Author: "Blok MJ" - Searchworks@Jio Institute Digital Library Search Results

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1. A multi-centre international quality control study comparing mRNA splicing assay protocols and reporting practices from the ENIGMA consortium

Author: Whiley P, Walker LC, De LA Hoya M, Wappenschmidt B, Becker A, Blanco A, Blok MJ, Caligo MA, Chatfield C, Couch F, Diez O, Fachal L, Guidugli L, Enríquez S, Hansen T, Houdayer C, Imrie S, Lafferty A, Lázaro C, Menéndez M, Montagna M, Montalbán G, Santamariña M, Pederson I, Southey M, Tancredi M, Tenès A, Thomassen M, Van Overeem Vega A, Spurdle AB, and Brown MA
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Genetics, QH426-470
Published: 2012
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2. FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women

Author: Figlioli, G, Billaud, A, Ahearn, TU, Antonenkova, NN, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blok, MJ, Bogdanova, NV, Bonanni, B, Burwinkel, B, Camp, NJ, Campbell, A, Castelao, JE, Cessna, MH, Chanock, SJ, Czene, K, Devilee, P, Doerk, T, Engel, C, Eriksson, M, Fasching, PA, Figueroa, JD, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Gonzalez-Neira, A, Grassmann, F, Guenel, P, Guendert, M, Hadjisavvas, A, Hahnen, E, Hall, P, Hamann, U, Harrington, PA, He, W, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoppe, R, Howell, A, Humphreys, K, Jager, A, Jakubowska, A, Khusnutdinova, EK, Ko, Y-D, Kristensen, VN, Lindblom, A, Lissowska, J, Lubinski, J, Mannermaa, A, Manoukian, S, Margolin, S, Mavroudis, D, Newman, WG, Obi, N, Panayiotidis, MI, Rashid, MU, Rhenius, V, Rookus, MA, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Shah, M, Sironen, R, Southey, MC, Suvanto, M, Tollenaar, RAEM, Tomlinson, I, Truong, T, van der Kolk, LE, van Veen, EM, Wappenschmidt, B, Yang, XR, Bolla, MK, Dennis, J, Dunning, AM, Easton, DF, Lush, M, Michailidou, K, Pharoah, PDP, Wang, Q, Adank, MA, Schmidt, MK, Andrulis, IL, Chang-Claude, J, Nevanlinna, H, Chenevix-Trench, G, Evans, DG, Milne, RL, Radice, P, Peterlongo, P, Figlioli, G, Billaud, A, Ahearn, TU, Antonenkova, NN, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blok, MJ, Bogdanova, NV, Bonanni, B, Burwinkel, B, Camp, NJ, Campbell, A, Castelao, JE, Cessna, MH, Chanock, SJ, Czene, K, Devilee, P, Doerk, T, Engel, C, Eriksson, M, Fasching, PA, Figueroa, JD, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Gonzalez-Neira, A, Grassmann, F, Guenel, P, Guendert, M, Hadjisavvas, A, Hahnen, E, Hall, P, Hamann, U, Harrington, PA, He, W, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoppe, R, Howell, A, Humphreys, K, Jager, A, Jakubowska, A, Khusnutdinova, EK, Ko, Y-D, Kristensen, VN, Lindblom, A, Lissowska, J, Lubinski, J, Mannermaa, A, Manoukian, S, Margolin, S, Mavroudis, D, Newman, WG, Obi, N, Panayiotidis, MI, Rashid, MU, Rhenius, V, Rookus, MA, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Shah, M, Sironen, R, Southey, MC, Suvanto, M, Tollenaar, RAEM, Tomlinson, I, Truong, T, van der Kolk, LE, van Veen, EM, Wappenschmidt, B, Yang, XR, Bolla, MK, Dennis, J, Dunning, AM, Easton, DF, Lush, M, Michailidou, K, Pharoah, PDP, Wang, Q, Adank, MA, Schmidt, MK, Andrulis, IL, Chang-Claude, J, Nevanlinna, H, Chenevix-Trench, G, Evans, DG, Milne, RL, Radice, P, and Peterlongo, P
Abstract: Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) in FANCM confer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association between FANCM missense variants (MVs) and breast cancer risk has been postulated. In this study, we further used the BRIDGES study to test 689 FANCM MVs for association with breast cancer risk, overall and in ER-negative and TNBC subtypes, in 39,885 cases (7566 selected for family history) and 35,271 controls of European ancestry. Sixteen common MVs were tested individually; the remaining rare 673 MVs were tested by burden analyses considering their position and pathogenicity score. We also conducted a meta-analysis of our results and those from published studies. We did not find evidence for association for any of the 16 variants individually tested. The rare MVs were significantly associated with increased risk of ER-negative breast cancer by burden analysis comparing familial cases to controls (OR = 1.48; 95% CI 1.07-2.04; P = 0.017). Higher ORs were found for the subgroup of MVs located in functional domains or predicted to be pathogenic. The meta-analysis indicated that FANCM MVs overall are associated with breast cancer risk (OR = 1.22; 95% CI 1.08-1.38; P = 0.002). Our results support the definition from previous analyses of FANCM as a moderate-risk breast cancer gene and provide evidence that FANCM MVs could be low/moderate risk factors for ER-negative and TNBC subtypes. Further genetic and functional analyses are necessary to clarify better the increased risks due to FANCM MVs.
Published: 2023

3. Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

Author: Hakkaart, C, Pearson, JF, Marquart, L, Dennis, J, Wiggins, GAR, Barnes, DR, Robinson, BA, Mace, PD, Aittomaki, K, Andrulis, IL, Arun, BK, Azzollini, J, Balmana, J, Barkardottir, RB, Belhadj, S, Berger, L, Blok, MJ, Boonen, SE, Borde, J, Bradbury, AR, Brunet, J, Buys, SS, Caligo, MA, Campbell, I, Chung, WK, Claes, KBM, Collonge-Rame, M-A, Cook, J, Cosgrove, C, Couch, FJ, Daly, MB, Dandiker, S, Davidson, R, de la Hoya, M, de Putter, R, Delnatte, C, Dhawan, M, Diez, O, Ding, YC, Domchek, SM, Donaldson, A, Eason, J, Easton, DF, Ehrencrona, H, Engel, C, Evans, DG, Faust, U, Feliubadalo, L, Fostira, F, Friedman, E, Frone, M, Frost, D, Garber, J, Gayther, SA, Gehrig, A, Gesta, P, Godwin, AK, Goldgar, DE, Greene, MH, Hahnen, E, Hake, CR, Hamann, U, Hansen, TVO, Hauke, J, Hentschel, J, Herold, N, Honisch, E, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Izquierdo, A, Jakubowska, A, James, PA, Janavicius, R, John, EM, Joseph, V, Karlan, BY, Kemp, Z, Kirk, J, Konstantopoulou, I, Koudijs, M, Kwong, A, Laitman, Y, Lalloo, F, Lasset, C, Lautrup, C, Lazaro, C, Legrand, C, Leslie, G, Lesueur, F, Mai, PL, Manoukian, S, Mari, V, Martens, JWM, McGuffog, L, Mebirouk, N, Meindl, A, Miller, A, Montagna, M, Moserle, L, Mouret-Fourme, E, Musgrave, H, Nambot, S, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Nguyen-Dumont, T, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, OI, Osorio, A, Ott, C-E, Park, SK, Parsons, MT, Pedersen, IS, Peixoto, A, Perez-Segura, P, Peterlongo, P, Pocza, T, Radice, P, Ramser, J, Rantala, J, Rodriguez, GC, Ronlund, K, Rosenberg, EH, Rossing, M, Schmutzler, RK, Shah, PD, Sharif, S, Sharma, P, Side, LE, Simard, J, Singer, CF, Snape, K, Steinemann, D, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Thomassen, M, Thull, DL, Tischkowitz, M, Toland, AE, Trainer, AH, Tripathi, V, Tung, N, van Engelen, K, van Rensburg, EJ, Vega, A, Viel, A, Walker, L, Weitzel, JN, Wevers, MR, Chenevix-Trench, G, Spurdle, AB, Antoniou, AC, Walker, LC, Hakkaart, C, Pearson, JF, Marquart, L, Dennis, J, Wiggins, GAR, Barnes, DR, Robinson, BA, Mace, PD, Aittomaki, K, Andrulis, IL, Arun, BK, Azzollini, J, Balmana, J, Barkardottir, RB, Belhadj, S, Berger, L, Blok, MJ, Boonen, SE, Borde, J, Bradbury, AR, Brunet, J, Buys, SS, Caligo, MA, Campbell, I, Chung, WK, Claes, KBM, Collonge-Rame, M-A, Cook, J, Cosgrove, C, Couch, FJ, Daly, MB, Dandiker, S, Davidson, R, de la Hoya, M, de Putter, R, Delnatte, C, Dhawan, M, Diez, O, Ding, YC, Domchek, SM, Donaldson, A, Eason, J, Easton, DF, Ehrencrona, H, Engel, C, Evans, DG, Faust, U, Feliubadalo, L, Fostira, F, Friedman, E, Frone, M, Frost, D, Garber, J, Gayther, SA, Gehrig, A, Gesta, P, Godwin, AK, Goldgar, DE, Greene, MH, Hahnen, E, Hake, CR, Hamann, U, Hansen, TVO, Hauke, J, Hentschel, J, Herold, N, Honisch, E, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Izquierdo, A, Jakubowska, A, James, PA, Janavicius, R, John, EM, Joseph, V, Karlan, BY, Kemp, Z, Kirk, J, Konstantopoulou, I, Koudijs, M, Kwong, A, Laitman, Y, Lalloo, F, Lasset, C, Lautrup, C, Lazaro, C, Legrand, C, Leslie, G, Lesueur, F, Mai, PL, Manoukian, S, Mari, V, Martens, JWM, McGuffog, L, Mebirouk, N, Meindl, A, Miller, A, Montagna, M, Moserle, L, Mouret-Fourme, E, Musgrave, H, Nambot, S, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Nguyen-Dumont, T, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, OI, Osorio, A, Ott, C-E, Park, SK, Parsons, MT, Pedersen, IS, Peixoto, A, Perez-Segura, P, Peterlongo, P, Pocza, T, Radice, P, Ramser, J, Rantala, J, Rodriguez, GC, Ronlund, K, Rosenberg, EH, Rossing, M, Schmutzler, RK, Shah, PD, Sharif, S, Sharma, P, Side, LE, Simard, J, Singer, CF, Snape, K, Steinemann, D, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Thomassen, M, Thull, DL, Tischkowitz, M, Toland, AE, Trainer, AH, Tripathi, V, Tung, N, van Engelen, K, van Rensburg, EJ, Vega, A, Viel, A, Walker, L, Weitzel, JN, Wevers, MR, Chenevix-Trench, G, Spurdle, AB, Antoniou, AC, and Walker, LC
Abstract: The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.
Published: 2022

