 97 ] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA [ 98 ] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA [ 99 ] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA [ 100 ] Magee Womens Res Inst, Womens Canc Res Program, Pittsburgh, PA USA [ 101 ] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA [ 102 ] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA [ 103 ] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Canc Prevent & Control, Los Angeles, CA 90048 USA [ 104 ] Cedars Sinai Med Ctr, Dept Biomed Sci, Community & Populat Hlth Res Inst, Los Angeles, CA 90048 USA [ 105 ] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany [ 106 ] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany [ 107 ] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry CV4 7AL, W Midlands, England [ 108 ] Tech Univ Munich, Klinikum Rechts Isar, Dept Obstet & Gynaecol, Div Tumor Genet, D-80290 Munich, Germany [ 109 ] Univ Hosp Cologne, Ctr Integrated Oncol, Cologne, Germany [ 110 ] Univ Hosp Cologne, Ctr Mol Med, Cologne, Germany [ 111 ] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Cologne, Germany [ 112 ] Univ Hosp Cologne, Dept Obstet & Gynaecol, Cologne, Germany [ 113 ] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Auerbachstr 112, Stuttgart, Germany [ 114 ] Univ Tubingen, Tubingen, Germany [ 115 ] Ruhr Univ Bochum IPA, German Social Accid Insurance & Inst, Inst Prevent & Occupat Med, Bochum, Germany [ 116 ] Univ Helsinki, Dept Oncol, Helsinki, Finland [ 117 ] Helsinki Univ Hosp, Helsinki, Finland [ 118 ] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland [ 119 ] Univ Helsinki, Dept Clin Genet, Helsinki, Finland [ 120 ] Univ Helsinki, Dept Pathol, Helsinki, Finland [ 121 ] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany [ 122 ] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden [ 123 ] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden [ 124 ] Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden [ 125 ] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Sch Med, Kuopio, Finland [ 126 ] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland [ 127 ] Kuopio Univ Hosp, Ctr Canc, SF-70210 Kuopio, Finland [ 128 ] VIB, VRC, Leuven, Belgium [ 129 ] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium [ 130 ] Univ Hosp Leuven, Dept Oncol, Multidisciplinary Breast Ctr, Leuven, Belgium [ 131 ] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium [ 132 ] Univ Med Ctr Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany [ 133 ] Univ Med Ctr Hamburg Eppendorf, Clin Canc Registry, Dept Canc Epidemiol, Hamburg, Germany [ 134 ] Kliniken Essen Mitte Evang Huyssens Stiftung Knap, Dept Gynecol & Gynecol Oncol, Essen, Germany [ 135 ] Dr Horst Schmidt Kliniken Wiesbaden, Dept Gynecol & Gynecol Oncol, Wiesbaden, Germany [ 136 ] Charite, Campus Virchov Klinikum, Inst Human Genet, Berlin, Germany [ 137 ] Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy [ 138 ] Fdn IRCCS Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy [ 139 ] Aviano Natl Canc Inst, CRO, Div Expt Oncol, Aviano, Italy [ 140 ] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy [ 141 ] Fdn IRCCS Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Med Genet, Milan, Italy [ 142 ] Veneto Inst Oncol IOV IRCCS, Immunol & Mol Oncol Unit, Padua, Italy [ 143 ] ULSS5 Ovest Vicentino, UOC Oncol, Veneto, Italy [ 144 ] Portugese Oncol Inst, Dept Genet, Oporto, Portugal [ 145 ] Univ Porto, Biomed Sci Inst ICBAS, Rua Campo Alegre 823, P-4100 Oporto, Portugal [ 146 ] Univ Pisa, Dept Lab Med, Sect Genet Oncol, Pisa, Italy [ 147 ] Univ Hosp Pisa, Pisa, Italy [ 148 ] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA [ 149 ] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA [ 150 ] Prince Wales Hosp, Sydney, NSW, Australia [ 151 ] McGill Univ, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ H3A 1A1, Canada [ 152 ] McGill Univ, Dept Med, Montreal, PQ, Canada [ 153 ] McGill Univ, Dept Human Genet, Program Canc Genet, Montreal, PQ, Canada [ 154 ] McGill Univ, Dept Oncol, Program Canc Genet, Montreal, PQ, Canada [ 155 ] Univ Cambridge, Sch Med, Cambridge, England [ 156 ] Ctr Hosp Univ Quebec, Res Ctr, Quebec City, PQ, Canada [ 157 ] Univ Laval, Quebec City, PQ, Canada [ 158 ] Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England [ 159 ] BC Canc Agcy, Canc Control Res, Vancouver, BC, Canada [ 160 ] Oslo Univ Hosp, Radiumhosp, Inst Canc Res, Dept Genet, Oslo, Norway [ 161 ] Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway [ 162 ] Univ Oslo, Oslo Univ Hosp, Dept Clin Mol Biol, Oslo, Norway [ 163 ] Haukeland Hosp, Dept Gynecol & Obstet, N-5021 Bergen, Norway [ 164 ] Univ Bergen, Dept Clin Sci, Ctr Canc Biomarkers, Bergen, Norway [ 165 ] Rutgers Canc Inst New Jersey, New Brunswick, NJ USA [ 166 ] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA [ 167 ] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr,Vanderbilt Ingram Canc C, Div Epidemiol,Dept Med, 221 Kirkland Hall, Nashville, TN 37235 USA [ 168 ] Univ Oulu, Dept Clin Chem, Lab Canc Genet & Tumor Biol, Oulu, Finland [ 169 ] Univ Oulu, Bioctr Oulu, Oulu, Finland [ 170 ] Northern Finland Lab Ctr Nordlab, Lab Canc Genet & Tumor Biol, Oulu, Finland [ 171 ] Erasmus Univ, Med Ctr, Dept Surg Oncol, Rotterdam, Netherlands [ 172 ] Erasmus Univ, Med Ctr, Dept Clin Genet, Family Canc Clin, Rotterdam, Netherlands [ 173 ] Mt Sinai Hosp, Lunenfeld Res Inst, Ontario Canc Genet Network, Fred A Litwin Ctr Canc Genet, Toronto, ON M5G 1X5, Canada [ 174 ] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada [ 175 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada [ 176 ] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON, Canada [ 177 ] Univ Toronto, Womens Coll, Res Inst, Toronto, ON, Canada [ 178 ] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands [ 179 ] Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands [ 180 ] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA [ 181 ] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA [ 182 ] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England [ 183 ] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden [ 184 ] Univ Glasgow, Beatson Inst Canc Res, Wolfson Wohl Canc Res Ctr, Inst Canc Sci, Glasgow, Lanark, Scotland [ 185 ] Glasgow Royal Infirm, Dept Gynaecol Oncol, Glasgow G4 0SF, Lanark, Scotland [ 186 ] Beatson West Scotland Canc Ctr, Canc Res UK Clin Trials Unit, Glasgow, Lanark, Scotland [ 187 ] Hong Kong Sanat & Hosp, Canc Genet Ctr, Hong Kong Hereditary Breast Canc Family Registry, Hong Kong, Hong Kong, Peoples R China [ 188 ] Univ Hong Kong, Dept Surg, Hong Kong, Hong Kong, Peoples R China [ 189 ] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea [ 190 ] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea [ 191 ] Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul, South Korea [ 192 ] Sime Darby Med Ctr, Canc Res Initiat Fdn, Subang Jaya, Selangor, Malaysia [ 193 ] Univ Malaya, Med Ctr, Fac Med, Canc Res Inst, Kuala Lumpur, Malaysia [ 194 ] Aichi Canc Ctr Res Inst, Div Mol Med, Nagoya, Aichi, Japan [ 195 ] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi, Japan [ 196 ] Univ Malaya, Med Ctr, Dept Obstet & Gynecol, Kuala Lumpur, Malaysia [ 197 ] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China [ 198 ] Masaryk Mem Canc Inst & Med Fac, Brno, Czech Republic [ 199 ] Med Univ Vienna, Dept Obstet & Gynecol, Vienna, Austria [ 200 ] Med Univ Vienna, Ctr Comprehens Canc, Vienna, Austria [ 201 ] Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel [ 202 ] Carmel Hosp, Clalit Natl Israeli Canc Control Ctr, Haifa, Israel [ 203 ] Carmel Hosp, Dept Community Med & Epidemiol, Haifa, Israel [ 204 ] B Rappaport Fac Med, Haifa, Israel [ 205 ] NN Petrov Inst Oncol, St Petersburg, Russia [ 206 ] NorthShore Univ Hlth Syst, Ctr Med Genet, Evanston, IL USA [ 207 ] Univ Chicago, Med Ctr, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA [ 208 ] Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med, Div Human Genet, Columbus, OH 43210 USA [ 209 ] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary [ 210 ] Dartmouth Coll, Geisel Sch Med, Sect Biostat & Epidemiol, Dept Community & Family Med, Hanover, NH 03755 USA [ 211 ] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA [ 212 ] Duke Canc Inst, Canc Control & Populat Sci, Durham, NC USA [ 213 ] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, NL-6525 ED Nijmegen, Netherlands [ 214 ] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Life Sci, Dept Gynaecol, NL-6525 ED Nijmegen, Netherlands [ 215 ] Univ New Mexico, Dept Internal Med, Div Epidemiol & Biostat, Albuquerque, NM 87131 USA [ 216 ] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA [ 217 ] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA [ 218 ] Lund Univ, Dept Oncol, Lund, Sweden [ 219 ] Sahlgrens Univ Hosp, Dept Clin Genet, Gothenburg, Sweden [ 220 ] Fred Hutchinson Canc Res Ctr, Program Epidemiol, 1124 Columbia St, Seattle, WA 98104 USA [ 221 ] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA [ 222 ] Univ Lund Hosp, Ctr Oncol, Reg Tumour Registry, S-22185 Lund, Sweden [ 223 ] Univ Sheffield, Sheffield Canc Res Dept Oncol, Sheffield, S Yorkshire, England [ 224 ] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England [ 225 ] Pontificia Univ Javeriana, Inst Human Genet, Bogota, Colombia [ 226 ] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland [ 227 ] Landspitali Univ Hosp, Reykjavik, Iceland Organization-Enhanced Name(s) Landspitali National University Hospital [ 228 ] Univ Iceland, Sch Med, Reykjavik, Iceland [ 229 ] Maria Sklodowska Curie Mem Canc Ctr, Dept Pathol & Lab Diagnost, Warsaw, Poland [ 230 ] Inst Oncol, Warsaw, Poland [ 231 ] Natl Ctr Sci Res Demokritos, Mol Diagnost Lab, Inst Nucl & Radiol Sci & Technol, Energy & Safety, Athens, Greece [ 232 ] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA
Subjects: 0301 basic medicine, Oncology, Male, Cancer Research, endocrine system diseases, LOCI, Estrogen receptor, FAMILY-HISTORY, Prostate cancer, 0302 clinical medicine, Ovarian Neoplasms/pathology, Prostate, Risk Factors, Brjóstakrabbamein, Odds Ratio, skin and connective tissue diseases, Ovarian Neoplasms, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Prostatic Neoplasms/genetics, Research Support, Non-U.S. Gov't, SINGLE-NUCLEOTIDE POLYMORPHISMS, Middle Aged, BRCA2 Protein/genetics, PANCREATIC-CANCER, 3. Good health, SUSCEPTIBILITY GENE, medicine.anatomical_structure, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Codon, Terminator, Female, Risk Factors Substances, Adult, medicine.medical_specialty, Heterozygote, Breast Neoplasms, Blöðruhálskirtilskrabbamein, Breast Neoplasms/genetics, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Article, Ovarian Neoplasms/genetics, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Research Support, N.I.H., Extramural, Internal medicine, Pancreatic cancer, Krabbameinsrannsóknir, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Neoplasm Invasiveness, Lysine/genetics, Krabbamein, Aged, Gynecology, BRCA2 Protein, Proportional hazards model, Lysine, DNA RECOMBINATION, CONSORTIUM, GERM-LINE MUTATION, Prostatic Neoplasms, Odds ratio, Arfgengi, medicine.disease, ESTROGEN-RECEPTOR, 030104 developmental biology, Logistic Models, PTT12, Eggjastokkar, FANCONI-ANEMIA, Ovarian cancer
Abstract: Contains fulltext : 172007.pdf (Publisher’s version ) (Closed access) BACKGROUND: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. METHODS: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. RESULTS: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10(-) (6)) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10(-3)). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10(-5) and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10(-5), respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. CONCLUSIONS: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.
Published: 2016

218. Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility: Results from a large-scale collaboration

Author: Permuth, JB, Reid, B, Earp, M, Chen, YA, Monteiro, ANA, Chen, Z, Chenevix-Trench, G, Fasching, PA, Beckmann, MW, Lambrechts, D, Vanderstichele, A, Van Niewenhuyse, E, Vergote, I, Rossing, MA, Doherty, JA, Chang-Claude, J, Moysich, K, Odunsi, K, Goodman, MT, Shvetsov, YB, Wilkens, LR, Thompson, PJ, Dörk, T, Bogdanova, N, Butzow, R, Nevanlinna, H, Pelttari, L, Leminen, A, Modugno, F, Edwards, RP, Ness, RB, Kelley, J, Heitz, F, Karlan, B, Lester, J, Kjaer, SK, Jensen, A, Giles, G, Hildebrandt, M, Liang, D, Lu, KH, Wu, X, Levine, DA, Bisogna, M, Berchuck, A, Cramer, DW, Terry, KL, Tworoger, SS, Poole, EM, Bandera, EV, Fridley, B, Cunningham, J, Winham, SJ, Olson, SH, Orlow, I, Bjorge, L, Kiemeney, LA, Massuger, L, Pejovic, T, Moffitt, M, Le, N, Cook, LS, Brooks-Wilson, A, Kelemen, LE, Gronwald, J, Lubinski, J, Wentzensen, N, Brinton, LA, Lissowska, J, Yang, H, Hogdall, E, Hogdall, C, Lundvall, L, Pharoah, PDP, Song, H, Campbell, I, Eccles, D, and McNeish, I
Abstract: RNA editing in mammals is a form of post-transcriptional modification in which adenosine is converted to inosine by the adenosine deaminases acting on RNA (ADAR) family of enzymes. Based on evidence of altered ADAR expression in epithelial ovarian cancers (EOC), we hypothesized that single nucleotide polymorphisms (SNPs) in ADAR genes modify EOC susceptibility, potentially by altering ovarian tissue gene expression. Using directly genotyped and imputed data from 10,891 invasive EOC cases and 21,693 controls, we evaluated the associations of 5,303 SNPs in ADAD1, ADAR, ADAR2, ADAR3, and SND1. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), with adjustment for European ancestry. We conducted gene-level analyses using the Admixture Maximum Likelihood (AML) test and the Sequence-Kernel Association test for common and rare variants (SKAT-CR). Association analysis revealed top risk-associated SNP rs77027562 (OR (95% CI)= 1.39 (1.17-1.64), P=1.0x10-4) in ADAR3 and rs185455523 in SND1 (OR (95% CI)= 0.68 (0.56-0.83), P=2.0x10-4). When restricting to serous histology (n=6,500), the magnitude of association strengthened for rs185455523 (OR=0.60, P=1.0x10-4). Gene-level analyses revealed that variation in ADAR was associated (P
Published: 2016

219. RAD51B in familial breast cancer

Author: Pelttari, LM, Khan, S, Vuorela, M, Kiiski, JI, Vilske, S, Nevanlinna, V, Ranta, S, Schleutker, J, Winqvist, R, Kallioniemi, A, Dörk, T, Bogdanova, NV, Figueroa, J, Pharoah, PDP, Schmidt, MK, Dunning, AM, García-Closas, M, Bolla, MK, Dennis, J, Michailidou, K, Wang, Q, Hopper, JL, Southey, MC, Rosenberg, EH, Fasching, PA, Beckmann, MW, Peto, J, Dos-Santos-silva, I, Sawyer, EJ, Tomlinson, I, Burwinkel, B, Surowy, H, Guénel, P, Truong, T, Bojesen, SE, Nordestgaard, BG, Benitez, J, González-Neira, A, Neuhausen, SL, Anton-Culver, H, Brenner, H, Arndt, V, Meindl, A, Schmutzler, RK, Brauch, H, Brüning, T, Lindblom, A, Margolin, S, Mannermaa, A, Hartikainen, JM, Chenevix-Trench, G, Van Dyck, L, Janssen, H, Chang-Claude, J, Rudolph, A, Radice, P, Peterlongo, P, Hallberg, E, Olson, JE, Giles, GG, Milne, RL, Haiman, CA, Schumacher, F, Simard, J, and Dumont, M
Abstract: Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 × 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 × 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.
Published: 2016

220. Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Pfeiler, G, Vigorito, E, Kuchenbaecker, KB, Beesley, J, Adlard, J, Agnarsson, BA, Andrulis, IL, Arun, BK, Barjhoux, L, Belotti, M, Benitez, J, Berger, A, Phelan, CM, Piedmonte, M, Poppe, B, Pujana, MA, Radice, P, Rennert, G, Rodriguez, GC, Rookus, MA, Ross, EA, Bojesen, A, Schmutzler, RK, Simard, J, Singer, CF, Slavin, TP, Soucy, P, Southey, M, Steinemann, D, Stoppa-Lyonnet, D, Sukiennicki, G, Sutter, C, Bonanni, B, Szabo, CI, Tea, MK, Teixeira, MR, Teo, SH, Terry, MB, Thomassen, M, Tibiletti, MG, Tihomirova, L, Tognazzo, S, van Rensburg, EJ, Brewer, C, Varesco, L, Varon-Mateeva, R, Vratimos, A, Weitzel, JN, McGuffog, L, Kirk, J, Toland, AE, Hamann, U, Lindor, N, Ramus, SJ, Caldes, T, Greene, MH, Couch, FJ, Offit, K, Pharoah, PDP, Chenevix-Trench, G, Antoniou, AC, Prokunina-Olsson, L, Caligo, MA, Campbell, I, Chan, SB, Claes, KBM, Cohn, DE, Cook, J, Daly, MB, Damiola, F, Davidson, R, Pauw, AD, Delnatte, C, Diez, O, Domchek, SM, Dumont, M, Durda, K, Dworniczak, B, Easton, DF, Eccles, D, Edwinsdotter Ardnor, C, Eeles, R, Ejlertsen, B, Ellis, S, Evans, G, Feliubadalo, L, Fostira, F, Foulkes, WD, Friedman, E, Frost, D, Gaddam, P, Ganz, PA, Garber, J, Garcia-Barberan, V, Gauthier-Villars, M, Gehrig, A, Gerdes, AM, Giraud, S, Godwin, AK, Goldgar, DE, Hake, CR, Hansen, TVO, Healey, S, Hodgson, S, Hogervorst, FBL, Houdayer, C, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Izquierdo, A, Jacobs, L, Jakubowska, A, Janavicius, R, Jaworska-Bieniek, K, Jensen, UB, John, EM, Vijai, J, Karlan, BY, Kast, K, Investigators, K, Khan, S, Kwong, A, Laitman, Y, Lester, J, Lesueur, F, Liljegren, A, Lubinski, J, Mai, PL, Manoukian, S, Mazoyer, S, Meindl, A, Mensenkamp, AR, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Niederacher, D, Olah, E, Olopade, OI, Ong, KR, Osorio, A, Park, SK, Paulsson-Karlsson, Y, Pedersen, IS, Peissel, B, and Peterlongo, P
Subjects: endocrine system diseases, skin and connective tissue diseases
Abstract: Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA 1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10−16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10−6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population
Published: 2016

221. PALB2, CHEK2 and ATM rare variants and cancer risk:data from COGS

Author: Southey, M. C. (Melissa C.), Goldgar, D. E. (David E.), Winqvist, R. (Robert), Pylkäs, K. (Katri), Couch, F. (Fergus), Tischkowitz, M. (Marc), Foulkes, W. D. (William D.), Dennis, J. (Joe), Michailidou, K. (Kyriaki), van Rensburg, E. J. (Elizabeth J.), Heikkinen, T. (Tuomas), Nevanlinna, H. (Heli), Hopper, J. L. (John L.), Doerk, T. (Thilo), Claes, K. B. (Kathleen B. M.), Reis-Filho, J. (Jorge), Teo, Z. L. (Zhi Ling), Radice, P. (Paolo), Catucci, I. (Irene), Peterlongo, P. (Paolo), Tsimiklis, H. (Helen), Odefrey, F. A. (Fabrice A.), Dowty, J. G. (James G.), Schmidt, M. K. (Marjanka K.), Broeks, A. (Annegien), Hogervorst, F. B. (Frans B.), Verhoef, S. (Senno), Carpenter, J. (Jane), Clarke, C. (Christine), Scott, R. J. (Rodney J.), Fasching, P. A. (Peter A.), Haeberle, L. (Lothar), Ekici, A. B. (Arif B.), Beckmann, M. W. (Matthias W.), Peto, J. (Julian), dos-Santos-Silva, I. (Isabel), Fletcher, O. (Olivia), Johnson, N. (Nichola), Bolla, M. K. (Manjeet K.), Sawyer, E. J. (Elinor J.), Tomlinson, I. (Ian), Kerin, M. J. (Michael J.), Miller, N. (Nicola), Marme, F. (Federik), Burwinkel, B. (Barbara), Yang, R. (Rongxi), Guenel, P. (Pascal), Menegaux, F. (Florence), Sanchez, M. (Marie), Bojesen, S. (Stig), Nielsen, S. F. (Sune F.), Flyger, H. (Henrik), Benitez, J. (Javier), Pilar Zamora, M. (M.), Arias Perez, J. I. (Jose Ignacio), Menendez, P. (Primitiva), Anton-Culver, H. (Hoda), Neuhausen, S. (Susan), Ziogas, A. (Argyrios), Clarke, C. A. (Christina A.), Brenner, H. (Hermann), Arndt, V. (Volker), Stegmaier, C. (Christa), Brauch, H. (Hiltrud), Bruening, T. (Thomas), Ko, Y.-D. (Yon-Dschun), Muranen, T. A. (Taru A.), Aittomaki, K. (Kristiina), Blomqvist, C. (Carl), Bogdanova, N. V. (Natalia V.), Antonenkova, N. N. (Natalia N.), Lindblom, A. (Annika), Margolin, S. (Sara), Mannermaa, A. (Arto), Kataja, V. (Vesa), Kosma, V.-M. (Veli-Matti), Hartikainen, J. M. (Jaana M.), Spurdle, A. B. (Amanda B.), Wauters, E. (Els), Smeets, D. (Dominiek), Beuselinck, B. (Benoit), Floris, G. (Giuseppe), Chang-Claude, J. (Jenny), Rudolph, A. (Anja), Seibold, P. (Petra), Flesch-Janys, D. (Dieter), Olson, J. E. (Janet E.), Vachon, C. (Celine), Pankratz, V. S. (Vernon S.), McLean, C. (Catriona), Haiman, C. A. (Christopher A.), Henderson, B. E. (Brian E.), Schumacher, F. (Fredrick), Le Marchand, L. (Loic), Kristensen, V. (Vessela), Alnaes, G. G. (Grethe Grenaker), Zheng, W. (Wei), Hunter, D. J. (David J.), Lindstrom, S. (Sara), Hankinson, S. E. (Susan E.), Kraft, P. (Peter), Andrulis, I. (Irene), Knight, J. A. (Julia A.), Glendon, G. (Gord), Mulligan, A. M. (Anna Marie), Jukkola-Vuorinen, A. (Arja), Grip, M. (Mervi), Kauppila, S. (Saila), Devilee, P. (Peter), Tollenaar, R. A. (Robert A. E. M.), Seynaeve, C. (Caroline), Hollestelle, A. (Antoinette), Garcia-Closas, M. (Montserrat), Figueroa, J. (Jonine), Chanock, S. J. (Stephen J.), Lissowska, J. (Jolanta), Czene, K. (Kamila), Darabi, H. (Hatef), Eriksson, M. (Mikael), Eccles, D. M. (Diana M.), Rafiq, S. (Sajjad), Tapper, W. J. (William J.), Gerty, S. M. (Sue M.), Hooning, M. J. (Maartje J.), Martens, J. W. (John W. M.), Collee, J. M. (J. Margriet), Tilanus-Linthorst, M. (Madeleine), Hall, P. (Per), Li, J. (Jingmei), Brand, J. S. (Judith S.), Humphreys, K. (Keith), Cox, A. (Angela), Reed, M. W. (Malcolm W. R.), Luccarini, C. (Craig), Baynes, C. (Caroline), Dunning, A. M. (Alison M.), Hamann, U. (Ute), Torres, D. (Diana), Ulmer, H. U. (Hans Ulrich), Ruediger, T. (Thomas), Jakubowska, A. (Anna), Lubinski, J. (Jan), Jaworska, K. (Katarzyna), Durda, K. (Katarzyna), Slager, S. (Susan), Toland, A. E. (Amanda E.), Ambrosone, C. B. (Christine B.), Yannoukakos, D. (Drakoulis), Swerdlow, A. (Anthony), Ashworth, A. (Alan), Orr, N. (Nick), Jones, M. (Michael), Gonzalez-Neira, A. (Anna), Pita, G. (Guillermo), Rosario Alonso, M. (M.), Alvarez, N. (Nuria), Herrero, D. (Daniel), Tessier, D. C. (Daniel C.), Vincent, D. (Daniel), Bacot, F. (Francois), Simard, J. (Jacques), Dumont, M. (Martine), Soucy, P. (Penny), Eeles, R. (Rosalind), Muir, K. (Kenneth), Wiklund, F. (Fredrik), Gronberg, H. (Henrik), Schleutker, J. (Johanna), Nordestgaard, B. G. (Borge G.), Weischer, M. (Maren), Travis, R. C. (Ruth C.), Neal, D. (David), Donovan, J. L. (Jenny L.), Hamdy, F. C. (Freddie C.), Khaw, K.-T. (Kay-Tee), Stanford, J. L. (Janet L.), Blot, W. J. (William J.), Thibodeau, S. (Stephen), Schaid, D. J. (Daniel J.), Kelley, J. L. (Joseph L.), Maier, C. (Christiane), Kibel, A. S. (Adam S.), Cybulski, C. (Cezary), Cannon-Albright, L. (Lisa), Butterbach, K. (Katja), Park, J. (Jong), Kaneva, R. (Radka), Batra, J. (Jyotsna), Teixeira, M. R. (Manuel R.), Kote-Jarai, Z. (Zsofia), Al Olama, A. A. (Ali Amin), Benlloch, S. (Sara), Renner, S. P. (Stefan P.), Hartmann, A. (Arndt), Hein, A. (Alexander), Ruebner, M. (Matthias), Lambrechts, D. (Diether), Van Nieuwenhuysen, E. (Els), Vergote, I. (Ignace), Lambretchs, S. (Sandrina), Doherty, J. A. (Jennifer A.), Rossing, M. A. (Mary Anne), Nickels, S. (Stefan), Eilber, U. (Ursula), Wang-Gohrke, S. (Shan), Odunsi, K. (Kunle), Sucheston-Campbell, L. E. (Lara E.), Friel, G. (Grace), Lurie, G. (Galina), Killeen, J. L. (Jeffrey L.), Wilkens, L. R. (Lynne R.), Goodman, M. T. (Marc T.), Runnebaum, I. (Ingo), Hillemanns, P. A. (Peter A.), Pelttari, L. M. (Liisa M.), Butzow, R. (Ralf), Modugno, F. (Francesmary), Edwards, R. P. (Robert P.), Ness, R. B. (Roberta B.), Moysich, K. B. (Kirsten B.), du Bois, A. (Andreas), Heitz, F. (Florian), Harter, P. (Philipp), Kommoss, S. (Stefan), Karlan, B. Y. (Beth Y.), Walsh, C. (Christine), Lester, J. (Jenny), Jensen, A. (Allan), Kjaer, S. K. (Susanne Kruger), Hogdall, E. (Estrid), Peissel, B. (Bernard), Bonanni, B. (Bernardo), Bernard, L. (Loris), Goode, E. L. (Ellen L.), Fridley, B. L. (Brooke L.), Vierkant, R. A. (Robert A.), Cunningham, J. M. (Julie M.), Larson, M. C. (Melissa C.), Fogarty, Z. C. (Zachary C.), Kalli, K. R. (Kimberly R.), Liang, D. (Dong), Lu, K. H. (Karen H.), Hildebrandt, M. A. (Michelle A. T.), Wu, X. (Xifeng), Levine, D. A. (Douglas A.), Dao, F. (Fanny), Bisogna, M. (Maria), Berchuck, A. (Andrew), Iversen, E. S. (Edwin S.), Marks, J. R. (Jeffrey R.), Akushevich, L. (Lucy), Cramer, D. W. (Daniel W.), Schildkraut, J. (Joellen), Terry, K. L. (Kathryn L.), Poole, E. M. (Elizabeth M.), Stampfer, M. (Meir), Tworoger, S. S. (Shelley S.), Bandera, E. V. (Elisa V.), Orlow, I. (Irene), Olson, S. H. (Sara H.), Bjorge, L. (Line), Salvesen, H. B. (Helga B.), van Altena, A. M. (Anne M.), Aben, K. K. (Katja K. H.), Kiemeney, L. A. (Lambertus A.), Massuger, L. F. (Leon F. A. G.), Pejovic, T. (Tanja), Bean, Y. (Yukie), Brooks-Wilson, A. (Angela), Kelemen, L. E. (Linda E.), Cook, L. S. (Linda S.), Le, N. D. (Nhu D.), Grski, B. (Bohdan), Gronwald, J. (Jacek), Menkiszak, J. (Janusz), Hogdall, C. K. (Claus K.), Lundvall, L. (Lene), Nedergaard, L. (Lotte), Engelholm, S. A. (Svend Aage), Dicks, E. (Ed), Tyrer, J. (Jonathan), Campbell, I. (Ian), McNeish, I. (Iain), Paul, J. (James), Siddiqui, N. (Nadeem), Glasspool, R. (Rosalind), Whittemore, A. S. (Alice S.), Rothstein, J. H. (Joseph H.), McGuire, V. (Valerie), Sieh, W. (Weiva), Cai, H. (Hui), Shu, X.-O. (Xiao-Ou), Teten, R. T. (Rachel T.), Sutphen, R. (Rebecca), McLaughlin, J. R. (John R.), Narod, S. A. (Steven A.), Phelan, C. M. (Catherine M.), Monteiro, A. N. (Alvaro N.), Fenstermacher, D. (David), Lin, H.-Y. (Hui-Yi), Permuth, J. B. (Jennifer B.), Sellers, T. A. (Thomas A.), Chen, Y. A. (Y. Ann), Tsai, Y.-Y. (Ya-Yu), Chen, Z. (Zhihua), Gentry-Maharaj, A. (Aleksandra), Gayther, S. A. (Simon A.), Ramus, S. J. (Susan J.), Menon, U. (Usha), Wu, A. H. (Anna H.), Pearce, C. L. (Celeste L.), Van den Berg, D. (David), Pike, M. C. (Malcolm C.), Dansonka-Mieszkowska, A. (Agnieszka), Plisiecka-Halasa, J. (Joanna), Moes-Sosnowska, J. (Joanna), Kupryjanczyk, J. (Jolanta), Pharoah, P. D. (Paul D. P.), Song, H. (Honglin), Winship, I. (Ingrid), Chenevix-Trench, G. (Georgia), Giles, G. G. (Graham G.), Tavtigian, S. V. (Sean V.), Easton, D. F. (Doug F.), and Milne, R. L. (Roger L.)
Subjects: skin and connective tissue diseases
Abstract: Background: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p = 7.1 × 10⁻⁵), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p = 6.9 × 10⁻⁸) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p = 0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p ≤ 0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p = 0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p = 0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
Published: 2016

222. Corrigendum: Common variants at 19p13 are associated with susceptibility to ovarian cancer

Author: Bolton, KL, Tyrer, J, Song, H, Ramus, SJ, Notaridou, M, Jones, C, Sher, T, Gentry-Maharaj, A, Wozniak, E, Tsai, Y-Y, Weidhaas, J, Paik, D, Van Den Berg, DJ, Stram, DO, Pearce, CL, Wu, AH, Brewster, W, Anton-Culver, H, Ziogas, A, Narod, SA, Levine, DA, Kaye, SB, Brown, R, Paul, J, Flanagan, J, Sieh, W, McGuire, V, Whittemore, AS, Campbell, I, Gore, ME, Lissowska, J, Yang, HP, Medrek, K, Gronwald, J, Lubinski, J, Jakubowska, A, Le, ND, Cook, LS, Kelemen, LE, Brooks-Wilson, A, Massuger, LFAG, Kiemeney, LA, Aben, KKH, van Altena, AM, Houlston, R, Tomlinson, I, Palmieri, RT, Moorman, PG, Schildkraut, J, Iversen, ES, Phelan, C, Vierkant, RA, Cunningham, JM, Goode, EL, Fridley, BL, Kruger-Kjaer, S, Blaeker, J, Hogdall, E, Hogdall, C, Gross, J, Karlan, BY, Ness, RB, Edwards, RP, Odunsi, K, Moyisch, KB, Baker, JA, Modugno, F, Heikkinenen, T, Butzow, R, Nevanlinna, H, Leminen, A, Bogdanova, N, Antonenkova, N, Doerk, T, Hillemanns, P, Dürst, M, Runnebaum, I, Thompson, PJ, Carney, ME, Goodman, MT, Lurie, G, Wang-Gohrke, S, Hein, R, Chang-Claude, J, Rossing, MA, Cushing-Haugen, KL, Doherty, J, Chen, C, Rafnar, T, Besenbacher, S, Sulem, P, Stefansson, K, Birrer, MJ, Terry, KL, Hernandez, D, Cramer, DW, Vergote, I, Amant, F, Lambrechts, D, Despierre, E, Fasching, PA, Beckmann, MW, Thiel, FC, Ekici, AB, Chen, X, Australian Ovarian Cancer Study Group, Johnatty, SE, Webb, PM, Beesley, J, Chanock, S, Garcia-Closas, M, Sellers, T, Easton, DF, Berchuck, A, Chenevix-Trench, G, Pharoah, PDP, and Gayther, SA
Subjects: Australian Ovarian Cancer Study Group
Published: 2016

223. A Nonsynonymous Polymorphism in IRS1 Modifies Risk of Developing Breast and Ovarian Cancers in BRCA1 and Ovarian Cancer in BRCA2 Mutation Carriers

Author: Ding, Y.C., McGuffog, L., Healey, S., Friedman, E., Laitman, Y., Shani-Paluch-Shimon, Kaufman, B., Liljegren, A., Lindblom, A., Olsson, H., Kristoffersson, U., Stenmark-Askmalm, M., Melin, B., Domchek, S.M., Nathanson, K.L., Rebbeck, T.R., Jakubowska, A., Lubinski, J., Jaworska, K., Durda, K., Gronwald, J., Huzarski, T., Cybulski, C., Byrski, T., Osorio, A., Cajal, T.R., Stavropoulou, A.V., Benitez, J., Hamann, U., Rookus, M., Aalfs, C.M., Lange, J.L. de, Meijers-Heijboer, H.E.J., Oosterwijk, J.C., Asperen, C.J. van, Garcia, E.B.G., Hoogerbrugge, N., Jager, A., Luijt, R.B. van der, Easton, D.F., Peock, S., Frost, D., Ellis, S.D., Platte, R., Fineberg, E., Evans, D.G., Lalloo, F., Izatt, L., Eeles, R., Adlard, J., Davidson, R., Eccles, D., Cole, T., Cook, J., Brewer, C., Tischkowitz, M., Godwin, A.K., Pathak, H., Stoppa-Lyonnet, D., Sinilnikova, O.M., Mazoyer, S., Barjhoux, L., Leone, M., Gauthier-Villars, M., Caux-Moncoutier, V., Pauw, A. de, Hardouin, A., Berthet, P., Dreyfus, H., Ferrer, S.F., Collonge-Rame, M.A., Sokolowska, J., Buys, S., Daly, M., Miron, A., Terry, M.B., Chung, W., John, E.M., Southey, M., Goldgar, D., Singer, C.F., Tea, M.K.M., Gschwantler-Kaulich, D., Fink-Retter, A., Hansen, T.V.O., Ejlertsen, B., Johannsson, O.T., Offit, K., Sarrel, K., Gaudet, M.M., Vijai, J., Robson, M., Piedmonte, M.R., Andrews, L., Cohn, D., DeMars, L.R., DiSilvestro, P., Rodriguez, G., Toland, A.E., Montagna, M., Agata, S., Imyanitov, E., Isaacs, C., Janavicius, R., Lazaro, C., Blanco, I., Ramus, S.J., Sucheston, L., Karlan, B.Y., Gross, J., Ganz, P.A., Beattie, M.S., Schmutzler, R.K., Wappenschmidt, B., Meindl, A., Arnold, N., Niederacher, D., Preisler-Adams, S., Gadzicki, D., Varon-Mateeva, R., Deissler, H., Gehrig, A., Sutter, C., Kast, K., Nevanlinna, H., Aittomaki, K., Simard, J., Spurdle, A.B., Beesley, J., Chen, X.Q., Tomlinson, G.E., Weitzel, J., Garber, J.E., Olopade, O.I., Rubinstein, W.S., Tung, N., Blum, J.L., Narod, S.A., Brummel, S., Gillen, D.L., Lindor, N., Fredericksen, Z., Pankratz, V.S., Couch, F.J., Radice, P., Peterlongo, P., Greene, M.H., Loud, J.T., Mai, P.L., Andrulis, I.L., Glendon, G., Ozcelik, H., Gerdes, A.M., Thomassen, M., Jensen, U.B., Skytte, A.B., Caligo, M.A., Lee, A., Chenevix-Trench, G., Antoniou, A.C., Neuhausen, S.L., SWE-BRCA, HEBON, EMBRACE, GEMO Study Collaborators, KConFab Investigators, OCGN, Consortium Investigators Modifiers, Human genetics, CCA - Oncogenesis, Genetica & Celbiologie, RS: GROW - School for Oncology and Reproduction, Human Genetics, Cancer Center Amsterdam, Amsterdam Reproduction & Development (AR&D), Medical Oncology, Clinical Genetics, Damage and Repair in Cancer Development and Cancer Treatment (DARE), and Targeted Gynaecologic Oncology (TARGON)
Subjects: Nonsynonymous substitution, endocrine system diseases, Epidemiology, Genes, BRCA2, Genes, BRCA1, Cohort Studies, 0302 clinical medicine, Genotype, skin and connective tissue diseases, Ovarian Neoplasms, 0303 health sciences, GENETIC-VARIATION, INSULIN, 3. Good health, FAMILY, Oncology, 030220 oncology & carcinogenesis, Cohort, Female, Cohort study, EXPRESSION, AMINO-ACID POLYMORPHISM, endocrine system, PROTEINS, Hereditary cancer and cancer-related syndromes Genetics and epigenetic pathways of disease [ONCOL 1], NEOPLASIA, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Translational research [ONCOL 3], GROWTH-FACTOR-I, medicine, Humans, Genetic Predisposition to Disease, IGF, 030304 developmental biology, Hereditary cancer and cancer-related syndromes [ONCOL 1], RECEPTOR, Retrospective cohort study, medicine.disease, IRS1, Mutation, Cancer research, Insulin Receptor Substrate Proteins, Ovarian cancer
Abstract: Background: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers. Methods:IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers. Results: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06–1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39–3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28–2.70; class I HR, 0.86; 95%CI, 0.69–1.09; Pdifference, 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03). Conclusion: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers. Impact: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 21(8); 1362–70. ©2012 AACR.
Published: 2012

224. Annexin A1 expression in a pooled breast cancer series: association with tumor subtypes and prognosis

Author: Sobral-Leite, M., Wesseling, J., Smit, V.T., Nevanlinna, H., Miltenburg, M.H. van, Sanders, J., Hofland, I., Blows, F.M., Coulson, P., Patrycja, G., Schellens, J.H., Fagerholm, R., Heikkilä, P., Aittomäki, K., Blomqvist, C., Provenzano, E., Ali, H.R., Figueroa, J., Sherman, M., Lissowska, J., Mannermaa, A., Kataja, V., Kosma, V.M., Hartikainen, J.M., Phillips, K.A., Couch, F.J., Olson, J.E., Vachon, C., Visscher, D., Brenner, H., Butterbach, K., Arndt, V., Holleczek, B., Hooning, M.J., Hollestelle, A., Martens, J.W., Deurzen, C.H. van, Water, B. van de, Broeks, A., Chang-Claude, J., Chenevix-Trench, G., Easton, D.F., Pharoah, P.D., García-Closas, M., Graauw, M. de, Schmidt, M.K., Apollo - University of Cambridge Repository, Medical Oncology, and Pathology
Subjects: Adult, Medicine(all), endocrine system, Genes, BRCA2, Genes, BRCA1, Breast Neoplasms, Middle Aged, Prognosis, Immunohistochemistry, BRCA1 and BRCA2 mutations, Breast cancer, SDG 3 - Good Health and Well-being, Mutation, Biomarkers, Tumor, Humans, Female, Genetic Predisposition to Disease, skin and connective tissue diseases, Annexin A1, Research Article
Abstract: Background Annexin A1 (ANXA1) is a protein related with the carcinogenesis process and metastasis formation in many tumors. However, little is known about the prognostic value of ANXA1 in breast cancer. The purpose of this study is to evaluate the association between ANXA1 expression, BRCA1/2 germline carriership, specific tumor subtypes and survival in breast cancer patients. Methods Clinical-pathological information and follow-up data were collected from nine breast cancer studies from the Breast Cancer Association Consortium (BCAC) (n = 5,752) and from one study of familial breast cancer patients with BRCA1/2 mutations (n = 107). ANXA1 expression was scored based on the percentage of immunohistochemical staining in tumor cells. Survival analyses were performed using a multivariable Cox model. Results The frequency of ANXA1 positive tumors was higher in familial breast cancer patients with BRCA1/2 mutations than in BCAC patients, with 48.6 % versus 12.4 %, respectively; P
Published: 2015

225. Refined cut-off for TP53 immunohistochemistry improves prediction of TP53mutation status in ovarian mucinous tumors: implications for outcome analyses

Author: Kang, Eun Young, Cheasley, Dane, LePage, Cecile, Wakefield, Matthew J., da Cunha Torres, Michelle, Rowley, Simone, Salazar, Carolina, Xing, Zhongyue, Allan, Prue, Bowtell, David D.L., Mes-Masson, Anne-Marie, Provencher, Diane M., Rahimi, Kurosh, Kelemen, Linda E., Fasching, Peter A., Doherty, Jennifer A., Goodman, Marc T., Goode, Ellen L., Deen, Suha, Pharoah, Paul D.P., Brenton, James D., Sieh, Weiva, Mateoiu, Constantina, Sundfeldt, Karin, Cook, Linda S., Le, Nhu D., Anglesio, Michael S., Gilks, C. Blake, Huntsman, David G., Kennedy, Catherine J., Traficante, Nadia, Bowtell, D., Chenevix-Trench, G., Green, A., Webb, P., DeFazio, A., Gertig, D., Traficante, N., Fereday, S., Moore, S., Hung, J., Harrap, K., Sadkowsky, T., Pandeya, N., Malt, M., Mellon, A., Robertson, R., Bergh, T. Vanden, Jones, M., Mackenzie, P., Maidens, J., Nattress, K., Chiew, Y.E., Stenlake, A., Sullivan, H., Alexander, B., Ashover, P., Brown, S., Corrish, T., Green, L., Jackman, L., Ferguson, K., Martin, K., Martyn, A., Ranieri, B., White, J., Jayde, V., Mamers, P., Bowes, L., Galletta, L., Giles, D., Hendley, J., Alsop, K., Schmidt, T., Shirley, H., Ball, C., Young, C., Viduka, S., Tran, Hoa, Bilic, Sanela, Glavinas, Lydia, Brooks, Julia, Stuart-Harris, R., Kirsten, F., Rutovitz, J., Clingan, P., Glasgow, A., Proietto, A., Braye, S., Otton, G., Shannon, J., Bonaventura, T., Stewart, J., Begbie, S., Friedlander, M., Bell, D., Baron-Hay, S., Ferrier, A., Gard, G., Nevell, D., Pavlakis, N., Valmadre, S., Young, B., Camaris, C., Crouch, R., Edwards, L., Hacker, N., Marsden, D., Robertson, G., Beale, P., Beith, J., Carter, J., Dalrymple, C., Houghton, R., Russell, P., Links, M., Grygiel, J., Hill, J., Brand, A., Byth, K., Jaworski, R., Harnett, P., Sharma, R., Wain, G., Ward, B., Papadimos, D., Crandon, A., Cummings, M., Horwood, K., Obermair, A., Perrin, L., Wyld, D., Nicklin, J., Davy, M., Oehler, M.K., Hall, C., Dodd, T., Healy, T., Pittman, K., Henderson, D., Miller, J., Pierdes, J., Blomfield, P., Challis, D., McIntosh, R., Parker, A., Brown, B., Rome, R., Allen, D., Grant, P., Hyde, S., Laurie, R., Robbie, M., Healy, D., Jobling, T., Manolitsas, T., McNealage, J., Rogers, P., Susil, B., Sumithran, E., Simpson, I., Phillips, K., Rischin, D., Fox, S., Johnson, D., Lade, S., Loughrey, M., O'Callaghan, N., Murray, W., Waring, P., Billson, V., Pyman, J., Neesham, D., Quinn, M., Underhill, C., Bell, R., Ng, L.F., Blum, R., Ganju, V., Hammond, I., Leung, Y., McCartney, A., Buck, M., Haviv, I., Purdie, D., Whiteman, D., Zeps, N., DeFazio, Anna, Kaufmann, Scott, Churchman, Michael, Gourley, Charlie, Stephens, Andrew N., Meagher, Nicola S., Ramus, Susan J., Antill, Yoland C., Campbell, Ian, Scott, Clare L., Köbel, Martin, Gorringe, Kylie L., Cheasley, Dane, Wakefield, Matthew J., Ryland, Georgina L., Allan, Prue E., Alsop, Kathryn, Ananda, Sumitra, Anglesio, Michael S., Au-Yeung, George, Böhm, Maret, Bowtell, David D.L., Brand, Alison, Chenevix-Trench, Georgia, Christie, Michael, Chiew, Yoke-Eng, Churchman, Michael, DeFazio, Anna, Dudley, Rhiannon, Fairweather, Nicole, Fereday, Sian, Fox, Stephen B., Gilks, C. Blake, Gourley, Charlie, Hacker, Neville F., Hadley, Alison M., Hendley, Joy, Ho, Gwo-Yaw, Huntsman, David G., Hunter, Sally M., Jobling, Tom W., Kalli, Kimberly R., Kaufmann, Scott H., Kennedy, Catherine J., Köbel, Martin, Le Page, Cecile, McNally, Orla M., McAlpine, Jessica N., Mes-Masson, Anne-Marie, Mileshkin, Linda, Provencher, Diane M., Pyman, Jan, Rahimi, Kurosh, Samimi, Goli, Sharma, Ragwha, Stephens, Andrew N., Traficante, Nadia, Antill, Yoland C., Scott, Clare L., Campbell, Ian G., and Gorringe, Kylie L.
Abstract: TP53mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53mutation status in ovarian mucinous tumors and to evaluate the association of TP53mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5–14.3, p= 0.0087). Within MOC, 61.1% (259/424) harbored a TP53mutation, but this was not associated with survival (overall survival, p= 0.77). TP53 IHC is an accurate proxy for TP53mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53mutation status is an important biomarker to identify MBOT with a higher risk of mortality.
Published: 2021
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226. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair

Author: Day, FR, Ruth, KS, Thompson, DJ, Lunetta, KL, Pervjakova, N, Chasman, DI, Stolk, L, Finucane, HK, Sulem, P, Bulik-Sullivan, B, Esko, T, Johnson, AD, Elks, CE, Franceschini, N, He, C, Altmaier, E, Brody, JA, Franke, LL, EHuffman, J, Keller, MF, McArdle, PF, Nutile, T, Porcu, E, Robino, A, Rose, LM, Schick, UM, Smith, JA, Teumer, A, Traglia, M, Vuckovic, D, Yao, J, Zhao, W, Albrecht, E, Amin, N, Corre, T, Hottenga, JJ, Mangino, M, Smith, AV, Tanaka, T, Abecasis, GR, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Arndt, V, Arnold, AM, Barbieri, C, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bernstein, L, Bielinski, SJ, Blomqvist, C, Boerwinkle, E, Bogdanova, NV, Bojesen, SE, Bolla, MK, Borresen-Dale, AL, Boutin, TS, Brauch, H, Brenner, H, Brüning, T, Burwinkel, B, Campbell, A, Campbell, H, Chanock, SJ, Chapman, JR, Chen, YDI, Chenevix-Trench, G, and Couch, FJ
Abstract: © 2015 Nature America, Inc. Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in -1/470,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (-1/46% increase in risk per year; P = 3 × 10 -14), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.
Published: 2015

227. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

Author: Lawrenson, K, Li, Q, Kar, S, Seo, JH, Tyrer, J, Spindler, TJ, Lee, J, Chen, Y, Karst, A, Drapkin, R, Aben, KKH, Anton-Culver, H, Antonenkova, N, Baker, H, Bandera, EV, Bean, Y, Beckmann, MW, Berchuck, A, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Chenevix-Trench, G, Chen, A, Chen, Z, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Dicks, E, Doherty, JA, Dörk, T, Du Bois, A, Dürst, M, Eccles, D, Easton, DT, Edwards, RP, Eilber, U, Ekici, AB, Fasching, PA, Fridley, BL, Gao, YT, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goode, EL, Goodman, MT, Grownwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, E, Hogdall, C, Hosono, S, Iversen, ES, Jakubowska, A, James, P, Jensen, A, Ji, BT, Karlan, BY, Kjaer, SK, Kelemen, LE, Kellar, M, Kelley, JL, Kiemeney, LA, Krakstad, C, Kupryjanczyk, J, and Lambrechts, D
Abstract: © 2015 Macmillan Publishers Limited. All rights reserved. Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10-5). For three cis-eQTL associations (P
Published: 2015