4. Breast and ovarian cancer risks in a large series of clinically ascertained families with a high proportion of BRCA1 and BRCA2 Dutch founder mutations

Author: Brohet, Richard M, Velthuizen, Maria E, Hogervorst, Frans B L, EJ Meijers-Heijboer, Hanne, Seynaeve, Caroline, Collée, Margriet J, Verhoef, Senno, Ausems, Margreet G E M, Hoogerbrugge, Nicoline, van Asperen, Christi J, Gómez García, Encarna, Menko, Fred, Oosterwijk, Jan C, Devilee, Peter, Veer, Laura J vanʼt, van Leeuwen, Flora E, Easton, Douglas F, Rookus, Matti A, Antoniou, Antonis C, Rookus, MA, Brohet, RM, Hogervorst, FBL, van Leeuwen, FE, Verhoef, S, Schmidt, MK, de Lange, JL, Collée, JM, van den Ouweland, AMW, Hooning, MJ, Seynaeve, C, van Deurzen, CHM, van Asperen, CJ, Wijnen, JT, Tollenaar, RAEM, Devilee, P, van Cronenburg, TCTEF, Kets, CM, Mensenkamp, AR, Ausems, MGEM, van der Luijt, RB, Aalfs, CM, van Os, TAM, Gille, JJP, Waisfisz, Q, Meijers-Heijboer, HEJ, Gómez-Garcia, EB, Blok, MJ, Oosterwijk, JC, van der Hout, AH, Mourits, MJ, de Bock, GH, and Vasen, HFA
Published: 2014
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5. Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers

Author: Mavaddat, N, Antoniou, AC, Mooij, TM, Hooning, MJ, Heemskerk-Gerritsen, BA, Nogues, C, Laborde, L, Breysse, E, Stoppa-Lyonnet, D, Gauthier-Villars, M, Buecher, B, Caron, O, Fourme-Mouret, E, Fricker, J-P, Lasset, C, Bonadona, V, Berthet, P, Faivre, L, Luporsi, E, Mari, V, Gladieff, L, Gesta, P, Sobol, H, Eisinger, F, Longy, M, Dugast, C, Colas, C, Coupier, I, Pujol, P, Corsini, C, Lortholary, A, Vennin, P, Adenis, C, Nguyen, TD, Delnatte, C, Tinat, J, Tennevet, I, Limacher, J-M, Maugard, C, Bignon, Y-J, Demange, L, Penet, C, Dreyfus, H, Cohen-Haguenauer, O, Venat-Bouvet, L, Leroux, D, Zattara-Cannoni, H, Fert-Ferrer, S, Bera, O, Ellis, S, Barrowdale, D, Frost, D, Evans, DG, Izatt, L, Adlard, J, Eeles, R, Brewer, C, Tischkowitz, M, Henderson, A, Cook, J, Eccles, D, Hogervorst, FBL, Collee, JM, van Asperen, CJ, Mensenkamp, AR, Ausems, MGEM, Meijers-Heijboer, HEJ, van Engelen, K, Blok, MJ, Oosterwijk, JC, Verloop, J, van den Broek, E, Mourits, MJE, Koppert, LB, Hopper, JL, John, EM, Chung, WK, Andrulis, IL, Daly, MB, Buys, SS, Benitez, J, Caldes, T, Jakubowska, A, Simard, J, Singer, CF, Tan, Y, Olah, E, Navratilova, M, Foretova, L, Gerdes, A-M, Roos-Blom, M-J, Van Leeuwen, FE, Arver, B, Olsson, H, Schmutzler, RK, Engel, C, Kast, K, Phillips, K-A, Terry, MB, Milne, RL, Goldgar, DE, Rookus, MA, Andrieu, N, Easton, DF, Mavaddat, N, Antoniou, AC, Mooij, TM, Hooning, MJ, Heemskerk-Gerritsen, BA, Nogues, C, Laborde, L, Breysse, E, Stoppa-Lyonnet, D, Gauthier-Villars, M, Buecher, B, Caron, O, Fourme-Mouret, E, Fricker, J-P, Lasset, C, Bonadona, V, Berthet, P, Faivre, L, Luporsi, E, Mari, V, Gladieff, L, Gesta, P, Sobol, H, Eisinger, F, Longy, M, Dugast, C, Colas, C, Coupier, I, Pujol, P, Corsini, C, Lortholary, A, Vennin, P, Adenis, C, Nguyen, TD, Delnatte, C, Tinat, J, Tennevet, I, Limacher, J-M, Maugard, C, Bignon, Y-J, Demange, L, Penet, C, Dreyfus, H, Cohen-Haguenauer, O, Venat-Bouvet, L, Leroux, D, Zattara-Cannoni, H, Fert-Ferrer, S, Bera, O, Ellis, S, Barrowdale, D, Frost, D, Evans, DG, Izatt, L, Adlard, J, Eeles, R, Brewer, C, Tischkowitz, M, Henderson, A, Cook, J, Eccles, D, Hogervorst, FBL, Collee, JM, van Asperen, CJ, Mensenkamp, AR, Ausems, MGEM, Meijers-Heijboer, HEJ, van Engelen, K, Blok, MJ, Oosterwijk, JC, Verloop, J, van den Broek, E, Mourits, MJE, Koppert, LB, Hopper, JL, John, EM, Chung, WK, Andrulis, IL, Daly, MB, Buys, SS, Benitez, J, Caldes, T, Jakubowska, A, Simard, J, Singer, CF, Tan, Y, Olah, E, Navratilova, M, Foretova, L, Gerdes, A-M, Roos-Blom, M-J, Van Leeuwen, FE, Arver, B, Olsson, H, Schmutzler, RK, Engel, C, Kast, K, Phillips, K-A, Terry, MB, Milne, RL, Goldgar, DE, Rookus, MA, Andrieu, N, and Easton, DF
Abstract: BACKGROUND: The effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer risk for BRCA1 and BRCA2 mutation carriers is uncertain. Retrospective analyses have suggested a protective effect but may be substantially biased. Prospective studies have had limited power, particularly for BRCA2 mutation carriers. Further, previous studies have not considered the effect of RRSO in the context of natural menopause. METHODS: A multi-centre prospective cohort of 2272 BRCA1 and 1605 BRCA2 mutation carriers was followed for a mean of 5.4 and 4.9 years, respectively; 426 women developed incident breast cancer. RRSO was modelled as a time-dependent covariate in Cox regression, and its effect assessed in premenopausal and postmenopausal women. RESULTS: There was no association between RRSO and breast cancer for BRCA1 (HR = 1.23; 95% CI 0.94-1.61) or BRCA2 (HR = 0.88; 95% CI 0.62-1.24) mutation carriers. For BRCA2 mutation carriers, HRs were 0.68 (95% CI 0.40-1.15) and 1.07 (95% CI 0.69-1.64) for RRSO carried out before or after age 45 years, respectively. The HR for BRCA2 mutation carriers decreased with increasing time since RRSO (HR = 0.51; 95% CI 0.26-0.99 for 5 years or longer after RRSO). Estimates for premenopausal women were similar. CONCLUSION: We found no evidence that RRSO reduces breast cancer risk for BRCA1 mutation carriers. A potentially beneficial effect for BRCA2 mutation carriers was observed, particularly after 5 years following RRSO. These results may inform counselling and management of carriers with respect to RRSO.
Published: 2020

6. Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness

Author: Patel, VL, Busch, EL, Friebel, TM, Cronin, A, Leslie, G, McGuffog, L, Adlard, J, Agata, S, Agnarsson, BA, Ahmed, M, Aittomaki, K, Alducci, E, Andrulis, IL, Arason, A, Arnold, N, Artioli, G, Arver, B, Auber, B, Azzollini, J, Balmana, J, Barkardottir, RB, Barnes, DR, Barroso, A, Barrowdale, D, Belotti, M, Benitez, J, Bertelsen, B, Blok, MJ, Bodrogi, I, Bonadona, V, Bonanni, B, Bondavalli, D, Boonen, SE, Borde, J, Borg, A, Bradbury, AR, Brady, A, Brewer, C, Brunet, J, Buecher, B, Buys, SS, Cabezas-Camarero, S, Caldes, T, Caliebe, A, Caligo, MA, Calvello, M, Campbell, IG, Carnevali, I, Carrasco, E, Chan, TL, Chu, ATW, Chung, WK, Claes, KBM, Cook, J, Cortesi, L, Couch, FJ, Daly, MB, Damante, G, Darder, E, Davidson, R, de la Hoya, M, Della Puppa, L, Dennis, J, Diez, O, Ding, YC, Ditsch, N, Domchek, SM, Donaldson, A, Dworniczak, B, Easton, DF, Eccles, DM, Eeles, RA, Ehrencrona, H, Ejlertsen, B, Engel, C, Evans, DG, Faivre, L, Faust, U, Feliubadalo, L, Foretova, L, Fostira, F, Fountzilas, G, Frost, D, Garcia-Barberan, V, Garre, P, Gauthier-Villars, M, Geczi, L, Gehrig, A, Gerdes, A-M, Gesta, P, Giannini, G, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gutierrez-Barrera, AM, Hahnen, E, Hamann, U, Hauke, J, Herold, N, Hogervorst, FBL, Honisch, E, Hopper, JL, Hulick, PJ, Izatt, L, Jager, A, James, P, Janavicius, R, Jensen, UB, Jensen, TD, Johannsson, OT, John, EM, Joseph, V, Kang, E, Kast, K, Kiiski, J, Kim, S-W, Kim, Z, Ko, K-P, Konstantopoulou, I, Kramer, G, Krogh, L, Kruse, TA, Kwong, A, Larsen, M, Lasset, C, Lautrup, C, Lazaro, C, Lee, J, Lee, JW, Lee, MH, Lemke, J, Lesueur, F, Liljegren, A, Lindblom, A, Llovet, P, Lopez-Fernandez, A, Lopez-Perolio, I, Lorca, V, Loud, JT, Ma, ESK, Mai, PL, Manoukian, S, Mari, V, Martin, L, Matricardi, L, Mebirouk, N, Medici, V, Meijers-Heijboer, HEJ, Meindl, A, Mensenkamp, AR, Miller, C, Gomes, DM, Montagna, M, Mooij, TM, Moserle, L, Mouret-Fourme, E, Mulligan, AM, Nathanson, KL, Navratilova, M, Nevanlinna, H, Niederacher, D, Nielsen, FCC, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, O, Ong, K-R, Osorio, A, Ott, C-E, Palli, D, Park, SK, Parsons, MT, Pedersen, IS, Peissel, B, Peixoto, A, Perez-Segura, P, Peterlongo, P, Petersen, AH, Porteous, ME, Angel Pujana, M, Radice, P, Ramser, J, Rantala, J, Rashid, MU, Rhiem, K, Rizzolo, P, Robson, ME, Rookus, MA, Rossing, CM, Ruddy, KJ, Santos, C, Saule, C, Scarpitta, R, Schmutzler, RK, Schuster, H, Senter, L, Seynaeve, CM, Shah, PD, Sharma, P, Shin, VY, Silvestri, V, Simard, J, Singer, CF, Skytte, A-B, Snape, K, Solano, AR, Soucy, P, Southey, MC, Spurdle, AB, Steele, L, Steinemann, D, Stoppa-Lyonnet, D, Stradella, A, Sunde, L, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Thomassen, M, Tibiletti, MG, Tischkowitz, M, Tognazzo, S, Toland, AE, Tommasi, S, Torres, D, Toss, A, Trainer, AH, Tung, N, van Asperen, CJ, van der Baan, FH, van der Kolk, LE, van der Luijt, RB, van Hest, LP, Varesco, L, Varon-Mateeva, R, Viel, A, Vierstraete, J, Villa, R, von Wachenfeldt, A, Wagner, P, Wang-Gohrke, S, Wappenschmidt, B, Weitzel, JN, Wieme, G, Yadav, S, Yannoukakos, D, Yoon, S-Y, Zanzottera, C, Zorn, KK, D'Amico, A, Freedman, ML, Pomerantz, MM, Chenevix-Trench, G, Antoniou, AC, Neuhausen, SL, Ottini, L, Nielsen, HR, Rebbeck, TR, Patel, VL, Busch, EL, Friebel, TM, Cronin, A, Leslie, G, McGuffog, L, Adlard, J, Agata, S, Agnarsson, BA, Ahmed, M, Aittomaki, K, Alducci, E, Andrulis, IL, Arason, A, Arnold, N, Artioli, G, Arver, B, Auber, B, Azzollini, J, Balmana, J, Barkardottir, RB, Barnes, DR, Barroso, A, Barrowdale, D, Belotti, M, Benitez, J, Bertelsen, B, Blok, MJ, Bodrogi, I, Bonadona, V, Bonanni, B, Bondavalli, D, Boonen, SE, Borde, J, Borg, A, Bradbury, AR, Brady, A, Brewer, C, Brunet, J, Buecher, B, Buys, SS, Cabezas-Camarero, S, Caldes, T, Caliebe, A, Caligo, MA, Calvello, M, Campbell, IG, Carnevali, I, Carrasco, E, Chan, TL, Chu, ATW, Chung, WK, Claes, KBM, Cook, J, Cortesi, L, Couch, FJ, Daly, MB, Damante, G, Darder, E, Davidson, R, de la Hoya, M, Della Puppa, L, Dennis, J, Diez, O, Ding, YC, Ditsch, N, Domchek, SM, Donaldson, A, Dworniczak, B, Easton, DF, Eccles, DM, Eeles, RA, Ehrencrona, H, Ejlertsen, B, Engel, C, Evans, DG, Faivre, L, Faust, U, Feliubadalo, L, Foretova, L, Fostira, F, Fountzilas, G, Frost, D, Garcia-Barberan, V, Garre, P, Gauthier-Villars, M, Geczi, L, Gehrig, A, Gerdes, A-M, Gesta, P, Giannini, G, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gutierrez-Barrera, AM, Hahnen, E, Hamann, U, Hauke, J, Herold, N, Hogervorst, FBL, Honisch, E, Hopper, JL, Hulick, PJ, Izatt, L, Jager, A, James, P, Janavicius, R, Jensen, UB, Jensen, TD, Johannsson, OT, John, EM, Joseph, V, Kang, E, Kast, K, Kiiski, J, Kim, S-W, Kim, Z, Ko, K-P, Konstantopoulou, I, Kramer, G, Krogh, L, Kruse, TA, Kwong, A, Larsen, M, Lasset, C, Lautrup, C, Lazaro, C, Lee, J, Lee, JW, Lee, MH, Lemke, J, Lesueur, F, Liljegren, A, Lindblom, A, Llovet, P, Lopez-Fernandez, A, Lopez-Perolio, I, Lorca, V, Loud, JT, Ma, ESK, Mai, PL, Manoukian, S, Mari, V, Martin, L, Matricardi, L, Mebirouk, N, Medici, V, Meijers-Heijboer, HEJ, Meindl, A, Mensenkamp, AR, Miller, C, Gomes, DM, Montagna, M, Mooij, TM, Moserle, L, Mouret-Fourme, E, Mulligan, AM, Nathanson, KL, Navratilova, M, Nevanlinna, H, Niederacher, D, Nielsen, FCC, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, O, Ong, K-R, Osorio, A, Ott, C-E, Palli, D, Park, SK, Parsons, MT, Pedersen, IS, Peissel, B, Peixoto, A, Perez-Segura, P, Peterlongo, P, Petersen, AH, Porteous, ME, Angel Pujana, M, Radice, P, Ramser, J, Rantala, J, Rashid, MU, Rhiem, K, Rizzolo, P, Robson, ME, Rookus, MA, Rossing, CM, Ruddy, KJ, Santos, C, Saule, C, Scarpitta, R, Schmutzler, RK, Schuster, H, Senter, L, Seynaeve, CM, Shah, PD, Sharma, P, Shin, VY, Silvestri, V, Simard, J, Singer, CF, Skytte, A-B, Snape, K, Solano, AR, Soucy, P, Southey, MC, Spurdle, AB, Steele, L, Steinemann, D, Stoppa-Lyonnet, D, Stradella, A, Sunde, L, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Thomassen, M, Tibiletti, MG, Tischkowitz, M, Tognazzo, S, Toland, AE, Tommasi, S, Torres, D, Toss, A, Trainer, AH, Tung, N, van Asperen, CJ, van der Baan, FH, van der Kolk, LE, van der Luijt, RB, van Hest, LP, Varesco, L, Varon-Mateeva, R, Viel, A, Vierstraete, J, Villa, R, von Wachenfeldt, A, Wagner, P, Wang-Gohrke, S, Wappenschmidt, B, Weitzel, JN, Wieme, G, Yadav, S, Yannoukakos, D, Yoon, S-Y, Zanzottera, C, Zorn, KK, D'Amico, A, Freedman, ML, Pomerantz, MM, Chenevix-Trench, G, Antoniou, AC, Neuhausen, SL, Ottini, L, Nielsen, HR, and Rebbeck, TR
Abstract: Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.
Published: 2020

7. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

Author: Barnes, DR, Rookus, MA, McGuffog, L, Leslie, G, Mooij, TM, Dennis, J, Mavaddat, N, Adlard, J, Ahmed, M, Aittomaki, K, Andrieu, N, Andrulis, IL, Arnold, N, Arun, BK, Azzollini, J, Balmana, J, Barkardottir, RB, Barrowdale, D, Benitez, J, Berthet, P, Bialkowska, K, Blanco, AM, Blok, MJ, Bonanni, B, Boonen, SE, Borg, A, Bozsik, A, Bradbury, AR, Brennan, P, Brewer, C, Brunet, J, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Christensen, LL, Chung, WK, Claes, KBM, Colas, C, Collonge-Rame, M-A, Cook, J, Daly, MB, Davidson, R, de la Hoya, M, de Putter, R, Delnatte, C, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Dorfling, CM, Dumont, M, Eeles, R, Ejlertsen, B, Engel, C, Evans, DG, Faivre, L, Foretova, L, Fostira, F, Friedlander, M, Friedman, E, Frost, D, Ganz, PA, Garber, J, Gehrig, A, Gerdes, A-M, Gesta, P, Giraud, S, Glendon, G, Godwin, AK, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gschwantler-Kaulich, D, Hahnen, E, Hamann, U, Hanson, H, Hentschel, J, Hogervorst, FBL, Hooning, MJ, Horvath, J, Hu, C, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Izquierdo, A, Jakubowska, A, James, PA, Janavicius, R, John, EM, Joseph, V, Karlan, BY, Kast, K, Koudijs, M, Kruse, TA, Kwong, A, Laitman, Y, Lasset, C, Lazaro, C, Lester, J, Lesueur, F, Liljegren, A, Loud, JT, Lubinski, J, Mai, PL, Manoukian, S, Mari, V, Mebirouk, N, Meijers-Heijboer, HEJ, Meindl, A, Mensenkamp, AR, Miller, A, Montagna, M, Mouret-Fourme, E, Mukherjee, S, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Niederacher, D, Nielsen, FC, Nikitina-Zake, L, Nogues, C, Olah, E, Olopade, O, Ong, K-R, O'Shaughnessy-Kirwan, A, Osorio, A, Ott, C-E, Papi, L, Park, SK, Parsons, MT, Pedersen, IS, Peissel, B, Peixoto, A, Peterlongo, P, Pfeiler, G, Phillips, K-A, Prajzendanc, K, Pujana, MA, Radice, P, Ramser, J, Ramus, SJ, Rantala, J, Rennert, G, Risch, HA, Robson, M, Ronlund, K, Salani, R, Schuster, H, Senter, L, Shah, PD, Sharma, P, Side, LE, Singer, CF, Slavin, TP, Soucy, P, Southey, MC, Spurdle, AB, Steinemann, D, Steinsnyder, Z, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Thull, DL, Tischkowitz, M, Tognazzo, S, Toland, AE, Trainer, AH, Tung, N, van Engelen, K, van Rensburg, EJ, Vega, A, Vierstraete, J, Wagner, G, Walker, L, Wang-Gohrke, S, Wappenschmidt, B, Weitzel, JN, Yadav, S, Yang, X, Yannoukakos, D, Zimbalatti, D, Offit, K, Thomassen, M, Couch, FJ, Schmutzler, RK, Simard, J, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Barnes, DR, Rookus, MA, McGuffog, L, Leslie, G, Mooij, TM, Dennis, J, Mavaddat, N, Adlard, J, Ahmed, M, Aittomaki, K, Andrieu, N, Andrulis, IL, Arnold, N, Arun, BK, Azzollini, J, Balmana, J, Barkardottir, RB, Barrowdale, D, Benitez, J, Berthet, P, Bialkowska, K, Blanco, AM, Blok, MJ, Bonanni, B, Boonen, SE, Borg, A, Bozsik, A, Bradbury, AR, Brennan, P, Brewer, C, Brunet, J, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Christensen, LL, Chung, WK, Claes, KBM, Colas, C, Collonge-Rame, M-A, Cook, J, Daly, MB, Davidson, R, de la Hoya, M, de Putter, R, Delnatte, C, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Dorfling, CM, Dumont, M, Eeles, R, Ejlertsen, B, Engel, C, Evans, DG, Faivre, L, Foretova, L, Fostira, F, Friedlander, M, Friedman, E, Frost, D, Ganz, PA, Garber, J, Gehrig, A, Gerdes, A-M, Gesta, P, Giraud, S, Glendon, G, Godwin, AK, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gschwantler-Kaulich, D, Hahnen, E, Hamann, U, Hanson, H, Hentschel, J, Hogervorst, FBL, Hooning, MJ, Horvath, J, Hu, C, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Izquierdo, A, Jakubowska, A, James, PA, Janavicius, R, John, EM, Joseph, V, Karlan, BY, Kast, K, Koudijs, M, Kruse, TA, Kwong, A, Laitman, Y, Lasset, C, Lazaro, C, Lester, J, Lesueur, F, Liljegren, A, Loud, JT, Lubinski, J, Mai, PL, Manoukian, S, Mari, V, Mebirouk, N, Meijers-Heijboer, HEJ, Meindl, A, Mensenkamp, AR, Miller, A, Montagna, M, Mouret-Fourme, E, Mukherjee, S, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Niederacher, D, Nielsen, FC, Nikitina-Zake, L, Nogues, C, Olah, E, Olopade, O, Ong, K-R, O'Shaughnessy-Kirwan, A, Osorio, A, Ott, C-E, Papi, L, Park, SK, Parsons, MT, Pedersen, IS, Peissel, B, Peixoto, A, Peterlongo, P, Pfeiler, G, Phillips, K-A, Prajzendanc, K, Pujana, MA, Radice, P, Ramser, J, Ramus, SJ, Rantala, J, Rennert, G, Risch, HA, Robson, M, Ronlund, K, Salani, R, Schuster, H, Senter, L, Shah, PD, Sharma, P, Side, LE, Singer, CF, Slavin, TP, Soucy, P, Southey, MC, Spurdle, AB, Steinemann, D, Steinsnyder, Z, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Thull, DL, Tischkowitz, M, Tognazzo, S, Toland, AE, Trainer, AH, Tung, N, van Engelen, K, van Rensburg, EJ, Vega, A, Vierstraete, J, Wagner, G, Walker, L, Wang-Gohrke, S, Wappenschmidt, B, Weitzel, JN, Yadav, S, Yang, X, Yannoukakos, D, Zimbalatti, D, Offit, K, Thomassen, M, Couch, FJ, Schmutzler, RK, Simard, J, Easton, DF, Chenevix-Trench, G, and Antoniou, AC
Abstract: PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10-72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10-50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10-22) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10-12) carriers. The associations in the prospective cohort were similar. CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.
Published: 2020