228. No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing

Author: Easton, D.F., Lesueur, F., Decker, B., Michailidou, K., Li, J., Allen, J., Luccarini, C., Pooley, K.A., Shah, M., Bolla, M.K., Wang, Q., Dennis, J., Ahmad, J., Thompson, E.R., Damiola, F., Pertesi, M., Voegele, C., Mebirouk, N., Robinot, N., Durand, G., Forey, N., Luben, R.N., Ahmed, S., Aittomaki, K., Anton-Culver, H., Arndt, V., Baynes, C., Beckman, M.W., Benitez, J., Berg, D. van den, Blot, W.J., Bogdanova, N.V., Bojesen, S.E., Brenner, H., Chang-Claude, J., Chia, K.S., Choi, J.Y., Conroy, D.M., Cox, A., Cross, S.S., Czene, K., Darabi, H., Devilee, P., Eriksson, M., Fasching, P.A., Figueroa, J., Flyger, H., Fostira, F., Garcia-Closas, M., Giles, G.G., Glendon, G., Gonzalez-Neira, A., Guenel, P., Haiman, C.A., Hall, P., Hart, S.N., Hartman, M., Hooning, M.J., Hsiung, C.N., Ito, H., Jakubowska, A., James, P.A., John, E.M., Johnson, N., Jones, M., Kabisch, M., Kang, D., Kosma, V.M., Kristensen, V., Lambrechts, D., Li, N., Lindblom, A., Long, J., Lophatananon, A., Lubinski, J., Mannermaa, A., Manoukian, S., Margolin, S., Matsuo, K., Meindl, A., Mitchell, G., Muir, K., Nevelsteen, I., Ouweland, A. van den, Peterlongo, P., Phuah, S.Y., Pylkas, K., Rowley, S.M., Sangrajrang, S., Schmutzler, R.K., Shen, C.Y., Shu, X.O., Southey, M.C., Surowy, H., Swerdlow, A., Teo, S.H., Tollenaar, R.A.E.M., Tomlinson, I., Torres, D., Truong, T., Vachon, C., Verhoef, S., Wong-Brown, M., Zheng, W., Zheng, Y., Nevanlinna, H., Scott, R.J., Andrulis, I.L., Wu, A.H., Hopper, J.L., Couch, F.J., Winqvist, R., Burwinkel, B., Sawyer, E.J., Schmidt, M.K., Rudolph, A., Dork, T., Brauch, H., Hamann, U., Neuhausen, S.L., Milne, R.L., Fletcher, O., Pharoah, P.D.P., Campbell, I.G., Dunning, A.M., Calvez-Kelm, F. le, Goldgar, D.E., Tavtigian, S.V., Chenevix-Trench, G., Australian Ovarian Canc Study Grp, kConFab Investigators, Lifepool Investigators, NBCS Investigators, Luben, Robert N [0000-0002-5088-6343], Apollo - University of Cambridge Repository, Clinical Genetics, Medical Oncology, and Molecular Genetics
Subjects: 0301 basic medicine, Bioinformatics, Medical and Health Sciences, Cohort Studies, Breast cancer screening, 0302 clinical medicine, Medizinische Fakultät, Missense mutation, Genetics (clinical), Genetics & Heredity, education.field_of_study, medicine.diagnostic_test, Biological Sciences, Middle Aged, Fanconi Anemia Complementation Group Proteins, 3. Good health, ddc, DNA-Binding Proteins, 030220 oncology & carcinogenesis, kConFab Investigators, Female, RNA Helicases, Australian Ovarian Cancer Study Group, Adult, Risk, medicine.medical_specialty, PALB2, Population, European Continental Ancestry Group, Breast Neoplasms, NBCS Investigators, Biology, Article, White People, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Molecular genetics, Genetics, medicine, breast [Cancer], Humans, Genetic Predisposition to Disease, Genetic Testing, ddc:610, Allele, education, Genetic Association Studies, Aged, Cancer: breast, BRIP1, medicine.disease, 030104 developmental biology, Lifepool Investigators, Mutation
Abstract: Background: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. Methods: We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. Results: The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). Conclusions: These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.
Published: 2015

229. Cell-type-specific enrichment of risk-associated regulatory elements at ovarian cancer susceptibility loci

Author: Coetzee, SG, Shen, HC, Hazelett, DJ, Lawrenson, K, Kuchenbaecker, K, Tyrer, J, Rhie, SK, Levanon, K, Karst, A, Drapkin, R, Ramus, SJ, Couch, FJ, Offit, K, Chenevix-Trench, G, Monteiro, ANA, Antoniou, A, Freedman, M, Coetzee, GA, Pharoah, PDP, Noushmehr, H, Gayther, SA, Anton-Culver, H, Antonenkova, N, Baker, H, Bandera, EV, Bean, Y, Beckmann, MW, Berchuck, A, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Chen, A, Chen, Z, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Dicks, E, Doherty, JA, Dörk, T, Bois, AD, Dürst, M, Eccles, D, Easton, DF, Edwards, RP, Eilber, U, Ekici, AB, Fasching, PA, Fridley, BL, Gao, YT, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goode, EL, Goodman, MT, Grownwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, E, Hogdall, C, Hosono, S, Iversen, ES, Jakubowska, A, James, P, Jensen, A, Ji, BT, Karlan, BY, Kjaer, SK, Kelemen, LE, Kellar, M, Kelley, JL, Kiemeney, LA, Krakstad, C, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lele, S, Leminen, A, and Lester, J
Abstract: © The Author 2015. Published by Oxford University Press. All rights reserved. Understanding the regulatory landscape of the human genome is a central question in complex trait genetics. Most singlenucleotide polymorphisms (SNPs) associated with cancer risk lie in non-protein-coding regions, implicating regulatory DNA elements as functional targets of susceptibility variants. Here, we describe genome-wide annotation of regions of open chromatin and histone modification in fallopian tube and ovarian surface epithelial cells (FTSECs, OSECs), the debated cellular origins of high-grade serous ovarian cancers (HGSOCs) and in endometriosis epithelial cells (EECs), the likely precursor of clear cell ovarian carcinomas (CCOCs). The regulatory architecture of these cell types was compared with normal human mammary epithelial cells and LNCaP prostate cancer cells. We observed similar positional patterns of global enhancer signatures across the three different ovarian cancer precursor cell types, and evidence of tissue-specific regulatory signatures compared to nongynecological cell types. We found significant enrichment for risk-associated SNPs intersecting regulatory biofeatures at 17 known HGSOC susceptibility loci in FTSECs (P = 3.8 × 10-30), OSECs (P = 2.4 × 10-23) and HMECs (P = 6.7 × 10-15) but not for EECs (P = 0.45) or LNCaP cells (P = 0.88). Hierarchical clustering of risk SNPs conditioned on the six different cell types indicates FTSECs and OSECs are highly related (96% of samples using multi-scale bootstrapping) suggesting both cell types may be precursors of HGSOC. These data represent the first description of regulatory catalogues of normal precursor cells for different ovarian cancer subtypes, and provide unique insights into the tissue specific regulatory variation with respect to the likely functional targets of germline genetic susceptibility variants for ovarian cancer.
Published: 2015

230. Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants

Author: Mavaddat, N., Pharoah, P.D.P., Michailidou, K., Tyrer, J., Brook, M.N., Bolla, M.K., Wang, Q., Dennis, J., Dunning, A.M., Shah, M., Luben, R., Brown, J., Bojesen, S.E., Nordestgaard, B.G., Nielsen, S.F., Flyger, H., Czene, K., Darabi, H., Eriksson, M., Peto, J., dos-Santos-Silva, I., Dudbridge, F., Johnson, N., Schmidt, M.K., Broeks, A., Verhoef, S., Rutgers, E.J., Swerdlow, A., Ashworth, A., Orr, N., Schoemaker, M.J., Figueroa, J., Chanock, S.J., Brinton, L., Lissowska, J., Couch, F.J., Olson, J.E., Vachon, C., Pankratz, V.S., Lambrechts, D., Wildiers, H., Ongeval, C. van, Limbergen, E. van, Kristensen, V., Alnaes, G.G., Nord, S., Borresen-Dale, A.L., Nevanlinna, H., Muranen, T.A., Aittomaki, K., Blomqvist, C., Chang-Claude, J., Rudolph, A., Seibold, P., Flesch-Janys, D., Fasching, P.A., Haeberle, L., Ekici, A.B., Beckmann, M.W., Burwinkel, B., Marme, F., Schneeweiss, A., Sohn, C., Trentham-Dietz, A., Newcomb, P., Titus, L., Egan, K.M., Hunter, D.J., Lindstrom, S., Tamimi, R.M., Kraft, P., Rahman, N., Turnbull, C., Renwick, A., Seal, S., Li, J.M., Liu, J.J., Humphreys, K., Benitez, J., Zamora, M.P., Perez, J.I.A., Menendez, P., Jakubowska, A., Lubinski, J., Jaworska-Bieniek, K., Durda, K., Bogdanova, N.V., Antonenkova, N.N., Dork, T., Anton-Culver, H., Neuhausen, S.L., Ziogas, A., Bernstein, L., Devilee, P., Tollenaar, R.A.E.M., Seynaeve, C., Asperen, C.J. van, Cox, A., Cross, S.S., Reed, M.W.R., Khusnutdinova, E., Bermisheva, M., Prokofyeva, D., Takhirova, Z., Meindl, A., Schmutzler, R.K., Sutter, C., Yang, R.X., Schurmann, P., Bremer, M., Christiansen, H., Park-Simon, T.W., Hillemanns, P., Guenel, P., Truong, T., Menegaux, F., Sanchez, M., Radice, P., Peterlongo, P., Manoukian, S., Pensotti, V., Hopper, J.L., Tsimiklis, H., Apicella, C., Southey, M.C., Brauch, H., Bruning, T., Ko, Y.D., Sigurdson, A.J., Doody, M.M., Hamann, U., Torres, D., Ulmer, H.U., Forsti, A., Sawyer, E.J., Tomlinson, I., Kerin, M.J., Miller, N., Andrulis, I.L., Knight, J.A., Glendon, G., Mulligan, A.M., Chenevix-Trench, G., Balleine, R., Giles, G.G., Milne, R.L., McLean, C., Lindblom, A., Margolin, S., Haiman, C.A., Henderson, B.E., Schumacher, F., Marchand, L. le, Eilber, U., Wang-Gohrke, S., Hooning, M.J., Hollestelle, A., Ouweland, A.M.W. van den, Koppert, L.B., Carpenter, J., Clarke, C., Scott, R., Mannermaa, A., Kataja, V., Kosma, V.M., Hartikainen, J.M., Brenner, H., Arndt, V., Stegmaier, C., Dieffenbach, A.K., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Offit, K., Vijai, J., Robson, M., Rau-Murthy, R., Dwek, M., Swann, R., Perkins, K.A., Goldberg, M.S., Labreche, F., Dumont, M., Eccles, D.M., Tapper, W.J., Rafiq, S., John, E.M., Whittemore, A.S., Slager, S., Yannoukakos, D., Toland, A.E., Yao, S., Zheng, W., Halverson, S.L., Gonzalez-Neira, A., Pita, G., Alonso, M.R., Alvarez, N., Herrero, D., Tessier, D.C., Vincent, D., Bacot, F., Luccarini, C., Baynes, C., Ahmed, S., Maranian, M., Healey, C.S., Simard, J., Hall, P., Easton, D.F., Garcia-Closas, M., Clinical Genetics, Medical Oncology, Surgery, Department of Obstetrics and Gynecology, Clinicum, Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, Department of Oncology, HUS Gynecology and Obstetrics, Mavaddat, Nasim [0000-0003-0307-055X], Pharoah, Paul [0000-0001-8494-732X], Tyrer, Jonathan [0000-0003-3724-4757], Wang, Jean [0000-0002-9139-0627], Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Luben, Robert [0000-0002-5088-6343], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository
Subjects: Adult, Genotype, 3122 Cancers, Breast Neoplasms, consortium, Polymorphism, Single Nucleotide, Risk Assessment, Article, prevention, SDG 3 - Good Health and Well-being, Predictive Value of Tests, Risk Factors, 3123 Gynaecology and paediatrics, Biomarkers, Tumor, Odds Ratio, Humans, Genetic Predisposition to Disease, family-history, Aged, prostate, Gene Expression Profiling, subtypes, Middle Aged, susceptibility loci, Europe, Gene Expression Regulation, Neoplastic, Receptors, Estrogen, Tumor Markers, Biological, Cancer and Oncology, genome-wide association, Female, women
Abstract: Background: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. Methods: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. Results: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1 of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. Conclusions: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report. © 2015 © The Author 2015. Published by Oxford University Press.
Published: 2015

231. Identification of novel genetic markers of breast cancer survival

Author: Guo, Q., Schmidt, M.K., Kraft, P., Canisius, S., Chen, C., Khan, S., Tyrer, J., Bolla, M.K., Wang, Q., Dennis, J., Michailidou, K., Lush, M., Kar, S., Beesley, J., Dunning, A.M., Shah, M., Czene, K., Darabi, H., Eriksson, M., Lambrechts, D., Weltens, C., Leunen, K., Bojesen, S.E., Nordestgaard, B.G., Nielsen, S.F., Flyger, H., Chang-Claude, J., Rudolph, A., Seibold, P., Flesch-Janys, D., Blomqvist, C., Aittomaki, K., Fagerholm, R., Muranen, T.A., Couch, F.J., Olson, J.E., Vachon, C., Andrulis, I.L., Knight, J.A., Glendon, G., Mulligan, A.M., Broeks, A., Hogervorst, F.B., Haiman, C.A., Henderson, B.E., Schumacher, F., Marchand, L. le, Hopper, J.L., Tsimiklis, H., Apicella, C., Southey, M.C., Cox, A., Cross, S.S., Reed, M.W.R., Giles, G.G., Milne, R.L., McLean, C., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Hooning, M.J., Hollestelle, A., Martens, J.W.M., Ouweland, A.M.W. van den, Marme, F., Schneeweiss, A., Yang, R.X., Burwinkel, B., Figueroa, J., Chanock, S.J., Lissowska, J., Sawyer, E.J., Tomlinson, I., Kerin, M.J., Miller, N., Brenner, H., Dieffenbach, A.K., Arndt, V., Holleczek, B., Mannermaa, A., Kataja, V., Kosma, V.M., Hartikainen, J.M., Li, J.M., Brand, J.S., Humphreys, K., Devilee, P., Tollenaar, R.A.E.M., Seynaeve, C., Radice, P., Peterlongo, P., Bonanni, B., Mariani, P., Fasching, P.A., Beckmann, M.W., Hein, A., Ekici, A.B., Chenevix-Trench, G., Balleine, R., Phillips, K.A., Benitez, J., Zamora, M.P., Perez, J.I.A., Menendez, P., Jakubowska, A., Lubinski, J., Jaworska-Bieniek, K., Durda, K., Hamann, U., Kabisch, M., Ulmer, H.U., Rudiger, T., Margolin, S., Kristensen, V., Nord, S., Evans, D.G., Abraham, J.E., Earl, H.M., Hiller, L., Dunn, J.A., Bowden, S., Berg, C., Campa, D., Diver, W.R., Gapstur, S.M., Gaudet, M.M., Hankinson, S.E., Hoover, R.N., Husing, A., Kaaks, R., Machiela, M.J., Willett, W., Barrdahl, M., Canzian, F., Chin, S.F., Caldas, C., Hunter, D.J., Lindstrom, S., Garcia-Closas, M., Hall, P., Easton, D.F., Eccles, D.M., Rahman, N., Nevanlinna, H., Pharoah, P.D.P., kConFab Investigators, Tyrer, Jonathan [0000-0003-3724-4757], Wang, Jean [0000-0002-9139-0627], Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Abraham, Jean [0000-0003-0688-4807], Earl, Helena [0000-0003-1549-8094], Chin, Suet-Feung [0000-0001-5697-1082], Caldas, Carlos [0000-0003-3547-1489], Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: Genetic Markers, Genotype, Receptors, Estrogen, Humans, Breast Neoplasms, Female, Genetic Predisposition to Disease, Prognosis, Polymorphism, Single Nucleotide, Survival Analysis, White People
Abstract: BACKGROUND: Survival after a diagnosis of breast cancer varies considerably between patients, and some of this variation may be because of germline genetic variation. We aimed to identify genetic markers associated with breast cancer-specific survival. METHODS: We conducted a large meta-analysis of studies in populations of European ancestry, including 37954 patients with 2900 deaths from breast cancer. Each study had been genotyped for between 200000 and 900000 single nucleotide polymorphisms (SNPs) across the genome; genotypes for nine million common variants were imputed using a common reference panel from the 1000 Genomes Project. We also carried out subtype-specific analyses based on 6881 estrogen receptor (ER)-negative patients (920 events) and 23059 ER-positive patients (1333 events). All statistical tests were two-sided. RESULTS: We identified one new locus (rs2059614 at 11q24.2) associated with survival in ER-negative breast cancer cases (hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.55 to 2.47, P = 1.91 x 10(-8)). Genotyping a subset of 2113 case patients, of which 300 were ER negative, provided supporting evidence for the quality of the imputation. The association in this set of case patients was stronger for the observed genotypes than for the imputed genotypes. A second locus (rs148760487 at 2q24.2) was associated at genome-wide statistical significance in initial analyses; the association was similar in ER-positive and ER-negative case patients. Here the results of genotyping suggested that the finding was less robust. CONCLUSIONS: This is currently the largest study investigating genetic variation associated with breast cancer survival. Our results have potential clinical implications, as they confirm that germline genotype can provide prognostic information in addition to standard tumor prognostic factors.
Published: 2015

232. Common germline polymorphisms\ud associated with breast cancer-specific survival

Author: Pirie, A., Guo, Q., Kraft, P., Canisius, S., Eccles, D.M., Rahman, N., Nevanlinna, H., Chen, C., Khan, S., Tyrer, J., Bolla, M.K., Wang, Q., Dennis, J., Michailidou, K., Lush, M., Dunning, A.M., Shah, M., Czene, K., Darabi, H., Eriksson, M., Lambrechts, D., Weltens, C., Leunen, K., van Ongeval, C., Nordestgaard, B.G., Nielsen, S.F., Flyger, H., Rudolph, A., Seibold, P., Flesch-Janys, D., Blomqvist, C., Aittomaki, K., Fagerholm, R., Muranen, T.A., Olsen, J.E., Hallberg, E., Vachon, C., Knight, J.A., Glendon, G., Mulligan, A.M., Broeks, A., Cornelissen, S., Haiman, C.A., Henderson, B.E., Schumacher, F., Le Marchand, L., Hopper, J.L., Tsimiklis, H., Apicella, C., Southey, M.C., Cross, S.S., Reed, M.W.R., Giles, G.G., Milne, R.L., McLean, C., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Hooning, M.J., Hollestelle, A., Martens, J.W.M., van den Ouweland, A.M.W., Marme, F., Schneeweiss, A., Yang, R., Burwinkel, B., Figueroa, J., Chanock, S.J., Lissowska, J., Sawyer, E.J., Tomlinson, I., Kerin, M.J., Miller, N., Brenner, H., Butterbach, K., Holleczek, B., Kataja, V., Kosma, V-M., Hartikainen, J.M., Li, J., Brand, J.S., Humphreys, K., Devilee, P., Tollenaar, R.A.E.M., Seynaeve, C., Radice, P., Peterlongo, P., Manoukian, S., Ficarazzi, F., Beckmann, M.W., Hein, A., Ekici, A.B., Balleine, R., Phillips, K-A., Benitez, J., Zamora, M.P., Perez, J.I.A., Menendez, P., Jakubowska, A., Lubinski, J., Gronwald, J., Durda, K., Hamann, U., Kabisch, M., Ulmer, H.U., Ruediger, T., Margolin, S., Kristensen, V., Nord, S., Evans, D.G., Abraham, J., Earl, H., Poole, C.J., Hiller, L., Dunn, J.A., Bowden, S., Campa, D., Diver, W.R., Gapstur, S.M., Gaudet, M.M., Hankinson, S., Hoover, R.N., Husing, A., Kaaks, R., Machiela, M.J., Willett, W., Barrdahl, M., Canzian, F., Chin, S-F., Caldas, C., Hunter, D.J., Lindstrom, S., Garcia-Closas, M., Couch, F.J., Investigators, kConFab, Chenevix-Trench, G., Mannermaa, A., Andrulis, I.L., Hall, P., Chang-Claude, J., Easton, D.F., Bojesen, S.E., Cox, A., Fasching, P.A., Pharoah, P.D.P., Schmidt, M.K., and Investigators, NBCS
Abstract: Introduction: Previous studies have identified common germline variants nominally associated with breast cancer\ud survival. These associations have not been widely replicated in further studies. The purpose of this study was to\ud evaluate the association of previously reported SNPs with breast cancer-specific survival using data from a pooled\ud analysis of eight breast cancer survival genome-wide association studies (GWAS) from the Breast Cancer Association\ud Consortium.\ud Methods: A literature review was conducted of all previously published associations between common germline\ud variants and three survival outcomes: breast cancer-specific survival, overall survival and disease-free survival.\ud All associations that reached the nominal significance level of P value
Published: 2015

233. Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers

Author: Blanco, I., Kuchenbaecker, K., Cuadras, D., Wang, X.S., Barrowdale, D., Garibay, G.R., Librado, P., Sanchez-Gracia, A., Rozas, J., Bonifaci, N., McGuffog, L., Pankratz, V.S., Islam, A., Mateo, F., Berenguer, A., Petit, A., Catala, I., Brunet, J., Feliubadalo, L., Tornero, E., Benitez, J., Osorio, A., Cajal, T.R.Y., Nevanlinna, H., Aittomaki, K., Arun, B.K., Toland, A.E., Karlan, B.Y., Walsh, C., Lester, J., Greene, M.H., Mai, P.L., Nussbaum, R.L., Andrulis, I.L., Domchek, S.M., Nathanson, K.L., Rebbeck, T.R., Barkardottir, R.B., Jakubowska, A., Lubinski, J., Durda, K., Jaworska-Bieniek, K., Claes, K., Maerken, T. van, Diez, O., Hansen, T.V., Jonson, L., Gerdes, A.M., Ejlertsen, B., Hoya, M. de la, Caldees, T., Dunning, A.M., Oliver, C., Fineberg, E., Cook, M., Peock, S., McCann, E., Murray, A., Jacobs, C., Pichert, G., Lalloo, F., Chu, C., Dorkins, H., Paterson, J., Ong, K.R., Teixeira, M.R., Teixeira, Hogervorst, F.B.L., Hout, A.H. van der, Seynaeve, C., Luijt, R.B. van der, Ligtenberg, M.J.L., Devilee, P., Wijnen, J.T., Rookus, M.A., Meijers-Heijboer, H.E.J., Blok, M.J., Ouweland, A.M.W. van den, Aalfs, C.M., Rodriguez, G.C., Phillips, K.A.A., Piedmonte, M., Nerenstone, S.R., Bae-Jump, V.L., O'Malley, D.M., Ratner, E.S., Schmutzler, R.K., Wappenschmidt, B., Rhiem, K., Engel, C., Meindl, A., Ditsch, N., Arnold, N., Plendl, H.J., Niederacher, D., Sutter, C., Wang-Gohrke, S., Steinemann, D., Preisler-Adams, S., Kast, K., Varon-Mateeva, R., Gehrig, A., Bojesen, A., Pedersen, I.S., Sunde, L., Jensen, U.B., Thomassen, M., Kruse, T.A., Foretova, L., Peterlongo, P., Bernard, L., Peissel, B., Scuvera, G., Manoukian, S., Radice, P., Ottini, L., Montagna, M., Agata, S., Maugard, C., Simard, J., Soucy, P., Berger, A., Fink-Retter, A., Singer, C.F., Rappaport, C., Geschwantler-Kaulich, D., Tea, M.K., Pfeiler, G., John, E.M., Miron, A., Neuhausen, S.L., Terry, M.B., Chung, W.K., Daly, M.B., Goldgar, D.E., Janavicius, R., Dorfling, C.M., Rensburg, E.J. van, Fostira, F., Konstantopoulou, I., Garber, J., Godwin, A.K., Olah, E., Narod, S.A., Rennert, G., Paluch, S.S., Laitman, Y., Friedman, E., Liljegren, A., Rantala, J., Stenmark-Askmalm, M., Loman, N., Imyanitov, E.N., Hamann, U., Spurdle, A.B., Healey, S., Weitzel, J.N., Herzog, J., Margileth, D., Gorrini, C., Esteller, M., Gomez, A., Sayols, S., Vidal, E., Heyn, H., Stoppa-Lyonnet, Leone, M., Barjhoux, L., Fassy-Colcombet, M., Pauw, A. de, Lasset, C., Ferrer, S.F., Castera, L., Berthet, P., Cornelis, F., Bignon, Y.J., Damiola, F., Mazoyer, S., Sinilnikova, O.M., Maxwell, C.A., Vijai, J., Robson, M., Kauff, N., Corines, M.J., Villano, D., Cunningham, J., Lee, A., Lindor, N., Lazaro, C., Easton, D.F., Offit, K., Chenevix-Trench, G., Couch, F.J., Antoniou, A.C., Pujana, M.A., BCFR, SWE-BRCA, KConFab Investigators, GEMO, Human genetics, CCA - Oncogenesis, Medical Oncology, Clinical Genetics, Suzuki, Hiromu, MUMC+: DA KG Lab Centraal Lab (9), RS: GROW - Oncology, RS: GROW - R4 - Reproductive and Perinatal Medicine, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Human Genetics, Department of Obstetrics and Gynecology, Clinicum, Medicum, Haartman Institute (-2014), and Department of Medical and Clinical Genetics
Subjects: single nucleotide, Oncology, Carcinogenesis, TUBG1, Genes, BRCA2, Genes, BRCA1, Càncer d'ovari, MODIFIERS, Genome-wide association study, Cell Cycle Proteins, Breast cancer, mammary glands, Aetiology, genes, skin and connective tissue diseases, Cancer, Extracellular Matrix Proteins, Hazard ratio, CHIP-SEQ, 3. Good health, ddc, Hyaluronan Receptors, Medicine, Teixeira, Human, medicine.medical_specialty, Evolution, Science, Non-P.H.S, Single-nucleotide polymorphism, Evolution, Molecular, SDG 3 - Good Health and Well-being, Ovarian cancer, Genetics, biochemistry, Humans, human, CELL, Polymorphism, GENOME-WIDE ASSOCIATION, medicine (all), Retrospective Studies, Cancer och onkologi, Prevention, Mutació (Biologia), Biology and Life Sciences, Molecular, SWE-BRCA, BRCA1, medicine.disease, BRCA2, POLYMORPHISM, Genes, Genetic Loci, Cancer and Oncology, Mutation, U.S. Gov't, Bioinformatics, medicine.disease_cause, 3123 Gynaecology and paediatrics, Tubulin, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], ELEMENTS, 2.1 Biological and endogenous factors, CD44, Non-U.S. Gov't, Aurora Kinase A, Likelihood Functions, Multidisciplinary, Research Support, Non-U.S. Gov't, agricultural and biological sciences (all), genetics and molecular biology (all), BCFR, Nuclear Proteins, Single Nucleotide, Mammary Glands, SURVIVAL, kConFab Investigators, Female, Microtubule-Associated Proteins, Research Article, Antigens, CD44, aurora kinase A, breast neoplasms, carcinogenesis, cell cycle proteins, estrogen receptor alpha, evolution, molecular, extracellular matrix proteins, female, genetic loci, genetic predisposition to disease, humans, likelihood functions, mammary glands, human, microtubule-associated proteins, nuclear proteins, polymorphism, retrospective studies, tubulin, genes, BRCA1, genes, BRCA2, mutation, biochemistry, genetics and molecular biology (all), SUSCEPTIBILITY LOCI, General Science & Technology, 3122 Cancers, Breast Neoplasms, Biology, Research Support, Polymorphism, Single Nucleotide, N.I.H, GENETIC INTERACTION NETWORKS, Càncer de mama, EXPRESSION SIGNATURE, Amino acid sequence, Research Support, N.I.H., Extramural, Internal medicine, Seqüència d'aminoàcids, evolution, Genetic variation, Journal Article, medicine, Genetic Predisposition to Disease, ddc:610, molecular, Antigens, Mammary Glands, Human, ddc:611, Intramural, Estrogen Receptor alpha, Extramural, Mutation (Biology), Research Support, N.I.H., Intramural, 3111 Biomedicine, GEMO, Research Support, U.S. Gov't, Non-P.H.S
Abstract: While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04 - 1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03 - 1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted p(interaction) values greater than 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers. Funding Agencies|National Cancer Institute [UM1 CA164920]; Lithuania (BFBOCC-LT): Research Council of Lithuania grant [LIG-07/2012]; Hereditary Cancer Association (Paveldimo vezio asociacija); LSC grant [10.0010.08]; ESF [2009/0220/1DP/1.1.1.2.0/09/APIA/VIAA/016]; Liepajas municipal council; Cancer Association of South Africa (CANSA); Morris and Horowitz Familes Endowed Professorship; NEYE Foundation; Spanish Association against Cancer [AECC08, RTICC 06/0020/1060, FISPI08/1120]; Mutua Madrilena Foundation (FMMA); COH-CCGCRN: City of Hope Clinical Cancer Genetics Community Network from the National Cancer Institute and the Office of the Director, National Institutes of Health; Hereditary Cancer Research Registry from the National Cancer Institute and the Office of the Director, National Institutes of Health [RC4CA153828]; Fondazione IRCCS Istituto Nazionale Tumori; Cancer Research-United Kingdom grant [C12292/A11174, C1287/ A10118]; NHMRC Program Grant; DKFZ; European Union (European Social Fund-ESF); Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF)-Research Funding Program of the General Secretariat for Research and Technology: ARISTEIA; European Social Fund; Cancer Research United Kingdom Grants [C1287/A10118, C1287/A11990]; National Institute of Health Research (NIHR) grant; NIHR grant; Royal Marsden NHS Foundation Trust; Cancer Research United Kingdom Grant [C5047/A8385]; University of Kansas Cancer Center [P30 CA168524]; Kansas Bioscience Authority Eminent Scholar Program; Chancellors Distinguished Chair in Biomedical Sciences Professorship; AKG [5U01CA113916, R01CA140323]; German Cancer Aid [109076]; Center for Molecular Medicine Cologne (CMMC); Ligue National Contre le Cancer; Association "Le cancer du sein, parlonsen!" Award; Canadian Institutes of Health Research; Fund for Scientific Research Flanders (FWO); National Cancer Institute grant [CA 27469]; GOG Statistical and Data Center [CA 37517]; GOGs Cancer Prevention and Control Committee [CA 101165]; Intramural Research Program, NCI; ISCIII (Spain) [RD12/00369/0006, 12/00539]; European Regional Development FEDER funds; Helsinki University Central Hospital Research Fund; Academy of Finland [132473]; Finnish Cancer Society; Sigrid Juselius Foundation; Dutch Cancer Society grant [NKI1998-1854, NKI2004-3088, NKI2007-3756]; Netherlands Organization of Scientific Research [NWO 91109024]; Pink Ribbon grant [110005]; BBMRI grant [NWO 184.021.007/CP46]; Hungarian Research Grant [KTIA-OTKA CK-80745]; Norwegian EEA Financial Mechanism [HU0115/NA/2008-3/OP-9]; Spanish Ministry of Health ISCIII FIS [PI10/01422, PI12/01528, PI13/00285]; RTICC [RD12/0036/0008]; Ramon Areces (XV) Foundation; Eugenio Rodriguez Pascual Foundation; Roses Contra el Cancer Foundation; Spanish Association Against Cancer (AECC); AGAUR Generalitat de Catalunya [2009-SGR290, 2009-SGR293]; Polish Foundation of Science; Icelandic Association "Walking for Breast Cancer Research"; Nordic Cancer Union; Landspitali University Hospital Research Fund; Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program; Canadian Breast Cancer Research Alliance-grant [019511]; Ministry of Economic Development, Innovation and Export Trade-grant [PSR-SIIRI-701]; Ministero dellIstruzione, dellUniversita e della Ricerca and Ministero della Salute; Liga Portuguesa Contra o Cancro; National Breast Cancer Foundation; National Health and Medical Research Council (NHMRC); Queensland Cancer Fund; Cancer Council of New South Wales; Cancer Council of Victoria; Cancer Foundation of Western Australia; Cancer Councils of Tasmania; National Institutes of Health grant [CA128978]; NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; United States Department of Defence Ovarian Cancer Idea award [W81XWH-10-1-0341]; Breast Cancer Research Foundation; Jewish General Hospital Weekend; Quebec Ministry of Economic Development, Innovation and Export Trade; Cancer Councils of South Australia; European Regional Development Fund; State Budget of the Czech Republic (RECAMO) [CZ.1.05/2.1.00/03.0101]; MH CZ-DRO (MMCI) [00209805]; Niehaus Family Genetics Research Fund; STARR Cancer Consortium Grant; NAROD [1R01 CA149429-01]; NCI Intramural Research Program, National Institutes of Health [NO2-CP-11019-50, N02-CP-65504]; Westat, Inc, Rockville, Maryland; Clalit Health Services in Israel; Israel Cancer Association; Breast Cancer Research Foundation (BCRF), New York; Russian Federation for Basic Research [11-04-00227, 12-04-00928, 12-04-01490]; Federal Agency for Science and Innovations, Russia [02.740.11.0780]; Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program and grant from the National Cancer Institute [UM1 CA164920]; Breast Cancer Family Registry (BCFR); United States Government or the BCFR; Ohio State University Comprehensive Cancer Center; Isreal cancer association; Israeli Inherited breast cancer consortium; Swedish Cancer Society; Ralph and Marion Falk Medical Research Trust; Entertainment Industry Fund National Womens Cancer Research Alliance; National Institutes of Health (NIH) [R01-CA102776, R01-CA083855]; Rooney Family Foundation; Susan G. Komen Foundation for the cure, Basser Research Center; American Cancer Society Early Detection Professorship [SIOP-06-258-01-COUN]; SAF2010-20493; [PBZ_KBN_122/P05/2004]
Published: 2015

234. Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

Author: Orr, N., Dudbridge, F., Dryden, N., Maguire, S., Novo, D., Perrakis, E., Johnson, N., Ghoussaini, M., Hopper, J.L., Southey, M.C., Apicella, C., Stone, J., Schmidt, M.K., Broeks, A., Van't Veer, L.J., Hogervorst, F.B., Fasching, P.A., Haeberle, L., Ekici, A.B., Beckmann, M.W., Gibson, L., Aitken, Z., Warren, H., Sawyer, E., Tomlinson, I., Kerin, M.J., Miller, N., Burwinkel, B., Marme, F., Schneeweiss, A., Sohn, C., Guenel, P., Truong, T., Cordina-Duverger, E., Sanchez, M., Bojesen, S.E., Nordestgaard, B.G., Nielsen, S.F., Flyger, H., Benitez, J., Zamora, M.P., Perez, J.I.A., Menendez, P., Anton-Culver, H., Neuhausen, S.L., Brenner, H., Dieffenbach, A.K., Arndt, V., Stegmaier, C., Hamann, U., Brauch, H., Justenhoven, C., Bruning, T., Ko, Y.D., Nevanlinna, H., Aittomaki, K., Blomqvist, C., Khan, S., Bogdanova, N., Dork, T., Lindblom, A., Margolin, S., Mannermaa, A., Kataja, V., Kosma, V.M., Hartikainen, J.M., Chenevix-Trench, G., Beesley, J., Lambrechts, D., Moisse, M., Floris, G., Beuselinck, B., Chang-Claude, J., Rudolph, A., Seibold, P., Flesch-Janys, D., Radice, P., Peterlongo, P., Peissel, B., Pensotti, V., Couch, F.J., Olson, J.E., Slettedahl, S., Vachon, C., Giles, G.G., Milne, R.L., McLean, C., Haiman, C.A., Henderson, B.E., Schumacher, F., Marchand, L. le, Simard, J., Goldberg, M.S., Labreche, F., Dumont, M., Kristensen, V., Alnaes, G.G., Nord, S., Borresen-Dale, A.L., Zheng, W., Deming-Halverson, S., Shrubsole, M., Long, J.R., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Andrulis, I.L., Knight, J.A., Glendon, G., Tchatchou, S., Devilee, P., Tollenaar, R.A.E.M., Seynaeve, C.M., Asperen, C.J. van, Garcia-Closas, M., Figueroa, J., Chanock, S.J., Lissowska, J., Czene, K., Darabi, H., Eriksson, M., Klevebring, D., Hooning, M.J., Hollestelle, A., Deurzen, C.H.M. van, Kriege, M., Hall, P., Li, J.M., Liu, J.J., Humphreys, K., Cox, A., Cross, S.S., Reed, M.W.R., Pharoah, P.D.P., Dunning, A.M., Shah, M., Perkins, B.J., Jakubowska, A., Lubinski, J., Jaworska-Bieniek, K., Durda, K., Ashworth, A., Swerdlow, A., Jones, M., Schoemaker, M.J., Meindl, A., Schmutzler, R.K., Olswold, C., Slager, S., Toland, A.E., Yannoukakos, D., Muir, K., Lophatananon, A., Stewart-Brown, S., Siriwanarangsan, P., Matsuo, K., Ito, H., Iwata, H., Ishiguro, J., Wu, A.H., Tseng, C.C., Berg, D. van den, Stram, D.O., Teo, S.H., Yip, C.H., Kang, P., Ikram, M.K., Shu, X.O., Lu, W., Gao, Y.T., Cai, H., Kang, D., Choi, J.Y., Park, S.K., Noh, D.Y., Hartman, M., Miao, H., Lim, W.Y., Lee, S.C., Sangrajrang, S., Gaborieau, V., Brennan, P., McKay, J., Wu, P.E., Hou, M.F., Yu, J.C., Shen, C.Y., Blot, W., Cai, Q.Y., Signorello, L.B., Luccarini, C., Bayes, C., Ahmed, S., Maranian, M., Healey, C.S., Gonzalez-Neira, A., Pita, G., Alonso, M.R., Alvarez, N., Herrero, D., Tessier, D.C., Vincent, D., Bacot, F., Hunter, D.J., Lindstrom, S., Dennis, J., Michailidou, K., Bolla, M.K., Easton, D.F., Silva, I.D., Fletcher, O., Peto, J., GENICA Network, kConFab Investigators, Australian Ovarian Canc Study Grp, Obstetrics & Gynecology, Medical Oncology, Pathology, Ophthalmology, Cardiothoracic Surgery, and Clinical Genetics
Subjects: Asian Continental Ancestry Group, Adult, Hepatocyte Nuclear Factor 3-alpha, Risk, binding, European Continental Ancestry Group, Kruppel-Like Transcription Factors, estrogen-receptor-alpha, Breast Neoplasms, GATA3 Transcription Factor, Polymorphism, Single Nucleotide, White People, Kruppel-Like Factor 4, Asian People, SDG 3 - Good Health and Well-being, Medizinische Fakultät, common variants, expression, Humans, Genetic Predisposition to Disease, ddc:610, Genetic Association Studies, Aged, Association Studies Articles, Estrogen Receptor alpha, Chromosome Mapping, foxa1, Middle Aged, confer susceptibility, analyses reveal, Enhancer Elements, Genetic, risk locus, Genetic Loci, functional variants, genome-wide association, Female, Chromosomes, Human, Pair 9
Abstract: We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 × 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 × 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 × 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 × 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis. ispartof: Human Molecular Genetics vol:24 issue:10 pages:2966-84 ispartof: location:England status: published
Published: 2015

235. Large-Scale Genomic Analyses Link Reproductive Aging to Hypothalamic Signaling, Breast Cancer Susceptibility, and BRCA1-Mediated DNA Repair EDITORIAL COMMENT

Author: Day, FR, Ruth, KS, Thompson, DJ, Lunetta, KL, Pervjakova, N, Chasman, DI, Stolk, Lisette, Finucane, HK, Sulem, P, Bulik-Sullivan, B, Esko, T, Johnson, AD, Elks, CE, Franceschini, N, He, C, Altmaier, E, Brody, JA, Franke, LL, Huffman, JE, Keller, MF, McArdle, PF, Nutile, T, Porcu, E, Robino, A, Rose, LM, Schick, UM, Smith, JA, Teumer, A, Traglia, M, Vuckovic, D, Yao, J, Zhao, W, Albrecht, E, Amin, Najaf, Corre, T, Hottenga, JJ (Jouke Jan), Mangino, M, Smith, AV, Tanaka, T, Abecasis, GR, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Arndt, V, Arnold, AM, Barbieri, C, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bernstein, L, Bielinski, SJ, Blomqvist, C, Boerwinkle, E, Bogdanova, NV, Bojesen, SE, Bolla, MK, Borresen-Dale, AL, Boutin, TS, Brauch, H, Brenner, H, Bruning, T, Burwinkel, B, Campbell, A (Archie), Campbell, H, Chanock, SJ, Chapman, JR, Chen, YDI, Chenevix-Trench, G, Couch, FJ, Coviello, AD, Cox, A, Czene, K, Darabi, H, de Vivo, I, Demerath, EW, Dennis, J, Devilee, P, Dork, T, dos-Santos-Silva, I, Dunning, AM, Eicher, JD, Fasching, PA, Faul, JD, Figueroa, J, Flesch-Janys, D, Gandin, I, Garcia, ME, Garcia-Closas, M, Giles, GG, Girotto, GG, Goldberg, MS, Gonzalez-Neira, A, Goodarzi, MO, Grove, ML, Gudbjartsson, DF, Guenel, P, Guo, XQ, Haiman, CA, Hall, P, Hamann, U, Henderson, BE, Hocking, LJ, Hofman, Bert, Homuth, G, Hooning, Maartje, Hopper, JL, Hu, FB, Huang, JY, Humphreys, K, Hunter, DJ, Jakubowska, A, Jones, SE, Kabisch, M, Karasik, D, Knight, JA, Kolcic, I, Kooperberg, C, Kosma, VM, Kriebel, J, Kristensen, V, Lambrechts, D, Langenberg, C, Li, JM, Li, X, Lindstrom, S, Liu, YM, Luan, JA, Lubinski, J, Magi, R, Mannermaa, A, Manz, J, Margolin, S, Marten, J, Martin, NG, Masciullo, C, Meindl, A, Michailidou, K, Mihailov, E, Milani, L, Milne, RL, Muller-Nurasyid, M, Nalls, M, Neale, BM, Nevanlinna, H, Neven, P, Newman, AB, Nordestgaard, BG, Olson, JE, Padmanabhan, S, Peterlongo, P, Peters, U, Petersmann, A, Peto, J, Pharoah, PDP, Pirastu, NN, Pirie, A, Pistis, G, Polasek, O, Porteous, D, Psaty, BM, Pylkas, K, Radice, P, Raffel, LJ, Rivadeneira, Fernando, Rudan, I, Rudolph, A, Ruggiero, D, Sala, CF, Sanna, S, Sawyer, EJ, Schlessinger, D, Schmidt, MK (Marjanka), Schmidt, F, Schmutzler, RK, Schoemaker, MJ, Scott, RA, Seynaeve, Caroline, Simard, J, Sorice, R, Southey, MC, Stockl, D, Strauch, K, Swerdlow, A, Taylor, KD, Thorsteinsdottir, U, Toland, AE, Tomlinson, I, Truong, T, Tryggvadottir, L, Turner, ST, Vozzi, D, Wang, Q (Qing), Wellons, M, Willemsen, G, Wilson, JF, Winqvist, R, Wolffenbuttel, BBHR, Wright, AF, Yannoukakos, D, Zemunik, T, Zheng, W, Zygmunt, M, Bergmann, S, Boomsma, DI, Buring, JE, Ferrucci, L, Montgomery, GW, Gudnason, V, Spector, TD, Duijn, Cornelia, Alizadeh, BZ, Ciullo, M, Crisponi, L, Easton, DF, Gasparini, PP, Gieger, C, Harris, TB, Hayward, C, Kardia, SLR, Kraft, P, McKnight, B, Metspalu, A, Morrison, AC, Reiner, AP, Ridker, PM, Rotter, JI, Toniolo, D, Uitterlinden, André, Ulivi, S, Volzke, H, Wareham, NJ, Weir, DR, Yerges-Armstrong, LM, Price, AL, Stefansson, K, Visser, Jenny, Ong, KK, Chang-Claude, J, Murabito, JM, Perry, JRB, Murray, A, Systems Ecology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Internal Medicine, Epidemiology, Medical Oncology, and Clinical Genetics
Subjects: SDG 3 - Good Health and Well-being
Published: 2015

236. Evaluating the ovarian cancer gonadotropin hypothesis: A candidate gene study

Author: Lee, AW, Tyrer, JP, Doherty, JA, Stram, DA, Kupryjanczyk, J, Dansonka-Mieszkowska, A, Plisiecka-Halasa, J, Spiewankiewicz, B, Myers, EJ, Chenevix-Trench, G, Fasching, PA, Beckmann, MW, Ekici, AB, Hein, A, Vergote, I, Van Nieuwenhuysen, E, Lambrechts, D, Wicklund, KG, Eilber, U, Wang-Gohrke, S, Chang-Claude, J, Rudolph, A, Sucheston-Campbell, L, Odunsi, K, Moysich, KB, Shvetsov, YB, Thompson, PJ, Goodman, MT, Wilkens, LR, Dörk, T, Hillemanns, P, Dürst, M, Runnebaum, IB, Bogdanova, N, Pelttari, LM, Nevanlinna, H, Leminen, A, Edwards, RP, Kelley, JL, Harter, P, Schwaab, I, Heitz, F, Du Bois, A, Orsulic, S, Lester, J, Walsh, C, Karlan, BY, Hogdall, E, Kjaer, SK, Jensen, A, Vierkant, RA, Cunningham, JM, Goode, EL, Fridley, BL, Southey, MC, Giles, GG, Bruinsma, F, Wu, X, Hildebrandt, MAT, Lu, K, Liang, D, Bisogna, M, Levine, DA, Weber, RP, Schildkraut, JM, Iversen, ES, Berchuck, A, Terry, KL, Cramer, DW, Tworoger, SS, Poole, EM, Olson, SH, Orlow, I, Bandera, EV, Bjorge, L, Tangen, IL, Salvesen, HB, Krakstad, C, and Massuger, LFAG
Subjects: endocrine system
Abstract: © 2014 Elsevier Inc. All rights reserved. Objective: Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted. Methods: Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations. Results: We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p = 0.045, mucinous), LHCGR (p = 0.046, high-grade serous), GNRH (p = 0.041, high-grade serous), and FSHB (p = 0.036, overall invasive). There was also suggestive evidence for INHA (p = 0.060, overall invasive). Conclusions: Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available.
Published: 2015

237. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer

Author: Rebbeck, TR, Mitra, N, Wan, F, Sinilnikova, OM, Healey, S, McGuffog, L, Chenevix-Trench, G, Easton, DF, Antoniou, AC, Nathanson, KL, Laitman, Y, Kushnir, A, Paluch-Shimon, S, Berger, R, Zidan, J, Friedman, E, Ehrencrona, H, Stenmark-Askmalm, M, Einbeigi, Z, Loman, N, Harbst, K, Rantala, J, Melin, B, Huo, D, Olopade, OI, Seldon, J, Ganz, PA, Nussbaum, RL, Chan, SB, Odunsi, K, Gayther, SA, Domchek, SM, Arun, BK, Lu, KH, Mitchell, G, Karlan, BY, Walsh, C, Lester, J, Godwin, AK, Pathak, H, Ross, E, Daly, MB, Whittemore, AS, John, EM, Miron, A, Terry, MB, Chung, WK, Goldgar, DE, Buys, SS, Janavičius, R, Tihomirova, L, Tung, N, Dorfling, CM, Van Rensburg, EJ, Steele, L, Neuhausen, SL, Ding, YC, Ejlertsen, B, Gerdes, AM, Hansen, TVO, Ramon Y Cajal, T, Osorio, A, Benitez, J, Godino, J, Tejada, MI, Duran, M, Weitzel, JN, Bobolis, KA, Sand, SR, Fontaine, A, Savarese, A, Pasini, B, Peissel, B, Bonanni, B, Zaffaroni, D, Vignolo-Lutati, F, Scuvera, G, Giannini, G, Bernard, L, Genuardi, M, Radice, P, Dolcetti, R, Manoukian, S, Pensotti, V, Gismondi, V, Yannoukakos, D, Fostira, F, Garber, J, Torres, D, and Rashid, MU
Subjects: endocrine system diseases, skin and connective tissue diseases
Abstract: Importance: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. Objective: To identify mutation-specific cancer risks for carriers of BRCA1/2. Design, Setting, and Participants: Observational study ofwomen whowere ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19 581 carriers of BRCA1 mutations and 11 900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents.We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position.We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. Exposures: Mutations of BRCA1 or BRCA2. Main Outcomes and Measures: Breast and ovarian cancer risks. Results: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95%CI, 1.22-1.74; P = 2 × 10-6), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95%CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95%CI, 1.22-1.55; P = 6 × 10-9).We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95%CI, 0.56-0.70; P = 9 × 10-17). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95%CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95%CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95%CI, 1.69-3.16; P = .00002).We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95%CI, 0.44-0.60; P = 6 × 10-17). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95%CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. Conclusions and Relevance: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.
Published: 2015