8. Alcohol Consumption, Cigarette Smoking, and Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Results from The BRCA1 and BRCA2 Cohort Consortium

Author: Li, H, Terry, MB, Antoniou, AC, Phillips, K-A, Kast, K, Mooij, TM, Engel, C, Nogues, C, Stoppa-Lyonnet, D, Lasset, C, Berthet, P, Mari, V, Caron, O, Barrowdale, D, Frost, D, Brewer, C, Evans, DG, Izatt, L, Side, L, Walker, L, Tischkowitz, M, Rogers, MT, Porteous, ME, Snape, K, Meijers-Heijboer, HEJ, Gille, JJP, Blok, MJ, Hoogerbrugge, N, Daly, MB, Andrulis, IL, Buys, SS, John, EM, McLachlan, S-A, Friedlander, M, Tan, YY, Osorio, A, Caldes, T, Jakubowska, A, Simard, J, Singer, CF, Olah, E, Navratilova, M, Foretova, L, Gerdes, A-M, Roos-Blom, M-J, Arver, B, Olsson, H, Schmutzler, RK, Hopper, JL, Milne, RL, Easton, DF, Van Leeuwen, FE, Rookus, MA, Andrieu, N, Goldgar, DE, Li, H, Terry, MB, Antoniou, AC, Phillips, K-A, Kast, K, Mooij, TM, Engel, C, Nogues, C, Stoppa-Lyonnet, D, Lasset, C, Berthet, P, Mari, V, Caron, O, Barrowdale, D, Frost, D, Brewer, C, Evans, DG, Izatt, L, Side, L, Walker, L, Tischkowitz, M, Rogers, MT, Porteous, ME, Snape, K, Meijers-Heijboer, HEJ, Gille, JJP, Blok, MJ, Hoogerbrugge, N, Daly, MB, Andrulis, IL, Buys, SS, John, EM, McLachlan, S-A, Friedlander, M, Tan, YY, Osorio, A, Caldes, T, Jakubowska, A, Simard, J, Singer, CF, Olah, E, Navratilova, M, Foretova, L, Gerdes, A-M, Roos-Blom, M-J, Arver, B, Olsson, H, Schmutzler, RK, Hopper, JL, Milne, RL, Easton, DF, Van Leeuwen, FE, Rookus, MA, Andrieu, N, and Goldgar, DE
Abstract: BACKGROUND: Tobacco smoking and alcohol consumption have been intensively studied in the general population to assess their effects on the risk of breast cancer, but very few studies have examined these effects in BRCA1 and BRCA2 mutation carriers. Given the high breast cancer risk for mutation carriers and the importance of BRCA1 and BRCA2 in DNA repair, better evidence on the associations of these lifestyle factors with breast cancer risk is essential. METHODS: Using a large international pooled cohort of BRCA1 and BRCA2 mutation carriers, we conducted retrospective (5,707 BRCA1 mutation carriers and 3,525 BRCA2 mutation carriers) and prospective (2,276 BRCA1 mutation carriers and 1,610 BRCA2 mutation carriers) analyses of alcohol and tobacco consumption using Cox proportional hazards models. RESULTS: For both BRCA1 and BRCA2 mutation carriers, none of the smoking-related variables was associated with breast cancer risk, except smoking for more than 5 years before a first full-term pregnancy (FFTP) when compared with parous women who never smoked. For BRCA1 mutation carriers, the HR from retrospective analysis (HRR) was 1.19 [95% confidence interval (CI), 1.02-1.39] and the HR from prospective analysis (HRP) was 1.36 (95% CI, 0.99-1.87). For BRCA2 mutation carriers, smoking for more than 5 years before an FFTP showed an association of a similar magnitude, but the confidence limits were wider (HRR = 1.25; 95% CI, 1.01-1.55 and HRP = 1.30; 95% CI, 0.83-2.01). For both carrier groups, alcohol consumption was not associated with breast cancer risk. CONCLUSIONS: The finding that smoking during the prereproductive years increases breast cancer risk for mutation carriers warrants further investigation. IMPACT: This is the largest prospective study of BRCA mutation carriers to assess these important risk factors.
Published: 2020

9. Somatic mosaicism in a mother of two children with Pitt–Hopkins syndrome

Author: Steinbusch, CVM, van Roozendaal, KEP, Tserpelis, D, Smeets, EEJ, Kranenburg-de Koning, TJ, de Waal, KH, Zweier, C, Rauch, A, Hennekam, RCM, Blok, MJ, and Schrander-Stumpel, CTRM
Published: 2013
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10. BRCA1 and BRCA2 5′ noncoding region variants identified in breast cancer patients alter promoter activity and protein binding

Author: Burke, LJ, Sevcik, J, Gambino, G, Tudini, E, Mucaki, EJ, Shirley, BC, Whiley, P, Parsons, MT, De Leeneer, K, Gutierrez-Enriquez, S, Santamarina, M, Caputo, SM, dos Santos, ES, Soukupova, J, Janatova, M, Zemankova, P, Lhotova, K, Stolarova, L, Borecka, M, Moles-Fernandez, A, Manoukian, S, Bonanni, B, Edwards, SL, Blok, MJ, Hansen, TVO, Rossing, M, Diez, O, Vega, A, Claes, KBM, Goldgar, DE, Rouleau, E, Radice, P, Peterlongo, P, Rogan, PK, Caligo, M, Spurdle, AB, Brown, MA, Burke, LJ, Sevcik, J, Gambino, G, Tudini, E, Mucaki, EJ, Shirley, BC, Whiley, P, Parsons, MT, De Leeneer, K, Gutierrez-Enriquez, S, Santamarina, M, Caputo, SM, dos Santos, ES, Soukupova, J, Janatova, M, Zemankova, P, Lhotova, K, Stolarova, L, Borecka, M, Moles-Fernandez, A, Manoukian, S, Bonanni, B, Edwards, SL, Blok, MJ, Hansen, TVO, Rossing, M, Diez, O, Vega, A, Claes, KBM, Goldgar, DE, Rouleau, E, Radice, P, Peterlongo, P, Rogan, PK, Caligo, M, Spurdle, AB, and Brown, MA
Abstract: The widespread use of next generation sequencing for clinical testing is detecting an escalating number of variants in noncoding regions of the genome. The clinical significance of the majority of these variants is currently unknown, which presents a significant clinical challenge. We have screened over 6,000 early-onset and/or familial breast cancer (BC) cases collected by the ENIGMA consortium for sequence variants in the 5' noncoding regions of BC susceptibility genes BRCA1 and BRCA2, and identified 141 rare variants with global minor allele frequency < 0.01, 76 of which have not been reported previously. Bioinformatic analysis identified a set of 21 variants most likely to impact transcriptional regulation, and luciferase reporter assays detected altered promoter activity for four of these variants. Electrophoretic mobility shift assays demonstrated that three of these altered the binding of proteins to the respective BRCA1 or BRCA2 promoter regions, including NFYA binding to BRCA1:c.-287C>T and PAX5 binding to BRCA2:c.-296C>T. Clinical classification of variants affecting promoter activity, using existing prediction models, found no evidence to suggest that these variants confer a high risk of disease. Further studies are required to determine if such variation may be associated with a moderate or low risk of BC.
Published: 2018