238. Identification of novel genetic markers of breast cancer survival

Author: Guo, Q, Schmidt, Mk, Kraft, P, Canisius, S, Chen, C, Khan, S, Tyrer, J, Bolla, Mk, Wang, Q, Dennis, J, Michailidou, K, Lush, M, Kar, S, Beesley, J, Dunning, Am, Shah, M, Czene, K, Darabi, H, Eriksson, M, Lambrechts, D, Weltens, C, Leunen, K, Bojesen, Se, Nordestgaard, Bg, Nielsen, Sf, Flyger, H, Chang Claude, J, Rudolph, A, Seibold, P, Flesch Janys, D, Blomqvist, C, Aittomäki, K, Fagerholm, R, Muranen, Ta, Couch, Fj, Olson, Je, Vachon, C, Andrulis, Il, Knight, Ja, Glendon, G, Mulligan, Am, Broeks, A, Hogervorst, Fb, Haiman, Ca, Henderson, Be, Schumacher, F, Le Marchand, L, Hopper, Jl, Tsimiklis, H, Apicella, C, Southey, Mc, Cox, A, Cross, Ss, Reed, Mw, Giles, Gg, Milne, Rl, Mclean, C, Winqvist, R, Pylkäs, K, Jukkola Vuorinen, A, Grip, M, Hooning, Mj, Hollestelle, A, Martens, Jw, van den Ouweland, Am, Marme, F, Schneeweiss, A, Yang, R, Burwinkel, B, Figueroa, J, Chanock, Sj, Lissowska, J, Sawyer, Ej, Tomlinson, I, Kerin, Mj, Miller, N, Brenner, H, Dieffenbach, Ak, Arndt, V, Holleczek, B, Mannermaa, A, Kataja, V, Kosma, Vm, Hartikainen, Jm, Li, J, Brand, Js, Humphreys, K, Devilee, P, Tollenaar, Ra, Seynaeve, C, Radice, P, Peterlongo, P, Bonanni, B, Mariani, P, Fasching, Beckmann, Mw, Hein, A, Ekici, Ab, Chenevix Trench, G, Balleine, R, Kconfab, Investigators, Phillips, Ka, Benitez, J, Zamora, Mp, Arias Perez, Ji, Menéndez, P, Jakubowska, A, Lubinski, J, Jaworska Bieniek, K, Durda, K, Hamann, U, Kabisch, M, Ulmer, Hu, Rüdiger, T, Margolin, S, Kristensen, V, Nord, S, Evans, Dg, Abraham, Je, Earl, Hm, Hiller, L, Dunn, Ja, Bowden, S, Berg, C, Campa, Daniele, Diver, Wr, Gapstur, Sm, Gaudet, Mm, Hankinson, Se, Hoover, Rn, Hüsing, A, Kaaks, R, Machiela, Mj, Willett, W, Barrdahl, M, Canzian, F, Chin, Sf, Caldas, C, Hunter, Dj, Lindstrom, S, García Closas, M, Hall, P, Easton, Df, Eccles, Dm, Rahman, N, Nevanlinna, H, and Pharoah, P. d.
Subjects: GENOME-WIDE ASSOCIATION, SINGLE-NUCLEOTIDE POLYMORPHISMS, GENOTYPE IMPUTATION, PROGNOSIS, RISK, LOCI, CYCLOPHOSPHAMIDE, METAANALYSIS, PROGRESSION, EPIRUBICIN
Published: 2015

239. Network-based integration of GWAS and gene expression identifies a HOX-centric network associated with serous ovarian cancer risk

Author: Kar, SP, Tyrer, JP, Li, Q, Lawrenson, K, Aben, KKH, Anton-Culver, H, Antonenkova, N, Chenevix-Trench, G, Baker, H, Bandera, EV, Bean, YT, Beckmann, MW, Berchuck, A, Bisogna, M, Bjørge, L, Bogdanova, N, Brinton, L, Brooks-Wilson, A, Butzow, R, Campbell, I, Carty, K, Chang-Claude, J, Chen, YA, Chen, Z, Cook, LS, Cramer, D, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Dicks, E, Doherty, JA, Dörk, T, Du Bois, A, Dürst, M, Eccles, D, Easton, DF, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, YT, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goode, EL, Goodman, MT, Grownwald, J, Harrington, P, Harter, P, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, E, Hogdall, CK, Hosono, S, Iversen, ES, Jakubowska, A, Paul, J, Jensen, A, Ji, BT, Karlan, BY, Kjaer, SK, Kelemen, LE, Kellar, M, Kelley, J, Kiemeney, LA, Krakstad, C, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, and Liang, D
Subjects: endocrine system diseases, female genital diseases and pregnancy complications
Abstract: © 2015 American Association for Cancer Research. Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. Methods: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). Results: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization.
Published: 2015

240. Refined histopathological predictors of BRCA1\ud and BRCA2 mutation status: a large-scale analysis\ud of breast cancer characteristics from the BCAC,\ud CIMBA, and ENIGMA consortia

Author: Spurdle, A.B., Couch, F.J., Parsons, M.T., McGuffog, L., Barrowdale, D., Bolla, M.K., Wang, Q., Healey, S., Schmutzler, R.K., Wappenschmidt, B., Rhiem, K., Hahnen, E., Engel, C., Meindl, A., Ditsch, N., Arnold, N., Plendl, H., Niederacher, D., Sutter, C., Wang-Gohrke, S., Steinemann, D., Preisler-Adams, S., Kast, K., Varon-Mateeva, R., Ellis, S., Frost, D., Platte, R., Perkins, J., Evans, D.G., Izatt, L., Eeles, R., Adlard, J., Davidson, R., Cole, T., Scuvera, G., Manoukian, S., Bonanni, B., Mariette, F., Fortuzzi, S., Viel, A., Pasini, B., Papi, L., Varesco, L., Balleine, R., Nathanson, K.L., Domchek, S.M., Offitt, K., Jakubowska, A., Lindor, N., Thomassen, M., Jensen, U.B., Rantala, J., Borg, A., Andrulis, I.L., Miron, A., Hansen, T.V.O., Caldes, T., Neuhausen, S.L., Toland, A.E., Nevanlinna, H., Montagna, M., Garber, J., Godwin, A.K., Osorio, A., Factor, R.E., Terry, M.B., Rebbeck, T.R., Karlan, B.Y., Southey, M., Rashid, M.U., Tung, N., Pharoah, P.D.P., Blows, F.M., Dunning, A.M., Provenzano, E., Hall, P., Czene, K., Schmidt, M.K., Broeks, A., Cornelissen, S., Verhoef, S., Fasching, P.A., Beckmann, M.W., Ekici, A.B., Slamon, D.J., Bojesen, S.E., Nordestgaard, B.G., Nielsen, S.F., Flyger, H., Chang-Claude, J., Flesch-Janys, D., Rudolph, A., Seibold, P., Aittomaki, K., Muranen, T.A., Heikkila, P., Blomqvist, C., Figueroa, J., Chanock, S.J., Brinton, L., Lissowska, J., Olson, J.E., Pankratz, V.S., John, E.M., Whittemore, A.S., West, D.W., Hamann, U., Torres, D., Ulmer, H.U., Rudiger, T., Devilee, P., Tollenaar, R.A.E.M., Seynaeve, C., Van Asperen, C.J., Eccles, D.M., Tapper, W.J., Durcan, L., Jones, L., Peto, J., dos-Santos-Silva, I., Fletcher, O., Johnson, N., Dwek, M., Swann, R., Bane, A.L., Glendon, G., Mulligan, A.M., Giles, G.G., Milne, R.L., Baglietto, L., McLean, C., Carpenter, J., Clarke, C., Scott, R., Brauch, H., Bruning, T., Ko, Y-D., Cox, A., Cross, S.S., Reed, M.W.R., Lubinski, J., Jaworska-Bieniek, K., Durda, K., Gronwald, J., Dork, T., Bogdanova, N., Park-Simon, T-W., Hillemanns, P., Haiman, C.A., Henderson, B.E., Schumacher, F., Le Marchand, L., Burwinkel, B., Marme, F., Surovy, H., Yang, R., Anton-Culver, H., Ziogas, A., Hooning, M.J., Collee, J.M., Martens, J.W.M., Tilanus-Linthorst, M.M.A., Brenner, H., Dieffenbach, A.K., Arndt, V., Stegmaier, C., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Lindblom, A., Margolin, S., Joseph, V., Robson, M., Rau-Murthy, R., Gonzalez-Neira, A., Arias, J.I., Zamora, P., Benitez, J., Mannermaa, A., Kataja, V., Kosma, V-M., Hartikainen, J.M., Peterlongo, P., Zaffaroni, D., Barile, M., Capra, F., Radice, P., Teo, S.H., Easton, D.F., Antoniou, A.C., Chenevix-Trench, G., Goldgar, D.E., Investigators, ABCTB, Group, EMBRACE, Network, GENICA, Group, HEBON, and Investigators, KConFab
Subjects: endocrine system diseases, skin and connective tissue diseases
Abstract: Introduction: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline\ud mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have\ud utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of\ud uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of\ud Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological\ud predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical\ud modeling.\ud Methods: Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for\ud invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565\ud BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of\ud mutation status by histopathological markers were derived using a Mantel-Haenszel approach.\ud Results: ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to\ud 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years\ud or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3\ud phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3\ud features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor\ud status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and\ud 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years\ud or older (LR = 1.79 (1.42 to 2.24)).\ud Conclusions: These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using\ud commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is\ud more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2\ud variant classification and inform patient mutation testing and clinical management.
Published: 2014

241. Evidence of a genetic link between endometriosis and ovarian cancer

Author: Lee, A.W., Templeman, C., Stram, D.A., Beesley, J., Tyrer, J., Berchuck, A., Pharoah, P.P., Chenevix-Trench, G., Pearce, C.L., Massuger, L.F.A.G., Altena, A.M. van, Kiemeney, L.A.L.M., et al., Lee, A.W., Templeman, C., Stram, D.A., Beesley, J., Tyrer, J., Berchuck, A., Pharoah, P.P., Chenevix-Trench, G., Pearce, C.L., Massuger, L.F.A.G., Altena, A.M. van, Kiemeney, L.A.L.M., and et al.
Abstract: Contains fulltext : 172500.pdf (publisher's version ) (Closed access), OBJECTIVE: To evaluate whether endometriosis-associated genetic variation affects risk of ovarian cancer. DESIGN: Pooled genetic analysis. SETTING: University hospital. PATIENT(S): Genetic data from 46,176 participants (15,361 ovarian cancer cases and 30,815 controls) from 41 ovarian cancer studies. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Endometriosis-associated genetic variation and ovarian cancer. RESULT(S): There was significant evidence of an association between endometriosis-related genetic variation and ovarian cancer risk, especially for the high-grade serous and clear cell histotypes. Overall we observed 15 significant burden statistics, which was three times more than expected. CONCLUSION(S): By focusing on candidate regions from a phenotype associated with ovarian cancer, we have shown a clear genetic link between endometriosis and ovarian cancer that warrants further follow-up. The functional significance of the identified regions and SNPs is presently uncertain, though future fine mapping and histotype-specific functional analyses may shed light on the etiologies of both gynecologic conditions.
Published: 2016

242. Adult body mass index and risk of ovarian cancer by subtype: a Mendelian randomization study

Author: Dixon, S.C., Nagle, C.M., Thrift, A.P., Pharoah, P.D., Pearce, C.L., Zheng, W., Painter, J.N., Chenevix-Trench, G., Fasching, P.A., Beckmann, M.W., Lambrechts, D., Vergote, I., Lambrechts, S., Nieuwenhuysen, E. Van, Rossing, M.A., Doherty, J.A., Wicklund, K.G., Chang-Claude, J., Rudolph, A., Moysich, K.B., Odunsi, K., Goodman, M.T., Wilkens, L.R., Thompson, P.J., Shvetsov, Y.B., Dork, T., Park-Simon, T.W., Hillemanns, P., Bogdanova, N., Butzow, R., Nevanlinna, H., Pelttari, L.M., Leminen, A., Modugno, F., Ness, R.B., Edwards, R.P., Kelley, J.L., Heitz, F., Karlan, B.Y., Kjaer, S.K., Hogdall, E., Jensen, A., Goode, E.L., Fridley, B.L., Cunningham, J.M., Winham, S.J., Giles, G.G., Bruinsma, F., Milne, R.L., Southey, M.C., Hildebrandt, M.A.T., Wu, X., Lu, K.H., Liang, D., Levine, D.A., Bisogna, M., Schildkraut, J.M., Berchuck, A., Cramer, D.W, Terry, K.L., Bandera, E.V., Olson, S.H., Salvesen, H.B., Thomsen, L.C., Kopperud, R.K., Bjorge, L., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Pejovic, T., Cook, L.S., Le, N.D., Swenerton, K.D., Brooks-Wilson, A., Kelemen, L.E., Lubinski, J., Huzarski, T., Gronwald, J., Menkiszak, J., Wentzensen, N., Brinton, L., Yang, H., Lissowska, J., Hogdall, C.K., Lundvall, L., Song, H., Tyrer, J.P., Campbell, I., Eccles, D., Paul, J., Glasspool, R., Siddiqui, N., Whittemore, A.S., Sieh, W., McGuire, V., Rothstein, J.H., Narod, S.A., Phelan, C., Risch, H.A., McLaughlin, J.R., Anton-Culver, H., et al., Dixon, S.C., Nagle, C.M., Thrift, A.P., Pharoah, P.D., Pearce, C.L., Zheng, W., Painter, J.N., Chenevix-Trench, G., Fasching, P.A., Beckmann, M.W., Lambrechts, D., Vergote, I., Lambrechts, S., Nieuwenhuysen, E. Van, Rossing, M.A., Doherty, J.A., Wicklund, K.G., Chang-Claude, J., Rudolph, A., Moysich, K.B., Odunsi, K., Goodman, M.T., Wilkens, L.R., Thompson, P.J., Shvetsov, Y.B., Dork, T., Park-Simon, T.W., Hillemanns, P., Bogdanova, N., Butzow, R., Nevanlinna, H., Pelttari, L.M., Leminen, A., Modugno, F., Ness, R.B., Edwards, R.P., Kelley, J.L., Heitz, F., Karlan, B.Y., Kjaer, S.K., Hogdall, E., Jensen, A., Goode, E.L., Fridley, B.L., Cunningham, J.M., Winham, S.J., Giles, G.G., Bruinsma, F., Milne, R.L., Southey, M.C., Hildebrandt, M.A.T., Wu, X., Lu, K.H., Liang, D., Levine, D.A., Bisogna, M., Schildkraut, J.M., Berchuck, A., Cramer, D.W, Terry, K.L., Bandera, E.V., Olson, S.H., Salvesen, H.B., Thomsen, L.C., Kopperud, R.K., Bjorge, L., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Pejovic, T., Cook, L.S., Le, N.D., Swenerton, K.D., Brooks-Wilson, A., Kelemen, L.E., Lubinski, J., Huzarski, T., Gronwald, J., Menkiszak, J., Wentzensen, N., Brinton, L., Yang, H., Lissowska, J., Hogdall, C.K., Lundvall, L., Song, H., Tyrer, J.P., Campbell, I., Eccles, D., Paul, J., Glasspool, R., Siddiqui, N., Whittemore, A.S., Sieh, W., McGuire, V., Rothstein, J.H., Narod, S.A., Phelan, C., Risch, H.A., McLaughlin, J.R., and Anton-Culver, H., et al.
Abstract: Contains fulltext : 170949.pdf (publisher's version ) (Closed access), BACKGROUND: Observational studies have reported a positive association between body mass index (BMI) and ovarian cancer risk. However, questions remain as to whether this represents a causal effect, or holds for all histological subtypes. The lack of association observed for serous cancers may, for instance, be due to disease-associated weight loss. Mendelian randomization (MR) uses genetic markers as proxies for risk factors to overcome limitations of observational studies. We used MR to elucidate the relationship between BMI and ovarian cancer, hypothesizing that genetically predicted BMI would be associated with increased risk of non-high grade serous ovarian cancers (non-HGSC) but not HGSC. METHODS: We pooled data from 39 studies (14 047 cases, 23 003 controls) in the Ovarian Cancer Association Consortium. We constructed a weighted genetic risk score (GRS, partial F-statistic = 172), summing alleles at 87 single nucleotide polymorphisms previously associated with BMI, weighting by their published strength of association with BMI. Applying two-stage predictor-substitution MR, we used logistic regression to estimate study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted BMI and risk, and pooled these using random-effects meta-analysis. RESULTS: Higher genetically predicted BMI was associated with increased risk of non-HGSC (pooled OR = 1.29, 95% CI 1.03-1.61 per 5 units BMI) but not HGSC (pooled OR = 1.06, 95% CI 0.88-1.27). Secondary analyses stratified by behaviour/subtype suggested that, consistent with observational data, the association was strongest for low-grade/borderline serous cancers (OR = 1.93, 95% CI 1.33-2.81). CONCLUSIONS: Our data suggest that higher BMI increases risk of non-HGSC, but not the more common and aggressive HGSC subtype, confirming the observational evidence.
Published: 2016

243. Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility: results from a large-scale collaboration

Author: Permuth, J.B., Reid, B., Earp, M., Chen, Y.A., Monteiro, A.N., Chen, Z., Study, G., Chenevix-Trench, G., Fasching, P.A., Beckmann, M.W., Lambrechts, D., Vanderstichele, A., Niewenhuyse, E. Van, Vergote, I., Rossing, M.A., Doherty, J.A., Chang-Claude, J., Moysich, K., Odunsi, K., Goodman, M.T., Shvetsov, Y.B., Wilkens, L.R., Thompson, P.J., Dork, T., Bogdanova, N., Butzow, R., Nevanlinna, H., Pelttari, L., Leminen, A., Modugno, F., Edwards, R.P., Ness, R.B., Kelley, J., Heitz, F., Karlan, B., Lester, J., Kjaer, S.K., Jensen, A., Giles, G., Hildebrandt, M., Liang, D., Lu, K.H., Wu, X., Levine, D.A., Bisogna, M., Berchuck, A., Cramer, D.W, Terry, K.L., Tworoger, S.S., Poole, E.M., Bandera, E.V., Fridley, B., Cunningham, J., Winham, S.J., Olson, S.H., Orlow, I., Bjorge, L., Kiemeney, L.A.L.M., Massuger, L.F., Pejovic, T., Moffitt, M., Le, N., Cook, L.S., Brooks-Wilson, A., Kelemen, L.E., Gronwald, J., Lubinski, J., Wentzensen, N., Brinton, L.A., Lissowska, J., Yang, H., Hogdall, E., Hogdall, C., Lundvall, L., Pharoah, P.D., Song, H., Campbell, I., Eccles, D., McNeish, I., Whittemore, A., McGuire, V., Sieh, W., Rothstein, J., Phelan, C.M., Risch, H., Narod, S., McLaughlin, J., Anton-Culver, H., Ziogas, A., Menon, U., Gayther, S., Ramus, S.J., Gentry-Maharaj, A., Pearce, C.L., Wu, A.H., Kupryjanczyk, J., Dansonka-Mieszkowska, A., Schildkraut, J.M., Cheng, J.Q., Goode, E.L., Permuth, J.B., Reid, B., Earp, M., Chen, Y.A., Monteiro, A.N., Chen, Z., Study, G., Chenevix-Trench, G., Fasching, P.A., Beckmann, M.W., Lambrechts, D., Vanderstichele, A., Niewenhuyse, E. Van, Vergote, I., Rossing, M.A., Doherty, J.A., Chang-Claude, J., Moysich, K., Odunsi, K., Goodman, M.T., Shvetsov, Y.B., Wilkens, L.R., Thompson, P.J., Dork, T., Bogdanova, N., Butzow, R., Nevanlinna, H., Pelttari, L., Leminen, A., Modugno, F., Edwards, R.P., Ness, R.B., Kelley, J., Heitz, F., Karlan, B., Lester, J., Kjaer, S.K., Jensen, A., Giles, G., Hildebrandt, M., Liang, D., Lu, K.H., Wu, X., Levine, D.A., Bisogna, M., Berchuck, A., Cramer, D.W, Terry, K.L., Tworoger, S.S., Poole, E.M., Bandera, E.V., Fridley, B., Cunningham, J., Winham, S.J., Olson, S.H., Orlow, I., Bjorge, L., Kiemeney, L.A.L.M., Massuger, L.F., Pejovic, T., Moffitt, M., Le, N., Cook, L.S., Brooks-Wilson, A., Kelemen, L.E., Gronwald, J., Lubinski, J., Wentzensen, N., Brinton, L.A., Lissowska, J., Yang, H., Hogdall, E., Hogdall, C., Lundvall, L., Pharoah, P.D., Song, H., Campbell, I., Eccles, D., McNeish, I., Whittemore, A., McGuire, V., Sieh, W., Rothstein, J., Phelan, C.M., Risch, H., Narod, S., McLaughlin, J., Anton-Culver, H., Ziogas, A., Menon, U., Gayther, S., Ramus, S.J., Gentry-Maharaj, A., Pearce, C.L., Wu, A.H., Kupryjanczyk, J., Dansonka-Mieszkowska, A., Schildkraut, J.M., Cheng, J.Q., and Goode, E.L.
Abstract: Contains fulltext : 172820.pdf (publisher's version ) (Open Access), RNA editing in mammals is a form of post-transcriptional modification in which adenosine is converted to inosine by the adenosine deaminases acting on RNA (ADAR) family of enzymes. Based on evidence of altered ADAR expression in epithelial ovarian cancers (EOC), we hypothesized that single nucleotide polymorphisms (SNPs) in ADAR genes modify EOC susceptibility, potentially by altering ovarian tissue gene expression. Using directly genotyped and imputed data from 10,891 invasive EOC cases and 21,693 controls, we evaluated the associations of 5,303 SNPs in ADAD1, ADAR, ADAR2, ADAR3, and SND1. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), with adjustment for European ancestry. We conducted gene-level analyses using the Admixture Maximum Likelihood (AML) test and the Sequence-Kernel Association test for common and rare variants (SKAT-CR). Association analysis revealed top risk-associated SNP rs77027562 (OR (95% CI)= 1.39 (1.17-1.64), P=1.0x10-4) in ADAR3 and rs185455523 in SND1 (OR (95% CI)= 0.68 (0.56-0.83), P=2.0x10-4). When restricting to serous histology (n=6,500), the magnitude of association strengthened for rs185455523 (OR=0.60, P=1.0x10-4). Gene-level analyses revealed that variation in ADAR was associated (P<0.05) with EOC susceptibility, with PAML=0.022 and PSKAT-CR=0.020. Expression quantitative trait locus analysis in EOC tissue revealed significant associations (P<0.05) with ADAR expression for several SNPs in ADAR, including rs1127313 (G/A), a SNP in the 3' untranslated region. In summary, germline variation involving RNA editing genes may influence EOC susceptibility, warranting further investigation of inherited and acquired alterations affecting RNA editing.
Published: 2016

244. Common genomic variants are associated with incidence and clinicopathogenic features in familial breast cancer.

Author: Trainer A.H., James P.A., Mitchell G., Sawyer S.D., McInerny S.C., Beesley J., Chenevix-Trench G., Harris M., Lindeman G.J., Delatycki M.B., Trainer A.H., James P.A., Mitchell G., Sawyer S.D., McInerny S.C., Beesley J., Chenevix-Trench G., Harris M., Lindeman G.J., and Delatycki M.B.
Abstract: Objectives: Large-scale genome-wide association studies (GWAS) have identified more than 70 common genomic variants associated with breast cancer. It is estimated that these variants account for ~28% of the familial risk of breast cancer. We assessed the association of recently described variants with breast cancer cases from high-risk breast and/or ovarian cancer families. In addition, we investigated the association of these variants with clinicopathogenic features, including hormonal status and grade of tumour differentiation within our highly characterized cohort. Method(s): We examined 1136 female index cases from the Australian Victorian familial breast and ovarian cancer cohort. All individuals were assessed as high-risk through genetic testing services and had completed genetic screening for BRCA1 and BRCA2 mutations. High throughput genotyping was performed using the Fluidigm system for 62 common variants identified in GWAS (success rate > 0.95). Control genotype data was obtained from an Australian population-based control group (n = 711). Detailed breast cancer pathology was reviewed for 400 of the cases. Result(s): Individual associations in the familial setting were stronger compared to previous breast cancer GWAS. A significantly higher number of risk variants were found among women who did not harbour a BRCA1 or BRCA2 mutation when compared to population controls (p = 1.35x10-39) and those who did harbour a BRCA mutation (p = 0.0004). Women in the top quartile based on the number of risk variants had an average relative risk of 2.3. Many of the variants showed significant associations with hormone status and grade. Conclusion(s): Resultsofthisstudyconfirmtheimportantcontributionofcommonvariants to the incidence of breast cancer in the familial setting. The data indicate a direction for further research to determine if these associations can be used to help understand tumour heterogeneity and lead to improved treatment and prevention for high-risk brea
Published: 2016

245. Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

Author: Zeng, C. (Chenjie), Guo, X. (Xingyi), Long, J. (Jirong), Kuchenbaecker, K.B. (Karoline), Droit, A. (Arnaud), Michailidou, K. (Kyriaki), Ghoussaini, M. (Maya), Kar, S. (Siddhartha), Freeman, A. (Adam), Hopper, J.L. (John), Milne, R.L. (Roger), Bolla, M.K. (Manjeet K.), Wang, Q. (Qin), Dennis, J. (Joe), Agata, S. (Simona), Ahmed, S. (Shahana), Aittomäki, K. (Kristiina), Andrulis, I.L. (Irene), Anton-Culver, H. (Hoda), Antonenkova, N.N. (Natalia N.), Arason, A. (Adalgeir), Arndt, V. (Volker), Arun, B.K. (Banu), Arver, B. (Brita Wasteson), Bacot, F. (Francois), Barrowdale, D. (Daniel), Baynes, C. (Caroline), Beeghly-Fadiel, A. (Alicia), Benítez, J. (Javier), Bermisheva, M. (Marina), Blomqvist, C. (Carl), Blot, W.J. (William), Bogdanova, N.V. (Natalia), Bojesen, S.E. (Stig), Bonnani, B. (Bernardo), Borresen-Dale, A.-L. (Anne-Lise), Brand, J.S. (Judith S.), Brauch, H. (Hiltrud), Brennan, P. (Paul), Brenner, H. (Hermann), Broeks, A. (Annegien), Brüning, T. (Thomas), Burwinkel, B. (Barbara), Buys, S.S. (Saundra), Cai, Q. (Qiuyin), Caldes, T. (Trinidad), Campbell, I. (Ian), Carpenter, T.A. (Adrian), Chang-Claude, J. (Jenny), Choi, J.-Y. (Ji-Yeob), Claes, K.B.M. (Kathleen B.M.), Clarke, C. (Christine), Cox, A. (Angela), Cross, S.S. (Simon), Czene, K. (Kamila), Daly, M.B. (Mary B.), Hoya, M. (Miguel) de La, De Leeneer, K. (Kim), Devilee, P. (Peter), Díez, O. (Orland), Domchek, S.M. (Susan), Doody, M. (Michele), Dorfling, C.M. (Cecilia), Dörk, T. (Thilo), Santos Silva, I. (Isabel) dos, Dumont, M. (Martine), Dwek, M. (Miriam), Dworniczak, B. (Bernd), Egan, K.M. (Kathleen), Eilber, U. (Ursula), Einbeigi, Z. (Zakaria), Ejlertsen, B. (Bent), Ellis, S.D. (Steve), Frost, D. (Debra), Lalloo, F. (Fiona), Fasching, P.A. (Peter), Figueroa, J.D. (Jonine), Flyger, H. (Henrik), Friedlander, M. (Michael), Friedman, E. (Eitan), Gambino, G. (Gaetana), Gao, Y.-T. (Yu-Tang), Garber, J. (Judy), García-Closas, M. (Montserrat), Gehrig, P.A. (Paola A.), Damiola, F. (Francesca), Lesueur, F. (Fabienne), Mazoyer, S. (Sylvie), Stoppa-Lyonnet, D. (Dominique), Giles, G.G. (Graham G.), Godwin, A.K. (Andrew K.), Goldgar, D. (David), González-Neira, A. (Anna), Greene, M.H. (Mark H.), Guénel, P. (Pascal), Haeberle, L. (Lothar), Haiman, C.A. (Christopher A.), Hallberg, E. (Emily), Hamann, U. (Ute), Hansen, T.V.O. (Thomas), Hart, S. (Stewart), Hartikainen, J.M. (J.), Hartman, J.M. (Joost), Hassan, N. (Norhashimah), Healey, S. (Sue), Hogervorst, F.B.L. (Frans), Verhoef, S., Hendricks, C.B. (Carolyn B.), Hillemanns, P. (Peter), Hollestelle, A. (Antoinette), Hulick, P.J. (Peter), Hunter, D. (David), Imyanitov, E.N. (Evgeny), Isaacs, C. (Claudine), Ito, H. (Hidemi), Jakubowska, A. (Anna), Janavicius, R. (Ramunas), Jaworska-Bieniek, K. (Katarzyna), Jensen, U.B., John, E.M. (Esther), Joly Beauparlant, C. (Charles), Jones, M. (Michael), Kabisch, M. (Maria), Kang, D. (Daehee), Karlan, B.Y. (Beth Y.), Kauppila, S. (Saila), Kerin, M. (Michael), Khan, S. (Sofia), Khusnutdinova, E.K. (Elza), Knight, J.A. (Julia), Konstantopoulou, I. (I.), Kraft, P. (Peter), Kwong, A. (Ava), Laitman, Y. (Yael), Lambrechts, D. (Diether), Lázaro, C. (Conxi), Le Marchand, L. (Loic), Lee, C.N. (Chuen), Lee, M.H. (Min Hyuk), Lester, K.J. (Kathryn), Li, J. (Jingmei), Liljegren, A. (Annelie), Lindblom, A. (Annika), Lophatananon, A. (Artitaya), Lubinski, J. (Jan), Mai, P.L. (Phuong), Mannermaa, A. (Arto), Manoukian, S. (Siranoush), Margolin, S. (Sara), Marme, F. (Frederik), Matsuo, K. (Keitaro), McGuffog, L. (Lesley), Meindl, A. (Alfons), Menegaux, F. (Florence), Montagna, M. (Marco), Muir, K.R. (K.), Mulligan, A.-M. (Anna-Marie), Nathanson, K.L. (Katherine), Neuhausen, S.L. (Susan), Nevanlinna, H. (Heli), Newcomb, P. (Polly), Nord, S. (Silje), Nussbaum, R.L. (Robert L.), Offit, K. (Kenneth), Olah, E., Olopade, O.I. (Olufunmilayo I.), Olswold, C. (Curtis), Osorio, A. (Ana), Papi, L. (Laura), Park-Simon, T.-W., Paulsson-Karlsson, Y. (Ylva), Peeters, S.T.H. (Stephanie), Peissel, B. (Bernard), Peterlongo, P. (Paolo), Peto, J. (Julian), Pfeiler, G. (Georg), Phelan, C. (Catherine), Presneau, N. (Nadege), Radice, P. (Paolo), Rahman, N. (Nazneen), Ramus, S.J. (Susan), Rashid, M.U. (Muhammad), Rennert, G. (Gad), Rhiem, K. (Kerstin), Rudolph, A. (Anja), Salani, R. (Ritu), Sangrajrang, S. (Suleeporn), Sawyer, E.J. (Elinor), Schmidt, M.K. (Marjanka), Schmutzler, R.K. (Rita), Schoemaker, M. (Minouk), Schürmann, P. (Peter), Seynaeve, C.M. (Caroline), Shen, C.-Y. (Chen-Yang), Shrubsole, M. (Martha), Shu, X.-O. (Xiao-Ou), Sigurdson, A.J. (Alice), Singer, C.F. (Christian), Slager, S. (Susan), Soucy, P. (Penny), Southey, M.C. (Melissa), Steinemann, D. (Doris), Swerdlow, A.J. (Anthony ), Szabo, C. (Csilla), Tchatchou, S. (Sandrine), Teixeira, P.J., Teo, S.-H. (Soo-Hwang), Terry, M.B. (Mary Beth), Tessier, D.C. (Daniel C.), Teulé, A. (A.), Thomassen, M. (Mads), Tihomirova, L. (Laima), Tischkowitz, M. (Marc), Toland, A.E. (Amanda), Tung, N. (Nadine), Turnbull, C. (Clare), Ouweland, A.M.W. (Ans) van den, Rensburg, E.J. (Elizabeth) van, ven den Berg, D. (David), Vijai, J. (Joseph), Wang-Gohrke, S. (Shan), Weitzel, J.N. (Jeffrey), Whittemore, A.S. (Alice), Winqvist, R. (Robert), Wong, T.Y. (Tien Y.), Wu, A.H. (Anna), Yannoukakos, D. (Drakoulis), Yu, J-C. (Jyh-Cherng), Pharoah, P.D.P. (Paul), Hall, P. (Per), Chenevix-Trench, G. (Georgia), Dunning, A.M. (Alison), Simard, J. (Jacques), Couch, F.J. (Fergus), Antoniou, A.C. (Antonis), Easton, D.F. (Douglas F.), Zheng, W. (Wei), Zeng, C. (Chenjie), Guo, X. (Xingyi), Long, J. (Jirong), Kuchenbaecker, K.B. (Karoline), Droit, A. (Arnaud), Michailidou, K. (Kyriaki), Ghoussaini, M. (Maya), Kar, S. (Siddhartha), Freeman, A. (Adam), Hopper, J.L. (John), Milne, R.L. (Roger), Bolla, M.K. (Manjeet K.), Wang, Q. (Qin), Dennis, J. (Joe), Agata, S. (Simona), Ahmed, S. (Shahana), Aittomäki, K. (Kristiina), Andrulis, I.L. (Irene), Anton-Culver, H. (Hoda), Antonenkova, N.N. (Natalia N.), Arason, A. (Adalgeir), Arndt, V. (Volker), Arun, B.K. (Banu), Arver, B. (Brita Wasteson), Bacot, F. (Francois), Barrowdale, D. (Daniel), Baynes, C. (Caroline), Beeghly-Fadiel, A. (Alicia), Benítez, J. (Javier), Bermisheva, M. (Marina), Blomqvist, C. (Carl), Blot, W.J. (William), Bogdanova, N.V. (Natalia), Bojesen, S.E. (Stig), Bonnani, B. (Bernardo), Borresen-Dale, A.-L. (Anne-Lise), Brand, J.S. (Judith S.), Brauch, H. (Hiltrud), Brennan, P. (Paul), Brenner, H. (Hermann), Broeks, A. (Annegien), Brüning, T. (Thomas), Burwinkel, B. (Barbara), Buys, S.S. (Saundra), Cai, Q. (Qiuyin), Caldes, T. (Trinidad), Campbell, I. (Ian), Carpenter, T.A. (Adrian), Chang-Claude, J. (Jenny), Choi, J.-Y. (Ji-Yeob), Claes, K.B.M. (Kathleen B.M.), Clarke, C. (Christine), Cox, A. (Angela), Cross, S.S. (Simon), Czene, K. (Kamila), Daly, M.B. (Mary B.), Hoya, M. (Miguel) de La, De Leeneer, K. (Kim), Devilee, P. (Peter), Díez, O. (Orland), Domchek, S.M. (Susan), Doody, M. (Michele), Dorfling, C.M. (Cecilia), Dörk, T. (Thilo), Santos Silva, I. (Isabel) dos, Dumont, M. (Martine), Dwek, M. (Miriam), Dworniczak, B. (Bernd), Egan, K.M. (Kathleen), Eilber, U. (Ursula), Einbeigi, Z. (Zakaria), Ejlertsen, B. (Bent), Ellis, S.D. (Steve), Frost, D. (Debra), Lalloo, F. (Fiona), Fasching, P.A. (Peter), Figueroa, J.D. (Jonine), Flyger, H. (Henrik), Friedlander, M. (Michael), Friedman, E. (Eitan), Gambino, G. (Gaetana), Gao, Y.-T. (Yu-Tang), Garber, J. (Judy), García-Closas, M. (Montserrat), Gehrig, P.A. (Paola A.), Damiola, F. (Francesca), Lesueur, F. (Fabienne), Mazoyer, S. (Sylvie), Stoppa-Lyonnet, D. (Dominique), Giles, G.G. (Graham G.), Godwin, A.K. (Andrew K.), Goldgar, D. (David), González-Neira, A. (Anna), Greene, M.H. (Mark H.), Guénel, P. (Pascal), Haeberle, L. (Lothar), Haiman, C.A. (Christopher A.), Hallberg, E. (Emily), Hamann, U. (Ute), Hansen, T.V.O. (Thomas), Hart, S. (Stewart), Hartikainen, J.M. (J.), Hartman, J.M. (Joost), Hassan, N. (Norhashimah), Healey, S. (Sue), Hogervorst, F.B.L. (Frans), Verhoef, S., Hendricks, C.B. (Carolyn B.), Hillemanns, P. (Peter), Hollestelle, A. (Antoinette), Hulick, P.J. (Peter), Hunter, D. (David), Imyanitov, E.N. (Evgeny), Isaacs, C. (Claudine), Ito, H. (Hidemi), Jakubowska, A. (Anna), Janavicius, R. (Ramunas), Jaworska-Bieniek, K. (Katarzyna), Jensen, U.B., John, E.M. (Esther), Joly Beauparlant, C. (Charles), Jones, M. (Michael), Kabisch, M. (Maria), Kang, D. (Daehee), Karlan, B.Y. (Beth Y.), Kauppila, S. (Saila), Kerin, M. (Michael), Khan, S. (Sofia), Khusnutdinova, E.K. (Elza), Knight, J.A. (Julia), Konstantopoulou, I. (I.), Kraft, P. (Peter), Kwong, A. (Ava), Laitman, Y. (Yael), Lambrechts, D. (Diether), Lázaro, C. (Conxi), Le Marchand, L. (Loic), Lee, C.N. (Chuen), Lee, M.H. (Min Hyuk), Lester, K.J. (Kathryn), Li, J. (Jingmei), Liljegren, A. (Annelie), Lindblom, A. (Annika), Lophatananon, A. (Artitaya), Lubinski, J. (Jan), Mai, P.L. (Phuong), Mannermaa, A. (Arto), Manoukian, S. (Siranoush), Margolin, S. (Sara), Marme, F. (Frederik), Matsuo, K. (Keitaro), McGuffog, L. (Lesley), Meindl, A. (Alfons), Menegaux, F. (Florence), Montagna, M. (Marco), Muir, K.R. (K.), Mulligan, A.-M. (Anna-Marie), Nathanson, K.L. (Katherine), Neuhausen, S.L. (Susan), Nevanlinna, H. (Heli), Newcomb, P. (Polly), Nord, S. (Silje), Nussbaum, R.L. (Robert L.), Offit, K. (Kenneth), Olah, E., Olopade, O.I. (Olufunmilayo I.), Olswold, C. (Curtis), Osorio, A. (Ana), Papi, L. (Laura), Park-Simon, T.-W., Paulsson-Karlsson, Y. (Ylva), Peeters, S.T.H. (Stephanie), Peissel, B. (Bernard), Peterlongo, P. (Paolo), Peto, J. (Julian), Pfeiler, G. (Georg), Phelan, C. (Catherine), Presneau, N. (Nadege), Radice, P. (Paolo), Rahman, N. (Nazneen), Ramus, S.J. (Susan), Rashid, M.U. (Muhammad), Rennert, G. (Gad), Rhiem, K. (Kerstin), Rudolph, A. (Anja), Salani, R. (Ritu), Sangrajrang, S. (Suleeporn), Sawyer, E.J. (Elinor), Schmidt, M.K. (Marjanka), Schmutzler, R.K. (Rita), Schoemaker, M. (Minouk), Schürmann, P. (Peter), Seynaeve, C.M. (Caroline), Shen, C.-Y. (Chen-Yang), Shrubsole, M. (Martha), Shu, X.-O. (Xiao-Ou), Sigurdson, A.J. (Alice), Singer, C.F. (Christian), Slager, S. (Susan), Soucy, P. (Penny), Southey, M.C. (Melissa), Steinemann, D. (Doris), Swerdlow, A.J. (Anthony ), Szabo, C. (Csilla), Tchatchou, S. (Sandrine), Teixeira, P.J., Teo, S.-H. (Soo-Hwang), Terry, M.B. (Mary Beth), Tessier, D.C. (Daniel C.), Teulé, A. (A.), Thomassen, M. (Mads), Tihomirova, L. (Laima), Tischkowitz, M. (Marc), Toland, A.E. (Amanda), Tung, N. (Nadine), Turnbull, C. (Clare), Ouweland, A.M.W. (Ans) van den, Rensburg, E.J. (Elizabeth) van, ven den Berg, D. (David), Vijai, J. (Joseph), Wang-Gohrke, S. (Shan), Weitzel, J.N. (Jeffrey), Whittemore, A.S. (Alice), Winqvist, R. (Robert), Wong, T.Y. (Tien Y.), Wu, A.H. (Anna), Yannoukakos, D. (Drakoulis), Yu, J-C. (Jyh-Cherng), Pharoah, P.D.P. (Paul), Hall, P. (Per), Chenevix-Trench, G. (Georgia), Dunning, A.M. (Alison), Simard, J. (Jacques), Couch, F.J. (Fergus), Antoniou, A.C. (Antonis), Easton, D.F. (Douglas F.), and Zheng, W. (Wei)
Abstract: Background: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10-9), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10-5), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10-4) identified in the general populations, and rs113824616 (P = 7 × 10-5) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. Conclusion: This study id
Published: 2016
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246. Age-And tumor subtype-specific breast cancer risk estimates for CHEK2∗1100delC Carriers

Author: Schmidt, M.K. (Marjanka), Hogervorst, F.B.L. (Frans), Hien, R.R. (Richard) van, Cornelissen, S. (Sten), Broeks, A. (Annegien), Adank, M.A. (Muriel), Meijers, H. (Hanne), Waisfisz, Q. (Quinten), Hollestelle, A. (Antoinette), Schutte, A.E.M. (Mieke), Ouweland, A.M.W. (Ans) van den, Hooning, M.J. (Maartje), Andrulis, I.L. (Irene), Anton-Culver, H. (Hoda), Antonenkova, N.N. (Natalia N.), Antoniou, A.C. (Antonis), Arndt, V. (Volker), Bermisheva, M. (Marina), Bogdanova, N.V. (Natalia), Bolla, M.K. (Manjeet K.), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Brüning, T. (Thomas), Burwinkel, B. (Barbara), Chang-Claude, J. (Jenny), Chenevix-Trench, G. (Georgia), Couch, F.J. (Fergus), Cox, A. (Angela), Cross, S.S. (Simon), Czene, K. (Kamila), Dunning, A.M. (Alison), Fasching, P.A. (Peter), Figueroa, J.D. (Jonine), Fletcher, O. (Olivia), Flyger, H. (Henrik), Galle, E. (Eva), García-Closas, M. (Montserrat), Giles, G.G. (Graham G.), Haeberle, L. (Lothar), Hall, P. (Per), Hillemanns, P. (Peter), Hopper, J.L. (John), Jakubowska, A. (Anna), John, E.M. (Esther), Jones, M. (Michael), Khusnutdinova, E.K. (Elza), Knight, J.A. (Julia), Kosma, V-M. (Veli-Matti), Kristensen, V. (Vessela), Lee, A. (Andrew), Lindblom, A. (Annika), Lubinski, J. (Jan), Mannermaa, A. (Arto), Margolin, S. (Sara), Meindl, A. (Alfons), Milne, R.L. (Roger), Muranen, T.A. (Taru A.), Newcomb, P.A. (Polly A.), Offit, K. (Kenneth), Park-Simon, T.-W., Peto, J. (Julian), Pharoah, P.D.P. (Paul), Robson, M. (Mark), Rudolph, A. (Anja), Sawyer, E.J. (Elinor), Schmutzler, R.K. (Rita), Seynaeve, C.M. (Caroline), Soens, J. (Julie), Southey, M.C. (Melissa), Spurdle, A.B. (Amanda), Surowy, H. (Harald), Swerdlow, A.J. (Anthony ), Tollenaar, R.A.E.M. (Rob A.E.M.), Tomlinson, I.P. (Ian), Trentham-Dietz, A. (Amy), Vachon, C. (Celine), Wang, Q. (Qin), Whittemore, A.S. (Alice), Ziogas, A. (Argyrios), Kolk, L.E. (Lizet) van der, Nevanlinna, H. (Heli), Dörk, T. (Thilo), Bojesen, S.E. (Stig), Easton, D.F. (Douglas F.), Schmidt, M.K. (Marjanka), Hogervorst, F.B.L. (Frans), Hien, R.R. (Richard) van, Cornelissen, S. (Sten), Broeks, A. (Annegien), Adank, M.A. (Muriel), Meijers, H. (Hanne), Waisfisz, Q. (Quinten), Hollestelle, A. (Antoinette), Schutte, A.E.M. (Mieke), Ouweland, A.M.W. (Ans) van den, Hooning, M.J. (Maartje), Andrulis, I.L. (Irene), Anton-Culver, H. (Hoda), Antonenkova, N.N. (Natalia N.), Antoniou, A.C. (Antonis), Arndt, V. (Volker), Bermisheva, M. (Marina), Bogdanova, N.V. (Natalia), Bolla, M.K. (Manjeet K.), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Brüning, T. (Thomas), Burwinkel, B. (Barbara), Chang-Claude, J. (Jenny), Chenevix-Trench, G. (Georgia), Couch, F.J. (Fergus), Cox, A. (Angela), Cross, S.S. (Simon), Czene, K. (Kamila), Dunning, A.M. (Alison), Fasching, P.A. (Peter), Figueroa, J.D. (Jonine), Fletcher, O. (Olivia), Flyger, H. (Henrik), Galle, E. (Eva), García-Closas, M. (Montserrat), Giles, G.G. (Graham G.), Haeberle, L. (Lothar), Hall, P. (Per), Hillemanns, P. (Peter), Hopper, J.L. (John), Jakubowska, A. (Anna), John, E.M. (Esther), Jones, M. (Michael), Khusnutdinova, E.K. (Elza), Knight, J.A. (Julia), Kosma, V-M. (Veli-Matti), Kristensen, V. (Vessela), Lee, A. (Andrew), Lindblom, A. (Annika), Lubinski, J. (Jan), Mannermaa, A. (Arto), Margolin, S. (Sara), Meindl, A. (Alfons), Milne, R.L. (Roger), Muranen, T.A. (Taru A.), Newcomb, P.A. (Polly A.), Offit, K. (Kenneth), Park-Simon, T.-W., Peto, J. (Julian), Pharoah, P.D.P. (Paul), Robson, M. (Mark), Rudolph, A. (Anja), Sawyer, E.J. (Elinor), Schmutzler, R.K. (Rita), Seynaeve, C.M. (Caroline), Soens, J. (Julie), Southey, M.C. (Melissa), Spurdle, A.B. (Amanda), Surowy, H. (Harald), Swerdlow, A.J. (Anthony ), Tollenaar, R.A.E.M. (Rob A.E.M.), Tomlinson, I.P. (Ian), Trentham-Dietz, A. (Amy), Vachon, C. (Celine), Wang, Q. (Qin), Whittemore, A.S. (Alice), Ziogas, A. (Argyrios), Kolk, L.E. (Lizet) van der, Nevanlinna, H. (Heli), Dörk, T. (Thilo), Bojesen, S.E. (Stig), and Easton, D.F. (Douglas F.)
Abstract: Purpose CHEK2∗1100delC is a well-established breast cancer risk variant that is most prevalent in European populations; however, there are limited data on risk of breast cancer by age and tumor subtype, which limits its usefulness in breast cancer risk prediction. We aimed to generate tumor subtypeand age-specific risk estimates by using data from the Breast Cancer Association Consortium, including 44,777 patients with breast cancer and 42,997 controls from 33 studies genotyped for CHEK2∗1100delC. Patients and Methods CHEK2∗1100delC genotyping was mostly done by a custom Taqman assay. Breast cancer odds ratios (ORs) for CHEK2∗1100delC carriers versus noncarriers were
Published: 2016
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247. Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21

Author: Hamdi, Y. (Yosr), Soucy, P. (Penny), Adoue, V. (Véronique), Michailidou, K. (Kyriaki), Canisius, S. (Sander), Lemaçon, A. (Audrey), Droit, A. (Arnaud), Andrulis, I.L. (Irene), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Baynes, C. (Caroline), Blomqvist, C. (Carl), Bogdanova, N.V. (Natalia), Bojesen, S.E. (Stig), Bolla, M.K. (Manjeet K.), Bonnani, B. (Bernardo), Borresen-Dale, A.-L. (Anne-Lise), Brand, J.S. (Judith S.), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Broeks, A. (Annegien), Burwinkel, B. (Barbara), Chang-Claude, J. (Jenny), Couch, F.J. (Fergus J.), Cox, A. (Angela), Cross, S.S. (Simon), Czene, K. (Kamila), Darabi, H. (Hatef), Dennis, J. (Joe), Devilee, P. (Peter), Dörk, T. (Thilo), Santos Silva, I. (Isabel) dos, Eriksson, M. (Mats), Fasching, P.A. (Peter), Figueroa, J.D. (Jonine), Flyger, H. (Henrik), García-Closas, M. (Montserrat), Giles, G.G. (Graham G.), Goldberg, M.S. (Mark), González-Neira, A. (Anna), Grenaker Alnæs, G. (Grethe), Guénel, P. (Pascal), Haeberle, L. (Lothar), Haiman, C.A. (Christopher), Hamann, U. (Ute), Hallberg, E. (Emily), Hooning, M.J. (Maartje), Hopper, J.L. (John), Jakubowska, A. (Anna), Jones, M. (Michael), Kabisch, M. (Maria), Kataja, V. (Vesa), Lambrechts, D. (Diether), Le Marchand, L. (Loic), Lindblom, A. (Annika), Lubinski, J. (Jan), Mannermaa, A. (Arto), Maranian, M. (Melanie), Margolin, S. (Sara), Marme, F. (Frederik), Milne, R.L. (Roger), Neuhausen, S.L. (Susan), Nevanlinna, H. (Heli), Neven, P. (Patrick), Olswold, C. (Curtis), Peto, J. (Julian), Plaseska-Karanfilska, D. (Dijana), Pykäs, K. (Katri), Radice, P. (Paolo), Rudolph, A. (Anja), Sawyer, E.J. (Elinor), Schmidt, M.K. (Marjanka), Shu, X.-O. (Xiao-Ou), Southey, M.C. (Melissa), Swerdlow, A.J. (Anthony ), Tollenaar, R.A.E.M. (Rob), Tomlinson, I.P. (Ian), Torres, D. (Diana), Truong, T. (Thérèse), Vachon, C. (Celine), Ouweland, A.M.W. (Ans) van den, Wang, Q. (Qin), Winqvist, R. (Robert), Zheng, W. (Wei), Benítez, J. (Javier), Chenevix-Trench, G. (Georgia), Dunning, A.M. (Alison), Pharoah, P.D.P. (Paul), Kristensen, V. (Vessela), Hall, P. (Per), Easton, D.F. (Douglas), Pastinen, T. (Tomi), Nord, S. (Silje), Simard, J. (Jacques), Hamdi, Y. (Yosr), Soucy, P. (Penny), Adoue, V. (Véronique), Michailidou, K. (Kyriaki), Canisius, S. (Sander), Lemaçon, A. (Audrey), Droit, A. (Arnaud), Andrulis, I.L. (Irene), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Baynes, C. (Caroline), Blomqvist, C. (Carl), Bogdanova, N.V. (Natalia), Bojesen, S.E. (Stig), Bolla, M.K. (Manjeet K.), Bonnani, B. (Bernardo), Borresen-Dale, A.-L. (Anne-Lise), Brand, J.S. (Judith S.), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Broeks, A. (Annegien), Burwinkel, B. (Barbara), Chang-Claude, J. (Jenny), Couch, F.J. (Fergus J.), Cox, A. (Angela), Cross, S.S. (Simon), Czene, K. (Kamila), Darabi, H. (Hatef), Dennis, J. (Joe), Devilee, P. (Peter), Dörk, T. (Thilo), Santos Silva, I. (Isabel) dos, Eriksson, M. (Mats), Fasching, P.A. (Peter), Figueroa, J.D. (Jonine), Flyger, H. (Henrik), García-Closas, M. (Montserrat), Giles, G.G. (Graham G.), Goldberg, M.S. (Mark), González-Neira, A. (Anna), Grenaker Alnæs, G. (Grethe), Guénel, P. (Pascal), Haeberle, L. (Lothar), Haiman, C.A. (Christopher), Hamann, U. (Ute), Hallberg, E. (Emily), Hooning, M.J. (Maartje), Hopper, J.L. (John), Jakubowska, A. (Anna), Jones, M. (Michael), Kabisch, M. (Maria), Kataja, V. (Vesa), Lambrechts, D. (Diether), Le Marchand, L. (Loic), Lindblom, A. (Annika), Lubinski, J. (Jan), Mannermaa, A. (Arto), Maranian, M. (Melanie), Margolin, S. (Sara), Marme, F. (Frederik), Milne, R.L. (Roger), Neuhausen, S.L. (Susan), Nevanlinna, H. (Heli), Neven, P. (Patrick), Olswold, C. (Curtis), Peto, J. (Julian), Plaseska-Karanfilska, D. (Dijana), Pykäs, K. (Katri), Radice, P. (Paolo), Rudolph, A. (Anja), Sawyer, E.J. (Elinor), Schmidt, M.K. (Marjanka), Shu, X.-O. (Xiao-Ou), Southey, M.C. (Melissa), Swerdlow, A.J. (Anthony ), Tollenaar, R.A.E.M. (Rob), Tomlinson, I.P. (Ian), Torres, D. (Diana), Truong, T. (Thérèse), Vachon, C. (Celine), Ouweland, A.M.W. (Ans) van den, Wang, Q. (Qin), Winqvist, R. (Robert), Zheng, W. (Wei), Benítez, J. (Javier), Chenevix-Trench, G. (Georgia), Dunning, A.M. (Alison), Pharoah, P.D.P. (Paul), Kristensen, V. (Vessela), Hall, P. (Per), Easton, D.F. (Douglas), Pastinen, T. (Tomi), Nord, S. (Silje), and Simard, J. (Jacques)
Abstract: There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage disequilib
Published: 2016
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248. Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

Author: Lawrenson, K. (Kate), Kar, S. (Siddhartha), McCue, K. (Karen), Kuchenbaeker, K. (Karoline), Michailidou, K. (Kyriaki), Tyrer, J.P. (Jonathan), Beesley, J. (Jonathan), Ramus, S.J. (Susan), Li, Q. (Qiyuan), Delgado, M.K. (Melissa K.), Lee, J.M. (Janet M.), Aittomäki, K. (Kristiina), Andrulis, I.L. (Irene), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Arun, B.K. (Banu), Arver, B. (Brita Wasteson), Bandera, E.V. (Elisa), Barile, M. (Monica), Barkardottir, R.B. (Rosa B.), Barrowdale, D. (Daniel), Beckmann, M.W. (Matthias), Benítez, J. (Javier), Berchuck, A. (Andrew), Bisogna, M. (Maria), Bjorge, L. (Line), Blomqvist, C. (Carl), Blot, W.J. (William), Bogdanova, N.V. (Natalia), Bojesen, A. (Anders), Bojesen, S.E. (Stig), Bolla, M.K. (Manjeet K.), Bonnani, B. (Bernardo), Borresen-Dale, A.-L. (Anne-Lise), Brauch, H. (Hiltrud), Brennan, P. (Paul), Brenner, H. (Hermann), Bruinsma, F. (Fiona), Brunet, J. (Joan), Buhari, S.A.B.S. (Shaik Ahmad Bin Syed), Burwinkel, B. (Barbara), Butzow, R. (Ralf), Buys, S.S. (Saundra), Cai, Q. (Qiuyin), Caldes, T. (Trinidad), Campbell, I. (Ian), Canniotto, R. (Rikki), Chang-Claude, J. (Jenny), Chiquette, J. (Jocelyne), Choi, J.-Y. (Ji-Yeob), Claes, K.B.M. (Kathleen B.M.), Cook, L.S. (Linda S.), Cox, A. (Angela), Cramer, D.W. (Daniel), Cross, S.S. (Simon), Cybulski, C. (Cezary), Czene, K. (Kamila), Daly, M.B. (Mary B.), Damiola, F. (Francesca), Dansonka-Mieszkowska, A. (Agnieszka), Darabi, H. (Hatef), Dennis, J. (Joe), Devilee, P. (Peter), Díez, O. (Orland), Doherty, J.A. (Jennifer A.), Domchek, S.M. (Susan), Dorfling, C.M. (Cecilia), Dörk, T. (Thilo), Dumont, M. (Martine), Ehrencrona, H. (Hans), Ejlertsen, B. (Bent), Ellis, S.D. (Steve), Engel, C. (Christoph), Lee, E. (Eunjung), Evans, D.G. (D. Gareth), Fasching, P.A. (Peter), Feliubadaló, L. (L.), Figueroa, J.D. (Jonine), Flesch-Janys, D. (Dieter), Fletcher, O. (Olivia), Flyger, H. (Henrik), Foretova, L. (Lenka), Fostira, F. (Florentia), Foulkes, W.D. (William), Fridley, B.L. (Brooke), Friedman, E. (Eitan), Frost, D. (Debra), Gambino, G. (Gaetana), Ganz, P.A. (Patricia A.), Garber, J. (Judy), García-Closas, M. (Montserrat), Gentry-Maharaj, A. (Aleksandra), Ghoussaini, M. (Maya), Giles, G.G. (Graham), Glasspool, R. (Rosalind), Godwin, A.K. (Andrew K.), Goldberg, M.S. (Mark), Goldgar, D. (David), González-Neira, A. (Anna), Goode, E.L. (Ellen), Goodman, M.T. (Marc), Greene, M.H. (Mark H.), Gronwald, J. (Jacek), Guénel, P. (Pascal), Haiman, C.A. (Christopher A.), Hall, P. (Per), Hallberg, E. (Emily), Hamann, U. (Ute), Hansen, T.V.O. (Thomas), harrington, P. (Patricia), Hartman, J.M. (Joost), Hassan, N. (Norhashimah), Healey, S. (Sue), Heitz, P.U., Herzog, J. (Josef), Høgdall, E. (Estrid), Høgdall, C.K. (Claus), Hogervorst, F.B.L. (Frans), Hollestelle, A. (Antoinette), Hopper, J.L. (John), Hulick, P.J. (Peter), Huzarski, T. (Tomasz), Imyanitov, E.N. (Evgeny), Isaacs, C. (Claudine), Ito, H. (Hidemi), Jakubowska, A. (Anna), Janavicius, R. (Ramunas), Jensen, A. (Allan), John, E.M. (Esther), Johnson, N. (Nichola), Kabisch, M. (Maria), Kang, D. (Daehee), Kapuscinski, M.K. (Miroslav K.), Karlan, B.Y. (Beth Y.), Khan, S. (Sofia), Kiemeney, L.A.L.M. (Bart), Kjaer, M. (Michael), Knight, J.A. (Julia), Konstantopoulou, I. (I.), Kosma, V-M. (Veli-Matti), Kristensen, V. (Vessela), Kupryjanczyk, J. (Jolanta), Kwong, A. (Ava), Hoya, M. (Miguel) de La, Laitman, Y. (Yael), Lambrechts, D. (Diether), Le, N.D. (Nhu D.), De Leeneer, K. (Kim), Lester, K.J. (Kathryn), Levine, D.A. (Douglas), Li, J. (Jingmei), Lindblom, A. (Annika), Long, J. (Jirong), Lophatananon, A. (Artitaya), Loud, J.T. (Jennifer), Lu, K.H. (Karen), Lubinski, J. (Jan), Mannermaa, A. (Arto), Manoukian, S. (Siranoush), Le Marchand, L. (Loic), Margolin, S. (Sara), Marme, F. (Frederick), Massuger, L.F. (Leon), Matsuo, K. (Keitaro), Mazoyer, S. (Sylvie), McGuffog, L. (Lesley), McLean, C.A. (Catriona Ann), McNeish, I. (Iain), Meindl, A. (Alfons), Menon, U. (Usha), Mensenkamp, A.R. (Arjen R.), Milne, R.L. (Roger), Montagna, M. (Marco), Moysich, K.B. (Kirsten), Muir, K.R. (K.), Mulligan, A.-M. (Anna-Marie), Nathanson, K.L. (Katherine), Ness, R.B. (Roberta), Neuhausen, S.L. (Susan), Nevanlinna, H. (Heli), Nord, S. (Silje), Nussbaum, R.L. (Robert L.), Odunsi, K. (Kunle), Offit, K. (Kenneth), Olah, E., Olopade, O.I. (Olufunmilayo I.), Olson, J.E. (Janet), Olswold, C. (Curtis), O'Malley, D.M. (David M.), Orlow, I. (Irene), Orr, N. (Nick), Osorio, A. (Ana), Park, S.K. (Sue Kyung), Pearce, C.L. (Celeste), Pejovic, T. (Tanja), Peterlongo, P. (Paolo), Pfeiler, G. (Georg), Phelan, C. (Catherine), Poole, E.M. (Elizabeth), Pykäs, K. (Katri), Radice, P. (Paolo), Rantala, J. (Johanna), Rashid, M.U. (Muhammad), Rennert, G. (Gad), Rhenius, V. (Valerie), Rhiem, K. (Kerstin), Risch, H. (Harvey), Rodriguez, G.C. (Gustavo), Rossing, M.A. (Mary Anne), Rudolph, A. (Anja), Salvesen, H.B. (Helga), Sangrajrang, S. (Suleeporn), Sawyer, E.J. (Elinor J.), Schildkraut, J.M. (Joellen), Schmidt, M.K. (Marjanka), Schmutzler, R.K. (Rita), Sellers, T.A. (Thomas A.), Seynaeve, C.M. (Caroline), Shah, M. (Mitul), Shen, C.-Y. (Chen-Yang), Shu, X.-O. (Xiao-Ou), Sieh, W. (Weiva), Singer, C.F. (Christian), Sinilnikova, O. (Olga), Slager, S. (Susan), Song, H. (Honglin), Soucy, P. (Penny), Southey, M.C. (Melissa), Stenmark-Askmalm, M. (Marie), Stoppa-Lyonnet, D. (Dominique), Sutter, C. (Christian), Swerdlow, A.J. (Anthony ), Tchatchou, S. (Sandrine), Teixeira, P.J., Teo, S.-H. (Soo-Hwang), Terry, K.L. (Kathryn), Terry, M.B. (Mary Beth), Thomassen, M. (Mads), Tibiletti, M.G. (Maria Grazia), Tihomirova, L. (Laima), Tognazzo, S. (Silvia), Toland, A.E. (Amanda), Tomlinson, I.P. (Ian), Torres, D. (Diana), Truong, T. (Thérèse), Tseng, C.-C. (Chiu-Chen), Tung, N. (Nadine), Tworoger, S.S. (Shelley S.), Vachon, C. (Celine), Van Den Ouweland, A.M.W. (Ans M.W.), Van Doorn, H.C. (Helena C.), Rensburg, E.J. (Elizabeth) van, Veer, L.J. (Laura) van 't, Vanderstichele, A. (Adriaan), Vergote, I. (Ignace), Vijai, J. (Joseph), Wang, Q. (Qin), Wang-Gohrke, S. (Shan), Weitzel, J.N. (Jeffrey), Wentzensen, N. (N.), Whittemore, A.S. (Alice), Wildiers, H. (Hans), Winqvist, R. (Robert), Wu, A.H. (Anna), Yannoukakos, D. (Drakoulis), Yoon, S.-Y. (Sook-Yee), Yu, J-C. (Jyh-Cherng), Zheng, W. (Wei), Zheng, Y. (Ying), Khanna, K.K. (Kum Kum), Simard, J. (Jacques), Monteiro, A.N.A. (Alvaro N.), French, J.D. (Juliet), Couch, F.J. (Fergus), Freedman, M. (Matthew), Easton, D.F. (Douglas F.), Dunning, A.M. (Alison), Pharoah, P.D.P. (Paul), Edwards, S.L. (Stacey), Chenevix-Trench, G. (Georgia), Antoniou, A.C. (Antonis), Gayther, S.A. (Simon), Bowtell, D. (David), DeFazio, A. (Anna), Webb, P. (Penny), Collonge-Rame, M.-A., Damette, A. (Alexandre), Barouk-Simonet, E. (Emmanuelle), Bonnet, F. (Françoise), Bubien, V. (Virginie), Sevenet, N. (Nicolas), Longy, M. (Michel), Berthet, P. (Pascaline), Vaur, D. (Dominique), Castera, L. (Laurent), Ferrer, S.F., Bignon, Y.-J. (Yves-Jean), Uhrhammer, N. (Nancy), Coron, F. (Fanny), Faivre, L. (Laurence), Baurand, A. (Amandine), Jacquot, C. (Caroline), Bertolone, G. (Geoffrey), Lizard, S. (Sarab), Leroux, D. (Dominique), Dreyfus, H. (Hélène), Rebischung, C. (Christine), Peysselon, M. (Magalie), Peyrat, J.-P., Fournier, J. (Joëlle), Révillion, F. (Françoise), Adenis, C. (Claude), Vénat-Bouvet, L. (Laurence), Léone, M. (Mélanie), Boutry-Kryza, N. (N.), Calender, A. (Alain), Giraud, S. (Sophie), Verny-Pierre, C. (Carole), Lasset, C. (Christine), Bonadona, V. (Valérie), Barjhoux, L. (Laure), Sobol, H. (Hagay), Bourdon, V. (Violaine), Noguchi, T. (Tetsuro), Remenieras, A. (Audrey), Coupier, I. (Isabelle), Pujol, P. (Pascal), Sokolowska, J. (Johanna), Bronner, M. (Myriam), Delnatte, C.D. (Capucine), Bézieau, S. (Stéphane), Mari, V. (Véronique), Gauthier-Villars, M. (Marion), Buecher, B. (Bruno), Rouleau, E. (Etienne), Golmard, L. (Lisa), Moncoutier, V. (Virginie), Belotti, M. (Muriel), Pauw, A. (Antoine) de, Elan, C. (Camille), Fourme, E. (Emmanuelle), Birot, A.-M. (Anne-Marie), Saule, C. (Claire), Laurent, M. (Maïté), Houdayer, C. (Claude), Lesueur, F. (Fabienne), Mebirouk, N. (Noura), Coulet, F. (Florence), Colas, C. (Chrystelle), Soubrier, F., Warcoin, M. (Mathilde), Prieur, F. (Fabienne), Lebrun, M. (Marine), Kientz, C. (Caroline), Muller, D.W. (Danièle), Fricker, J.P. (Jean Pierre), Toulas, C. (Christine), Guimbaud, R. (Rosine), Gladieff, L. (Laurence), Feillel, V. (Viviane), Mortemousque, I. (Isabelle), Bressac-de Paillerets, B. (Brigitte), Caron, O. (Olivier), Guillaud-Bataille, M. (Marine), Gregory, H. (Helen), Miedzybrodzka, Z. (Zosia), Morrison, P.J. (Patrick), Donaldson, A. (Alan), Rogers, M.T. (Mark), Kennedy, M.J. (John), Porteous, M.E. (Mary), Brady, A. (A.), Barwell, J. (Julian), Foo, C. (Claire), Lalloo, F. (Fiona), Side, L. (Lucy), Eason, J. (Jacqueline), Henderson, A. (Alex), Walker, L.J. (Lisa), Cook, J. (Jackie), Snape, K. (Katie), Murray, A. (Alexandra), McCann, E. (Emma), Rookus, M.A. (Matti), Leeuwen, F.E. (Flora) van, Kolk, L.E. (Lizet) van der, Russell, N.S. (Nicola), Lange, J.L. (J.) de, Wijnands, R., Collée, J.M. (Margriet), Hooning, M.J. (Maartje), Seynaeve, C., Deurzen, C.H.M. (Carolien) van, Obdeijn, A.I.M. (Inge-Marie), Asperen, C.J. (Christi) van, Tollenaar, R.A.E.M. (Rob), Cronenburg, T.C.T.E.F. van, Kets, C.M. (Marleen), Ausems, M.G.E.M. (Margreet), Pol, C. (Carmen) van der, Os, T.A.M. (Theo) van, Waisfisz, Q. (Quinten), Meijers-Heijboer, E.J. (Hanne), Gómez García, E.B. (Encarna), Oosterwijk, J.C. (Jan), Mourits, M.J. (Marjan), Bock, G.H. (Geertruida) de, Vasen, H. (Hans), Siesling, S., Verloop, J., Overbeek, L.I.H. (Lucy), Fox, S.B. (Stephen), Kirk, J. (Judy), Lindeman, G.J. (Geoffrey), Price, M. (Melanie), Lawrenson, K. (Kate), Kar, S. (Siddhartha), McCue, K. (Karen), Kuchenbaeker, K. (Karoline), Michailidou, K. (Kyriaki), Tyrer, J.P. (Jonathan), Beesley, J. (Jonathan), Ramus, S.J. (Susan), Li, Q. (Qiyuan), Delgado, M.K. (Melissa K.), Lee, J.M. (Janet M.), Aittomäki, K. (Kristiina), Andrulis, I.L. (Irene), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Arun, B.K. (Banu), Arver, B. (Brita Wasteson), Bandera, E.V. (Elisa), Barile, M. (Monica), Barkardottir, R.B. (Rosa B.), Barrowdale, D. (Daniel), Beckmann, M.W. (Matthias), Benítez, J. (Javier), Berchuck, A. (Andrew), Bisogna, M. (Maria), Bjorge, L. (Line), Blomqvist, C. (Carl), Blot, W.J. (William), Bogdanova, N.V. (Natalia), Bojesen, A. (Anders), Bojesen, S.E. (Stig), Bolla, M.K. (Manjeet K.), Bonnani, B. (Bernardo), Borresen-Dale, A.-L. (Anne-Lise), Brauch, H. (Hiltrud), Brennan, P. (Paul), Brenner, H. (Hermann), Bruinsma, F. (Fiona), Brunet, J. (Joan), Buhari, S.A.B.S. (Shaik Ahmad Bin Syed), Burwinkel, B. (Barbara), Butzow, R. (Ralf), Buys, S.S. (Saundra), Cai, Q. (Qiuyin), Caldes, T. (Trinidad), Campbell, I. (Ian), Canniotto, R. (Rikki), Chang-Claude, J. (Jenny), Chiquette, J. (Jocelyne), Choi, J.-Y. (Ji-Yeob), Claes, K.B.M. (Kathleen B.M.), Cook, L.S. (Linda S.), Cox, A. (Angela), Cramer, D.W. (Daniel), Cross, S.S. (Simon), Cybulski, C. (Cezary), Czene, K. (Kamila), Daly, M.B. (Mary B.), Damiola, F. (Francesca), Dansonka-Mieszkowska, A. (Agnieszka), Darabi, H. (Hatef), Dennis, J. (Joe), Devilee, P. (Peter), Díez, O. (Orland), Doherty, J.A. (Jennifer A.), Domchek, S.M. (Susan), Dorfling, C.M. (Cecilia), Dörk, T. (Thilo), Dumont, M. (Martine), Ehrencrona, H. (Hans), Ejlertsen, B. (Bent), Ellis, S.D. (Steve), Engel, C. (Christoph), Lee, E. (Eunjung), Evans, D.G. (D. Gareth), Fasching, P.A. (Peter), Feliubadaló, L. (L.), Figueroa, J.D. (Jonine), Flesch-Janys, D. (Dieter), Fletcher, O. (Olivia), Flyger, H. (Henrik), Foretova, L. (Lenka), Fostira, F. (Florentia), Foulkes, W.D. (William), Fridley, B.L. (Brooke), Friedman, E. (Eitan), Frost, D. (Debra), Gambino, G. (Gaetana), Ganz, P.A. (Patricia A.), Garber, J. (Judy), García-Closas, M. (Montserrat), Gentry-Maharaj, A. (Aleksandra), Ghoussaini, M. (Maya), Giles, G.G. (Graham), Glasspool, R. (Rosalind), Godwin, A.K. (Andrew K.), Goldberg, M.S. (Mark), Goldgar, D. (David), González-Neira, A. (Anna), Goode, E.L. (Ellen), Goodman, M.T. (Marc), Greene, M.H. (Mark H.), Gronwald, J. (Jacek), Guénel, P. (Pascal), Haiman, C.A. (Christopher A.), Hall, P. (Per), Hallberg, E. (Emily), Hamann, U. (Ute), Hansen, T.V.O. (Thomas), harrington, P. (Patricia), Hartman, J.M. (Joost), Hassan, N. (Norhashimah), Healey, S. (Sue), Heitz, P.U., Herzog, J. (Josef), Høgdall, E. (Estrid), Høgdall, C.K. (Claus), Hogervorst, F.B.L. (Frans), Hollestelle, A. (Antoinette), Hopper, J.L. (John), Hulick, P.J. (Peter), Huzarski, T. (Tomasz), Imyanitov, E.N. (Evgeny), Isaacs, C. (Claudine), Ito, H. (Hidemi), Jakubowska, A. (Anna), Janavicius, R. (Ramunas), Jensen, A. (Allan), John, E.M. (Esther), Johnson, N. (Nichola), Kabisch, M. (Maria), Kang, D. (Daehee), Kapuscinski, M.K. (Miroslav K.), Karlan, B.Y. (Beth Y.), Khan, S. (Sofia), Kiemeney, L.A.L.M. (Bart), Kjaer, M. (Michael), Knight, J.A. (Julia), Konstantopoulou, I. (I.), Kosma, V-M. (Veli-Matti), Kristensen, V. (Vessela), Kupryjanczyk, J. (Jolanta), Kwong, A. (Ava), Hoya, M. (Miguel) de La, Laitman, Y. (Yael), Lambrechts, D. (Diether), Le, N.D. (Nhu D.), De Leeneer, K. (Kim), Lester, K.J. (Kathryn), Levine, D.A. (Douglas), Li, J. (Jingmei), Lindblom, A. (Annika), Long, J. (Jirong), Lophatananon, A. (Artitaya), Loud, J.T. (Jennifer), Lu, K.H. (Karen), Lubinski, J. (Jan), Mannermaa, A. (Arto), Manoukian, S. (Siranoush), Le Marchand, L. (Loic), Margolin, S. (Sara), Marme, F. (Frederick), Massuger, L.F. (Leon), Matsuo, K. (Keitaro), Mazoyer, S. (Sylvie), McGuffog, L. (Lesley), McLean, C.A. (Catriona Ann), McNeish, I. (Iain), Meindl, A. (Alfons), Menon, U. (Usha), Mensenkamp, A.R. (Arjen R.), Milne, R.L. (Roger), Montagna, M. (Marco), Moysich, K.B. (Kirsten), Muir, K.R. (K.), Mulligan, A.-M. 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Abstract: A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
Published: 2016
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249. BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers

Author: Meeks, H.D. (Huong D.), Song, H. (Honglin), Michailidou, K. (Kyriaki), Bolla, M.K. (Manjeet), Dennis, J. (Joe), Wang, Q. (Qing), Barrowdale, D. (Daniel), Frost, D. (Debra), McGuffog, L. (Lesley), Ellis, S.D. (Steve), Feng, B. (Bingjian), Buys, S.S. (Saundra), Hopper, J.L. (John), Southey, M.C. (Melissa), Tesoriero, A. (Andrea), James, M. (Margaret), Bruinsma, F. (Fiona), Campbell, I. (Ian), Broeks, A. (Annegien), Schmidt, M.K. (Marjanka), Hogervorst, F.B.L. (Frans), Beckmann, M.W. (Matthias), Fasching, P.A. (Peter), Fletcher, O. (Olivia), Johnson, N. (Nichola), Sawyer, E.J. (Elinor), Riboli, E. (Elio), Banerjee, S. (Susana), Menon, U. (Usha), Tomlinson, I. (Ian), Burwinkel, B. (Barbara), Hamann, U. (Ute), Marme, F. (Federick), Rudolph, A. (Anja), Janavicius, R. (Ramunas), Tihomirova, L. (Laima), Tung, N. (Nadine), Garber, J. (Judy), Cramer, D. (Daniel), Terry, K.L. (Kathryn), Poole, E.M. (Elizabeth), Tworoger, S. (Shelley), Dorfling, C.M. (Cecilia), Rensburg, E.J. (Elizabeth) van, Godwin, A.K. (Andrew K.), Guénel, P. (Pascal), Truong, T. (Thérèse), Stoppa-Lyonnet, D. (Dominique), Damiola, F. (Francesca), Mazoyer, S. (Sylvie), Sinilnikova, O. (Olga), Isaacs, C. (Claudine), Maugard, C., Bojesen, S.E. (Stig), Flyger, H. (Henrik), Gerdes, A-M. (Anne-Marie), Hansen, T.V.O. (Thomas), Jensen, A. (Allen), Kjaer, M. (Michael), Høgdall, C.K. (Claus), Høgdall, E. (Estrid), Pedersen, I.S. (Inge Sokilde), Thomassen, M. (Mads), Benítez, J. (Javier), González-Neira, A. (Anna), Osorio, A. (Ana), Hoya, M.D.L. (Miguel De La), Segura, P.P. (Pedro Perez), Díez, O. (Orland), Lázaro, C. (Conxi), Brunet, J. (Joan), Anton-Culver, H. (Hoda), Eunjung, L. (Lee), John, E.M. (Esther), Neuhausen, S.L. (Susan), Ding, Y.C. (Yuan), Castillo, D. (Danielle), Weitzel, J.N. (Jeffrey), Ganz, P.A. (Patricia A.), Nussbaum, R. (Robert), Chan, S. (Salina), Karlan, B.Y. (Beth Y.), Lester, K.J. (Kathryn), Wu, A. (Anna), Gayther, S.A. (Simon), Ramus, S.J. (Susan), Sieh, W. (Weiva), Whittermore, A.S. (Alice S.), Monteiro, A.N.A. (Alvaro N.A.), Phelan, C. (Catherine), Terry, M.B. (Mary Beth), Piedmonte, M. (Marion), Offit, K. (Kenneth), Robson, M. (Mark), Levine, D.A. (Douglas), Moysich, K.B. (Kirsten B.), Cannioto, R. (Rikki), Olson, S.H. (Sara), Daly, M.B. (Mary B.), Nathanson, K.L. (Katherine), Domchek, S.M. (Susan), Lu, K.H. (Karen), Liang, D. (Dong), Hildebrant, M.A.T. (Michelle A.T.), Ness, R.B. (Roberta), Modugno, F. (Francesmary), Pearce, L. (Leigh), Goodman, M.T. (Marc T.), Thompson, P.J. (Pamela J.), Brenner, H. (Hermann), Butterbach, K. (Katja), Meindl, A. (Alfons), Hahnen, E. (Eric), Wapenschmidt, B. (Barbara), Brauch, H. (Hiltrud), Brüning, T. (Thomas), Blomqvist, C. (Carl), Khan, S. (Sofia), Nevanlinna, H. (Heli), Pelttari, L.M. (Liisa), Aittomäki, K. (Kristiina), Butzow, R. (Ralf), Bogdanova, N.V. (Natalia), Dörk, T. (Thilo), Lindblom, A. (Annika), Margolin, S. (Sara), Rantala, J. (Johanna), Kosma, V-M. (Veli-Matti), Mannermaa, A. (Arto), Lambrechts, D. (Diether), Neven, P. (Patrick), Claes, K.B.M. (Kathleen B.M.), Van Maerken, T. (Tom), Chang-Claude, J. (Jenny), Flesch-Janys, D. (Dieter), Heitz, P.U., Varon-Mateeva, R. (Raymonda), Peterlongo, P. (Paolo), Radice, P. (Paolo), Viel, A. (Alessandra), Barile, M. (Monica), Peissel, B. (Bernard), Manoukian, S. (Siranoush), Montagna, M. (Marco), Oliani, C. (Cristina), Peixoto, A. (Ana), Teixeira, P.J., Collavoli, A. (Anita), Hallberg, B. (Boubou), Olson, J.E. (Janet), Goode, E.L. (Ellen L.), Hart, S.N. (Steven N.), Shimelis, H. (Hermela), Cunningham, J.M. (Julie), Giles, G.G. (Graham), Milne, R.L. (Roger), Healey, S. (Sue), Tucker, K. (Kathy), Haiman, C.A. (Christopher A.), Henderson, B.E. (Brian), Goldberg, M.S. (Mark), Tischkowitz, M. (Marc), Simard, J. (Jacques), Soucy, P. (Penny), Eccles, D. (Diana), Le, N. (Nhu), Borresen-Dale, A.-L. (Anne-Lise), Kristensen, V. (Vessela), Salvesen, H.B. (Helga), Bjorge, L. (Line), Bandera, E.V. (Elisa), Risch, H. 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(Jennifer A.), Schildkraut, J.M. (Joellen), Koppert, L.B. (Linetta), Kiemeney, L.A.L.M. (Bart), Massuger, L.F. (Leon), Cook, L.S. (Linda S.), Pejovic, T. (Tanja), Li, J. (Jingmei), Borg, Å. (Åke), Öfverholm, A. (Anna), Rossing, M.A. (Mary Anne), Wentzensen, N. (N.), Henriksson, K. (Karin), Cox, A. (Angela), Cross, S.S. (Simon), Pasini, B. (Barbara), Shah, M. (Mitul), Kabisch, M. (Maria), Torres, D. (Diana), Jakubowska, A. (Anna), Lubinski, J. (Jan), Gronwald, J. (Jacek), Agnarsson, B.A. (Bjarni), Kupryjanczyk, J. (Jolanta), Moes-Sosnowska, J. (Joanna), Fostira, F. (Florentia), Konstantopoulou, I. (I.), Slager, S. (Susan), Jones, M. (Michael), Antoniou, A.C. (Antonis), Berchuck, A. (Andrew), Swerdlow, A.J. (Anthony ), Chenevix-Trench, G. (Georgia), Dunning, A.M. (Alison), Pharoah, P.D.P. (Paul), Hall, P. (Per), Easton, D.F. (Douglas F.), Couch, F.J. (Fergus), Spurdle, A.B. (Amanda), Goldgar, D. (David), Meeks, H.D. (Huong D.), Song, H. (Honglin), Michailidou, K. (Kyriaki), Bolla, M.K. (Manjeet), Dennis, J. (Joe), Wang, Q. (Qing), Barrowdale, D. (Daniel), Frost, D. (Debra), McGuffog, L. (Lesley), Ellis, S.D. (Steve), Feng, B. (Bingjian), Buys, S.S. (Saundra), Hopper, J.L. (John), Southey, M.C. (Melissa), Tesoriero, A. (Andrea), James, M. (Margaret), Bruinsma, F. (Fiona), Campbell, I. (Ian), Broeks, A. (Annegien), Schmidt, M.K. (Marjanka), Hogervorst, F.B.L. (Frans), Beckmann, M.W. (Matthias), Fasching, P.A. (Peter), Fletcher, O. (Olivia), Johnson, N. (Nichola), Sawyer, E.J. (Elinor), Riboli, E. (Elio), Banerjee, S. (Susana), Menon, U. (Usha), Tomlinson, I. (Ian), Burwinkel, B. (Barbara), Hamann, U. (Ute), Marme, F. (Federick), Rudolph, A. (Anja), Janavicius, R. (Ramunas), Tihomirova, L. (Laima), Tung, N. (Nadine), Garber, J. (Judy), Cramer, D. (Daniel), Terry, K.L. (Kathryn), Poole, E.M. (Elizabeth), Tworoger, S. (Shelley), Dorfling, C.M. (Cecilia), Rensburg, E.J. (Elizabeth) van, Godwin, A.K. (Andrew K.), Guénel, P. (Pascal), Truong, T. (Thérèse), Stoppa-Lyonnet, D. (Dominique), Damiola, F. (Francesca), Mazoyer, S. (Sylvie), Sinilnikova, O. (Olga), Isaacs, C. (Claudine), Maugard, C., Bojesen, S.E. (Stig), Flyger, H. (Henrik), Gerdes, A-M. (Anne-Marie), Hansen, T.V.O. (Thomas), Jensen, A. (Allen), Kjaer, M. (Michael), Høgdall, C.K. (Claus), Høgdall, E. (Estrid), Pedersen, I.S. (Inge Sokilde), Thomassen, M. (Mads), Benítez, J. (Javier), González-Neira, A. (Anna), Osorio, A. (Ana), Hoya, M.D.L. (Miguel De La), Segura, P.P. (Pedro Perez), Díez, O. (Orland), Lázaro, C. (Conxi), Brunet, J. (Joan), Anton-Culver, H. (Hoda), Eunjung, L. (Lee), John, E.M. (Esther), Neuhausen, S.L. (Susan), Ding, Y.C. (Yuan), Castillo, D. (Danielle), Weitzel, J.N. (Jeffrey), Ganz, P.A. (Patricia A.), Nussbaum, R. (Robert), Chan, S. (Salina), Karlan, B.Y. (Beth Y.), Lester, K.J. (Kathryn), Wu, A. (Anna), Gayther, S.A. (Simon), Ramus, S.J. (Susan), Sieh, W. (Weiva), Whittermore, A.S. (Alice S.), Monteiro, A.N.A. (Alvaro N.A.), Phelan, C. (Catherine), Terry, M.B. (Mary Beth), Piedmonte, M. (Marion), Offit, K. (Kenneth), Robson, M. (Mark), Levine, D.A. (Douglas), Moysich, K.B. (Kirsten B.), Cannioto, R. (Rikki), Olson, S.H. (Sara), Daly, M.B. (Mary B.), Nathanson, K.L. (Katherine), Domchek, S.M. (Susan), Lu, K.H. (Karen), Liang, D. (Dong), Hildebrant, M.A.T. (Michelle A.T.), Ness, R.B. (Roberta), Modugno, F. (Francesmary), Pearce, L. (Leigh), Goodman, M.T. (Marc T.), Thompson, P.J. (Pamela J.), Brenner, H. (Hermann), Butterbach, K. (Katja), Meindl, A. (Alfons), Hahnen, E. (Eric), Wapenschmidt, B. (Barbara), Brauch, H. (Hiltrud), Brüning, T. (Thomas), Blomqvist, C. (Carl), Khan, S. (Sofia), Nevanlinna, H. (Heli), Pelttari, L.M. (Liisa), Aittomäki, K. (Kristiina), Butzow, R. (Ralf), Bogdanova, N.V. (Natalia), Dörk, T. (Thilo), Lindblom, A. (Annika), Margolin, S. (Sara), Rantala, J. (Johanna), Kosma, V-M. (Veli-Matti), Mannermaa, A. (Arto), Lambrechts, D. (Diether), Neven, P. (Patrick), Claes, K.B.M. (Kathleen B.M.), Van Maerken, T. (Tom), Chang-Claude, J. (Jenny), Flesch-Janys, D. (Dieter), Heitz, P.U., Varon-Mateeva, R. (Raymonda), Peterlongo, P. (Paolo), Radice, P. (Paolo), Viel, A. (Alessandra), Barile, M. (Monica), Peissel, B. (Bernard), Manoukian, S. (Siranoush), Montagna, M. (Marco), Oliani, C. (Cristina), Peixoto, A. (Ana), Teixeira, P.J., Collavoli, A. (Anita), Hallberg, B. (Boubou), Olson, J.E. (Janet), Goode, E.L. (Ellen L.), Hart, S.N. (Steven N.), Shimelis, H. (Hermela), Cunningham, J.M. (Julie), Giles, G.G. (Graham), Milne, R.L. (Roger), Healey, S. (Sue), Tucker, K. (Kathy), Haiman, C.A. (Christopher A.), Henderson, B.E. (Brian), Goldberg, M.S. (Mark), Tischkowitz, M. (Marc), Simard, J. (Jacques), Soucy, P. (Penny), Eccles, D. (Diana), Le, N. (Nhu), Borresen-Dale, A.-L. (Anne-Lise), Kristensen, V. (Vessela), Salvesen, H.B. (Helga), Bjorge, L. (Line), Bandera, E.V. (Elisa), Risch, H. (Harvey), Zheng, W. (Wei), Beeghly-Fadiel, A. (Alicia), Cai, H. (Hui), Pykäs, K. (Katri), Tollenaar, R.A.E.M. (Rob), Ouweland, A.M.W. (Ans) van den, Andrulis, I.L. (Irene), Knight, J.A. (Julia A.), Narod, S. (Steven), Devilee, P. (Peter), Winqvist, R. (Robert), Figueroa, J.D. (Jonine), Greene, M.H. (Mark H.), Mai, P.L. (Phuong), Loud, J.T. (Jennifer), García-Closas, M. (Montserrat), Schoemaker, M. (Minouk), Czene, K. (Kamila), Darabi, H. (Hatef), McNeish, I. (Iain), Siddiquil, N. (Nadeem), Glasspool, R. (Rosalind), Kwong, A. (Ava), Park, S.K. (Sue K.), Teo, S.-H. (Soo-Hwang), Yoon, S.-Y. (Sook-Yee), Matsuo, K. (Keitaro), Hosono, N. (Naoya), Woo, Y.L. (Yin Ling), Gao, Y. (Ying), Foretova, L. (Lenka), Singer, C.F. (Christian), Rappaport-Feurhauser, C. (Christine), Friedman, E. (Eitan), Laitman, Y. (Yael), Rennert, G. (Gad), Imyanitov, E.N. (Evgeny), Hulick, P.J. (Peter), Olopade, O.I. (Olufunmilayo I.), Senter, L. (Leigha), Olah, E. (Edith), Doherty, J.A. (Jennifer A.), Schildkraut, J.M. (Joellen), Koppert, L.B. (Linetta), Kiemeney, L.A.L.M. (Bart), Massuger, L.F. (Leon), Cook, L.S. (Linda S.), Pejovic, T. (Tanja), Li, J. (Jingmei), Borg, Å. (Åke), Öfverholm, A. (Anna), Rossing, M.A. (Mary Anne), Wentzensen, N. (N.), Henriksson, K. (Karin), Cox, A. (Angela), Cross, S.S. (Simon), Pasini, B. (Barbara), Shah, M. (Mitul), Kabisch, M. (Maria), Torres, D. (Diana), Jakubowska, A. (Anna), Lubinski, J. (Jan), Gronwald, J. (Jacek), Agnarsson, B.A. (Bjarni), Kupryjanczyk, J. (Jolanta), Moes-Sosnowska, J. (Joanna), Fostira, F. (Florentia), Konstantopoulou, I. (I.), Slager, S. (Susan), Jones, M. (Michael), Antoniou, A.C. (Antonis), Berchuck, A. (Andrew), Swerdlow, A.J. (Anthony ), Chenevix-Trench, G. (Georgia), Dunning, A.M. (Alison), Pharoah, P.D.P. (Paul), Hall, P. (Per), Easton, D.F. (Douglas F.), Couch, F.J. (Fergus), Spurdle, A.B. (Amanda), and Goldgar, D. (David)
Abstract: Background: The K3326X variant in BRCA2 (BRCA2∗c.9976A>T p.Lys3326∗rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormonerelated cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76637 cancer case patients and 83796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9×10-6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8×10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4×10-5 and ORw = 1.50, 95% CI = 1.28 to
Published: 2016
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250. Genetic predisposition to ductal carcinoma in situ of the breast

Author: Petridis, C. (Christos), Brook, R.H., Shah, V. (Vandna), Kohut, K. (Kelly), Gorman, P. (Patricia), Caneppele, M. (Michele), Levi, D. (Dina), Papouli, E. (Efterpi), Orr, N. (Nick), Cox, A. (Angela), Cross, S.S. (Simon), Santos Silva, I. (Isabel) dos, Peto, J. (Julian), Swerdlow, A.J. (Anthony ), Schoemaker, M. (Minouk), Bolla, M.K. (Manjeet), Wang, Q. (Qing), Dennis, J. (Joe), Michailidou, K. (Kyriaki), Benítez, J. (Javier), González-Neira, A. (Anna), Tessier, D.C. (Daniel C.), Vincent, D. (Daniel), Li, J. (Jingmei), Figueroa, J.D. (Jonine), Kristensen, V. (Vessela), Borresen-Dale, A.-L. (Anne-Lise), Soucy, P. (Penny), Simard, J. (Jacques), Milne, R.L. (Roger), Giles, G.G. (Graham), Margolin, S. (Sara), Lindblom, A. (Annika), Brüning, T. (Thomas), Brauch, H. (Hiltrud), Southey, M.C. (Melissa), Hopper, J.L. (John), Dörk, T. (Thilo), Bogdanova, N.V. (Natalia), Kabisch, M. (Maria), Hamann, U. (Ute), Schmutzler, R.K. (Rita), Meindl, A. (Alfons), Brenner, H. (Hermann), Arndt, V. (Volker), Winqvist, R. (Robert), Pykäs, K. (Katri), Fasching, P.A. (Peter), Beckmann, M.W. (Matthias), Lubinski, J. (Jan), Jakubowska, A. (Anna), Mulligan, A.M. (Anna Marie), Andrulis, I.L. (Irene), Tollenaar, R.A.E.M. (Rob), Devilee, P. (Peter), Le Marchand, L. (Loic), Haiman, C.A. (Christopher), Mannermaa, A. (Arto), Kosma, V-M. (Veli-Matti), Radice, P. (Paolo), Peterlongo, P. (Paolo), Marme, F. (Federick), Burwinkel, B. (Barbara), Deurzen, C.H.M. (Carolien) van, Hollestelle, A. (Antoinette), Miller, N. (Nicola), Kerin, M. (Michael), Lambrechts, D. (Diether), Floris, O.A.M., Wesseling, J. (Jelle), Flyger, H. (Henrik), Bojesen, S.E. (Stig), Yao, S. (Song), Ambrosone, C.B. (Christine), Chenevix-Trench, G. (Georgia), Truong, T. (Thérèse), Guénel, P. (Pascal), Rudolph, A. (Anja), Chang-Claude, J. (Jenny), Nevanlinna, H. (Heli), Blomqvist, C. (Carl), Czene, K. (Kamila), Brand, J.S. (Judith S.), Olson, J.E. (Janet), Couch, F.J. (Fergus), Dunning, A.M. (Alison), Hall, P. (Per), Easton, D.F. (Douglas), Pharoah, P.D.P. (Paul), Pinder, S. (Sarah), Schmidt, M.K. (Marjanka), Tomlinson, I.P. (Ian), Roylance, R. (Rebecca), García-Closas, M. (Montserrat), Sawyer, E.J. (Elinor), Petridis, C. (Christos), Brook, R.H., Shah, V. (Vandna), Kohut, K. (Kelly), Gorman, P. (Patricia), Caneppele, M. (Michele), Levi, D. (Dina), Papouli, E. (Efterpi), Orr, N. (Nick), Cox, A. (Angela), Cross, S.S. (Simon), Santos Silva, I. (Isabel) dos, Peto, J. (Julian), Swerdlow, A.J. (Anthony ), Schoemaker, M. (Minouk), Bolla, M.K. (Manjeet), Wang, Q. (Qing), Dennis, J. (Joe), Michailidou, K. (Kyriaki), Benítez, J. (Javier), González-Neira, A. (Anna), Tessier, D.C. (Daniel C.), Vincent, D. (Daniel), Li, J. (Jingmei), Figueroa, J.D. (Jonine), Kristensen, V. (Vessela), Borresen-Dale, A.-L. (Anne-Lise), Soucy, P. (Penny), Simard, J. (Jacques), Milne, R.L. (Roger), Giles, G.G. (Graham), Margolin, S. (Sara), Lindblom, A. (Annika), Brüning, T. (Thomas), Brauch, H. (Hiltrud), Southey, M.C. (Melissa), Hopper, J.L. (John), Dörk, T. (Thilo), Bogdanova, N.V. (Natalia), Kabisch, M. (Maria), Hamann, U. (Ute), Schmutzler, R.K. (Rita), Meindl, A. (Alfons), Brenner, H. (Hermann), Arndt, V. (Volker), Winqvist, R. (Robert), Pykäs, K. (Katri), Fasching, P.A. (Peter), Beckmann, M.W. (Matthias), Lubinski, J. (Jan), Jakubowska, A. (Anna), Mulligan, A.M. (Anna Marie), Andrulis, I.L. (Irene), Tollenaar, R.A.E.M. (Rob), Devilee, P. (Peter), Le Marchand, L. (Loic), Haiman, C.A. (Christopher), Mannermaa, A. (Arto), Kosma, V-M. (Veli-Matti), Radice, P. (Paolo), Peterlongo, P. (Paolo), Marme, F. (Federick), Burwinkel, B. (Barbara), Deurzen, C.H.M. (Carolien) van, Hollestelle, A. (Antoinette), Miller, N. (Nicola), Kerin, M. (Michael), Lambrechts, D. (Diether), Floris, O.A.M., Wesseling, J. (Jelle), Flyger, H. (Henrik), Bojesen, S.E. (Stig), Yao, S. (Song), Ambrosone, C.B. (Christine), Chenevix-Trench, G. (Georgia), Truong, T. (Thérèse), Guénel, P. (Pascal), Rudolph, A. (Anja), Chang-Claude, J. (Jenny), Nevanlinna, H. (Heli), Blomqvist, C. (Carl), Czene, K. (Kamila), Brand, J.S. (Judith S.), Olson, J.E. (Janet), Couch, F.J. (Fergus), Dunning, A.M. (Alison), Hall, P. (Per), Easton, D.F. (Douglas), Pharoah, P.D.P. (Paul), Pinder, S. (Sarah), Schmidt, M.K. (Marjanka), Tomlinson, I.P. (Ian), Roylance, R. (Rebecca), García-Closas, M. (Montserrat), and Sawyer, E.J. (Elinor)
Abstract: Background: Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer. It is often associated with invasive ductal carcinoma (IDC), and is considered to be a non-obligate precursor of IDC. It is not clear to what extent these two forms of cancer share low-risk susceptibility loci, or whether there are differences in the strength of association for shared loci. Methods: To identify genetic polymorphisms that predispose to DCIS, we pooled data from 38 studies comprising 5,067 cases of DCIS, 24,584 cases of IDC and 37,467 controls, all genotyped using the iCOGS chip. Results: Most (67 %) of the 76 known breast cancer predisposition loci showed an association with DCIS in the same direction as previously reported for invasive breast cancer. Case-only analysis showed no evidence for differences between associations for IDC and DCIS after considering multiple testing. Analysis by estrogen receptor (ER) status confirmed that loci associated with ER positive IDC were also associated with ER positive DCIS. Analysis of DCIS by grade suggested that two independent SNPs at 11q13.3 near CCND1 were specific to low/intermediate grade DCIS (rs75915166, rs554219). These associations with grade remained after adjusting for ER status and were also found in IDC. We found no novel DCIS-specific loci at a genome wide significance level of P < 5.0x10-8. Conclusion: In conclusion, this study provides the strongest evidence to date of a shared genetic susceptibility for IDC and DCIS. Studies with larger numbers of DCIS are needed to determine if IDC or DCIS specific loci exist.
Published: 2016
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