11. Oral Contraceptive Use and Breast Cancer Risk: Retrospective and Prospective Analyses From a BRCA1 and BRCA2 Mutation Carrier Cohort Study

Author: Schrijver, LH, Olsson, H, Phillips, K-A, Terry, MB, Goldgar, DE, Kast, K, Engel, C, Mooij, TM, Adlard, J, Barrowdale, D, Davidson, R, Eeles, R, Ellis, S, Evans, DG, Frost, D, Izatt, L, Porteous, ME, Side, LE, Walker, L, Berthet, P, Bonadona, V, Leroux, D, Mouret-Fourme, E, Venat-Bouvet, L, Buys, SS, Southey, MC, John, EM, Chung, WK, Daly, MB, Bane, A, van Asperen, CJ, Garcia, EBG, Mourits, MJE, van Os, TAM, Roos-Blom, M-J, Friedlander, ML, McLachlan, S-A, Singer, CF, Tan, YY, Foretova, L, Navratilova, M, Schmutzler, RK, Ellberg, C, Gerdes, A-M, Caldes, T, Simard, J, Olah, E, Jakubowska, A, Arver, B, Osorio, A, Nogues, C, Andrieu, N, Easton, DF, van Leeuwen, FE, Hopper, JL, Milne, RL, Antoniou, AC, Rookus, MA, Hogervorst, FBL, Adank, MA, Schmidt, MK, Russell, NS, de Lange, JL, Wijnands, R, Jenner, DJ, Collee, JM, van den Ouweland, AMW, Hooning, MJ, Seynaeve, C, van Deurzen, CHM, Obdeijn, IM, Wijnen, JT, Tollenaar, RAEM, Devilee, P, van Cronenburg, TCTEF, Kets, CM, Mensenkamp, AR, Ausems, MGEM, van der Luijt, RB, van der Pol, CC, Aalfs, CM, Meijers-Heijboer, HEJ, van Engelen, K, Gille, JJP, Waisfisz, Q, Gomez-Garcia, EB, Blok, MJ, Oosterwijk, JC, van der Hout, AH, Mourits, MJ, de Bock, GH, Siesling, S, Verloop, J, Overbeek, LIH, Schrijver, LH, Olsson, H, Phillips, K-A, Terry, MB, Goldgar, DE, Kast, K, Engel, C, Mooij, TM, Adlard, J, Barrowdale, D, Davidson, R, Eeles, R, Ellis, S, Evans, DG, Frost, D, Izatt, L, Porteous, ME, Side, LE, Walker, L, Berthet, P, Bonadona, V, Leroux, D, Mouret-Fourme, E, Venat-Bouvet, L, Buys, SS, Southey, MC, John, EM, Chung, WK, Daly, MB, Bane, A, van Asperen, CJ, Garcia, EBG, Mourits, MJE, van Os, TAM, Roos-Blom, M-J, Friedlander, ML, McLachlan, S-A, Singer, CF, Tan, YY, Foretova, L, Navratilova, M, Schmutzler, RK, Ellberg, C, Gerdes, A-M, Caldes, T, Simard, J, Olah, E, Jakubowska, A, Arver, B, Osorio, A, Nogues, C, Andrieu, N, Easton, DF, van Leeuwen, FE, Hopper, JL, Milne, RL, Antoniou, AC, Rookus, MA, Hogervorst, FBL, Adank, MA, Schmidt, MK, Russell, NS, de Lange, JL, Wijnands, R, Jenner, DJ, Collee, JM, van den Ouweland, AMW, Hooning, MJ, Seynaeve, C, van Deurzen, CHM, Obdeijn, IM, Wijnen, JT, Tollenaar, RAEM, Devilee, P, van Cronenburg, TCTEF, Kets, CM, Mensenkamp, AR, Ausems, MGEM, van der Luijt, RB, van der Pol, CC, Aalfs, CM, Meijers-Heijboer, HEJ, van Engelen, K, Gille, JJP, Waisfisz, Q, Gomez-Garcia, EB, Blok, MJ, Oosterwijk, JC, van der Hout, AH, Mourits, MJ, de Bock, GH, Siesling, S, Verloop, J, and Overbeek, LIH
Abstract: BACKGROUND: For BRCA1 and BRCA2 mutation carriers, the association between oral contraceptive preparation (OCP) use and breast cancer (BC) risk is still unclear. METHODS: Breast camcer risk associations were estimated from OCP data on 6030 BRCA1 and 3809 BRCA2 mutation carriers using age-dependent Cox regression, stratified by study and birth cohort. Prospective, left-truncated retrospective and full-cohort retrospective analyses were performed. RESULTS: For BRCA1 mutation carriers, OCP use was not associated with BC risk in prospective analyses (hazard ratio [HR] = 1.08, 95% confidence interval [CI] = 0.75 to 1.56), but in the left-truncated and full-cohort retrospective analyses, risks were increased by 26% (95% CI = 6% to 51%) and 39% (95% CI = 23% to 58%), respectively. For BRCA2 mutation carriers, OCP use was associated with BC risk in prospective analyses (HR = 1.75, 95% CI = 1.03 to 2.97), but retrospective analyses were inconsistent (left-truncated: HR = 1.06, 95% CI = 0.85 to 1.33; full cohort: HR = 1.52, 95% CI = 1.28 to 1.81). There was evidence of increasing risk with duration of use, especially before the first full-term pregnancy (BRCA1: both retrospective analyses, P < .001 and P = .001, respectively; BRCA2: full retrospective analysis, P = .002). CONCLUSIONS: Prospective analyses did not show that past use of OCP is associated with an increased BC risk for BRCA1 mutation carriers in young middle-aged women (40-50 years). For BRCA2 mutation carriers, a causal association is also not likely at those ages. Findings between retrospective and prospective analyses were inconsistent and could be due to survival bias or a true association for younger women who were underrepresented in the prospective cohort. Given the uncertain safety of long-term OCP use for BRCA1/2 mutation carriers, indications other than contraception should be avoided and nonhormonal contraceptive methods should be discussed.
Published: 2018

12. The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With BRCA1 or BRCA2 Mutations

Author: Terry, MB, Liao, Y, Kast, K, Antoniou, AC, McDonald, JA, Mooij, TM, Engel, C, Nogues, C, Buecher, B, Mari, V, Moretta-Serra, J, Gladieff, L, Luporsi, E, Barrowdale, D, Frost, D, Henderson, A, Brewer, C, Evans, DG, Eccles, D, Cook, J, Ong, K-R, Izatt, L, Ahmed, M, Morrison, PJ, Dommering, CJ, Oosterwijk, JC, Ausems, MGEM, Kriege, M, Buys, SS, Andrulis, IL, John, EM, Daly, M, Friedlander, M, McLachlan, SA, Osorio, A, Caldes, T, Jakubowska, A, Simard, J, Singer, CF, Tan, Y, Olah, E, Navratilova, M, Foretova, L, Gerdes, A-M, Roos-Blom, M-J, Arver, B, Olsson, H, Schmutzler, RK, Hopper, JL, van Leeuwen, FE, Goldgar, D, Milne, RL, Easton, DF, Rookus, MA, Andrieu, N, Evans, G, Adlard, J, Eeles, R, Davidson, R, Tischkowitz, M, Snape, K, Walker, L, Porteous, M, Donaldson, A, Morrison, P, Eason, J, Rogers, M, Miller, C, Brady, A, Kennedy, MJ, Barwell, J, Gregory, H, Pottinger, C, Murray, A, Angelakos, M, Dite, G, Tsimiklis, H, Breysse, E, Pontois, P, Laborde, L, Stoppa-Lyonnet, D, Gauthier-Villars, M, Caron, O, Fourme-Mouret, E, Fricker, J-P, Lasset, C, Bonadona, V, Fert-Ferrer, S, Berthet, P, Venat-Bouvet, L, Gilbert-Dussardier, B, Faivre, L, Gesta, P, Sobol, H, Eisinger, F, Longy, M, Dugast, C, Coupier, I, Colas, C, Soubrier, F, Pujol, P, Corsini, C, Lortholary, A, Vennin, P, Adenis, C, Tan, DN, Penet, C, Delnatte, C, Tinat, J, Tennevet, I, Limacher, J-M, Maugard, C, Demange, L, Dreyfus, H, Cohen-Haguenauer, O, Leroux, D, Zattara-Cannoni, H, Bera, O, Hogervorst, FBL, Adank, MA, Schmidt, MK, Russell, NS, Jenner, DJ, Collee, JM, van den Ouweland, AMW, Hooning, MJ, Seynaeve, CM, van Deurzen, CHM, Obdeijn, IM, van Asperen, CJ, Devilee, P, Kets, CM, Mensenkamp, AR, Koudijs, MJ, Aalfs, CM, van Engelen, K, Gille, JJP, Gomez-Garcia, EB, Blok, MJ, van der Hout, AH, Mourits, MJ, de Bock, GH, Siesling, S, Verloop, J, van den Belt-Dusebout, AW, Terry, MB, Liao, Y, Kast, K, Antoniou, AC, McDonald, JA, Mooij, TM, Engel, C, Nogues, C, Buecher, B, Mari, V, Moretta-Serra, J, Gladieff, L, Luporsi, E, Barrowdale, D, Frost, D, Henderson, A, Brewer, C, Evans, DG, Eccles, D, Cook, J, Ong, K-R, Izatt, L, Ahmed, M, Morrison, PJ, Dommering, CJ, Oosterwijk, JC, Ausems, MGEM, Kriege, M, Buys, SS, Andrulis, IL, John, EM, Daly, M, Friedlander, M, McLachlan, SA, Osorio, A, Caldes, T, Jakubowska, A, Simard, J, Singer, CF, Tan, Y, Olah, E, Navratilova, M, Foretova, L, Gerdes, A-M, Roos-Blom, M-J, Arver, B, Olsson, H, Schmutzler, RK, Hopper, JL, van Leeuwen, FE, Goldgar, D, Milne, RL, Easton, DF, Rookus, MA, Andrieu, N, Evans, G, Adlard, J, Eeles, R, Davidson, R, Tischkowitz, M, Snape, K, Walker, L, Porteous, M, Donaldson, A, Morrison, P, Eason, J, Rogers, M, Miller, C, Brady, A, Kennedy, MJ, Barwell, J, Gregory, H, Pottinger, C, Murray, A, Angelakos, M, Dite, G, Tsimiklis, H, Breysse, E, Pontois, P, Laborde, L, Stoppa-Lyonnet, D, Gauthier-Villars, M, Caron, O, Fourme-Mouret, E, Fricker, J-P, Lasset, C, Bonadona, V, Fert-Ferrer, S, Berthet, P, Venat-Bouvet, L, Gilbert-Dussardier, B, Faivre, L, Gesta, P, Sobol, H, Eisinger, F, Longy, M, Dugast, C, Coupier, I, Colas, C, Soubrier, F, Pujol, P, Corsini, C, Lortholary, A, Vennin, P, Adenis, C, Tan, DN, Penet, C, Delnatte, C, Tinat, J, Tennevet, I, Limacher, J-M, Maugard, C, Demange, L, Dreyfus, H, Cohen-Haguenauer, O, Leroux, D, Zattara-Cannoni, H, Bera, O, Hogervorst, FBL, Adank, MA, Schmidt, MK, Russell, NS, Jenner, DJ, Collee, JM, van den Ouweland, AMW, Hooning, MJ, Seynaeve, CM, van Deurzen, CHM, Obdeijn, IM, van Asperen, CJ, Devilee, P, Kets, CM, Mensenkamp, AR, Koudijs, MJ, Aalfs, CM, van Engelen, K, Gille, JJP, Gomez-Garcia, EB, Blok, MJ, van der Hout, AH, Mourits, MJ, de Bock, GH, Siesling, S, Verloop, J, and van den Belt-Dusebout, AW
Abstract: BACKGROUND: Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers. METHODS: Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort. RESULTS: For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] = 0.99, 95% confidence interval [CI] = 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc = 0.79, 95% CI = 0.69 to 0.91; HRc = 0.70, 95% CI = 0.59 to 0.82; HRc = 0.50, 95% CI = 0.40 to 0.63, for 2, 3, and ≥4 FTPs, respectively, P trend < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort P trend = .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] = 1.69, 95% CI = 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc = 1.33, 95% CI = 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc = 0.72, 95% CI = 0.54 to 0.98). CONCLUSIONS: These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers.
Published: 2018

13. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations

Author: Rebbeck, TR, Friebel, TM, Friedman, E, Hamann, U, Huo, D, Kwong, A, Olah, E, Olopade, OI, Solano, AR, Teo, S-H, Thomassen, M, Weitzel, JN, Chan, TL, Couch, FJ, Goldgar, DE, Kruse, TA, Palmero, EI, Park, SK, Torres, D, van Rensburg, EJ, McGuffog, L, Parsons, MT, Leslie, G, Aalfs, CM, Abugattas, J, Adlard, J, Agata, S, Aittomaki, K, Andrews, L, Andrulis, IL, Arason, A, Arnold, N, Arun, BK, Asseryanis, E, Auerbach, L, Azzollini, J, Balmana, J, Barile, M, Barkardottir, RB, Barrowdale, D, Benitez, J, Berger, A, Berger, R, Blanco, AM, Blazer, KR, Blok, MJ, Bonadona, V, Bonanni, B, Bradbury, AR, Brewer, C, Buecher, B, Buys, SS, Caldes, T, Caliebe, A, Caligo, MA, Campbell, I, Caputo, SM, Chiquette, J, Chung, WK, Claes, KBM, Collee, JM, Cook, J, Davidson, R, de la Hoya, M, De Leeneer, K, de Pauw, A, Delnatte, C, Diez, O, Ding, YC, Ditsch, N, Domchek, S, Dorfling, CM, Velazquez, C, Dworniczak, B, Eason, J, Easton, DF, Eeles, R, Ehrencrona, H, Ejlertsen, B, Engel, C, Engert, S, Evans, DG, Faivre, L, Feliubadalo, L, Ferrer, SF, Foretova, L, Fowler, J, Frost, D, Galvao, HCR, Ganz, PA, Garber, J, Gauthier-Villars, M, Gehrig, A, Gerdes, A-M, Gesta, P, Giannini, G, Giraud, S, Glendon, G, Godwin, AK, Greene, MH, Gronwald, J, Gutierrez-Barrera, A, Hahnen, E, Hauke, J, Henderson, A, Hentschel, J, Hogervorst, FBL, Honisch, E, Imyanitov, EN, Isaacs, C, Izatt, L, Izquierdo, A, Jakubowska, A, James, P, Janavicius, R, Jensen, UB, John, EM, Vijai, J, Kaczmarek, K, Karlan, BY, Kast, K, Kim, S-W, Konstantopoulou, I, Korach, J, Laitman, Y, Lasa, A, Lasset, C, Lazaro, C, Lee, A, Lee, MH, Lester, J, Lesueur, F, Liljegren, A, Lindor, NM, Longy, M, Loud, JT, Lu, KH, Lubinski, J, Machackova, E, Manoukian, S, Mari, V, Martinez-Bouzas, C, Matrai, Z, Mebirouk, N, Meijers-Heijboer, HEJ, Meindl, A, Mensenkamp, AR, Mickys, U, Miller, A, Montagna, M, Moysich, KB, Mulligan, AM, Musinsky, J, Neuhausen, SL, Nevanlinna, H, Ngeow, J, Nguyen, HP, Niederacher, D, Nielsen, HR, Nielsen, FC, Nussbaum, RL, Offit, K, Ofverholm, A, Ong, K-R, Osorio, A, Papi, L, Papp, J, Pasini, B, Pedersen, IS, Peixoto, A, Peruga, N, Peterlongo, P, Pohl, E, Pradhan, N, Prajzendanc, K, Prieur, F, Pujol, P, Radice, P, Ramus, SJ, Rantala, J, Rashid, MU, Rhiem, K, Robson, M, Rodriguez, GC, Rogers, MT, Rudaitis, V, Schmidt, AY, Schmutzler, RK, Senter, L, Shah, PD, Sharma, P, Side, LE, Simard, J, Singer, CF, Skytte, A-B, Slavin, TP, Snape, K, Sobol, H, Southey, M, Steele, L, Steinemann, D, Sukiennicki, G, Sutter, C, Szabo, CI, Tan, YY, Teixeira, MR, Terry, MB, Teule, A, Thomas, A, Thull, DL, Tischkowitz, M, Tognazzo, S, Toland, AE, Topka, S, Trainer, AH, Tung, N, van Asperen, CJ, van der Hout, AH, van der Kolk, LE, van der Luijt, RB, Van Heetvelde, M, Varesco, L, Varon-Mateeva, R, Vega, A, Villarreal-Garza, C, von Wachenfeldt, A, Walker, L, Wang-Gohrke, S, Wappenschmidt, B, Weber, BHF, Yannoukakos, D, Yoon, S-Y, Zanzottera, C, Zidan, J, Zorn, KK, Selkirk, CGH, Hulick, PJ, Chenevix-Trench, G, Spurdle, AB, Antoniou, AC, Nathanson, KL, Rebbeck, TR, Friebel, TM, Friedman, E, Hamann, U, Huo, D, Kwong, A, Olah, E, Olopade, OI, Solano, AR, Teo, S-H, Thomassen, M, Weitzel, JN, Chan, TL, Couch, FJ, Goldgar, DE, Kruse, TA, Palmero, EI, Park, SK, Torres, D, van Rensburg, EJ, McGuffog, L, Parsons, MT, Leslie, G, Aalfs, CM, Abugattas, J, Adlard, J, Agata, S, Aittomaki, K, Andrews, L, Andrulis, IL, Arason, A, Arnold, N, Arun, BK, Asseryanis, E, Auerbach, L, Azzollini, J, Balmana, J, Barile, M, Barkardottir, RB, Barrowdale, D, Benitez, J, Berger, A, Berger, R, Blanco, AM, Blazer, KR, Blok, MJ, Bonadona, V, Bonanni, B, Bradbury, AR, Brewer, C, Buecher, B, Buys, SS, Caldes, T, Caliebe, A, Caligo, MA, Campbell, I, Caputo, SM, Chiquette, J, Chung, WK, Claes, KBM, Collee, JM, Cook, J, Davidson, R, de la Hoya, M, De Leeneer, K, de Pauw, A, Delnatte, C, Diez, O, Ding, YC, Ditsch, N, Domchek, S, Dorfling, CM, Velazquez, C, Dworniczak, B, Eason, J, Easton, DF, Eeles, R, Ehrencrona, H, Ejlertsen, B, Engel, C, Engert, S, Evans, DG, Faivre, L, Feliubadalo, L, Ferrer, SF, Foretova, L, Fowler, J, Frost, D, Galvao, HCR, Ganz, PA, Garber, J, Gauthier-Villars, M, Gehrig, A, Gerdes, A-M, Gesta, P, Giannini, G, Giraud, S, Glendon, G, Godwin, AK, Greene, MH, Gronwald, J, Gutierrez-Barrera, A, Hahnen, E, Hauke, J, Henderson, A, Hentschel, J, Hogervorst, FBL, Honisch, E, Imyanitov, EN, Isaacs, C, Izatt, L, Izquierdo, A, Jakubowska, A, James, P, Janavicius, R, Jensen, UB, John, EM, Vijai, J, Kaczmarek, K, Karlan, BY, Kast, K, Kim, S-W, Konstantopoulou, I, Korach, J, Laitman, Y, Lasa, A, Lasset, C, Lazaro, C, Lee, A, Lee, MH, Lester, J, Lesueur, F, Liljegren, A, Lindor, NM, Longy, M, Loud, JT, Lu, KH, Lubinski, J, Machackova, E, Manoukian, S, Mari, V, Martinez-Bouzas, C, Matrai, Z, Mebirouk, N, Meijers-Heijboer, HEJ, Meindl, A, Mensenkamp, AR, Mickys, U, Miller, A, Montagna, M, Moysich, KB, Mulligan, AM, Musinsky, J, Neuhausen, SL, Nevanlinna, H, Ngeow, J, Nguyen, HP, Niederacher, D, Nielsen, HR, Nielsen, FC, Nussbaum, RL, Offit, K, Ofverholm, A, Ong, K-R, Osorio, A, Papi, L, Papp, J, Pasini, B, Pedersen, IS, Peixoto, A, Peruga, N, Peterlongo, P, Pohl, E, Pradhan, N, Prajzendanc, K, Prieur, F, Pujol, P, Radice, P, Ramus, SJ, Rantala, J, Rashid, MU, Rhiem, K, Robson, M, Rodriguez, GC, Rogers, MT, Rudaitis, V, Schmidt, AY, Schmutzler, RK, Senter, L, Shah, PD, Sharma, P, Side, LE, Simard, J, Singer, CF, Skytte, A-B, Slavin, TP, Snape, K, Sobol, H, Southey, M, Steele, L, Steinemann, D, Sukiennicki, G, Sutter, C, Szabo, CI, Tan, YY, Teixeira, MR, Terry, MB, Teule, A, Thomas, A, Thull, DL, Tischkowitz, M, Tognazzo, S, Toland, AE, Topka, S, Trainer, AH, Tung, N, van Asperen, CJ, van der Hout, AH, van der Kolk, LE, van der Luijt, RB, Van Heetvelde, M, Varesco, L, Varon-Mateeva, R, Vega, A, Villarreal-Garza, C, von Wachenfeldt, A, Walker, L, Wang-Gohrke, S, Wappenschmidt, B, Weber, BHF, Yannoukakos, D, Yoon, S-Y, Zanzottera, C, Zidan, J, Zorn, KK, Selkirk, CGH, Hulick, PJ, Chenevix-Trench, G, Spurdle, AB, Antoniou, AC, and Nathanson, KL
Abstract: The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.
Published: 2018

14. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

Author: Phelan, CM, Kuchenbaecker, KB, Tyrer, JP, Kar, SP, Lawrenson, K, Winham, SJ, Dennis, J, Pirie, A, Riggan, MJ, Chornokur, G, Earp, MA, Lyra, PC, Lee, JM, Coetzee, S, Beesley, J, McGuffog, L, Soucy, P, Dicks, E, Lee, A, Barrowdale, D, Lecarpentier, J, Leslie, G, Aalfs, CM, Aben, KKH, Adams, M, Adlard, J, Andrulis, IL, Anton-Culver, H, Antonenkova, N, Aravantinos, G, Arnold, N, Arun, BK, Arver, B, Azzollini, J, Balmaña, J, Banerjee, SN, Barjhoux, L, Barkardottir, RB, Bean, Y, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Bernardini, MQ, Birrer, MJ, Bjorge, L, Black, A, Blankstein, K, Blok, MJ, Bodelon, C, Bogdanova, N, Bojesen, A, Bonanni, B, Borg, Å, Bradbury, AR, Brenton, JD, Brewer, C, Brinton, L, Broberg, P, Brooks-Wilson, A, Bruinsma, F, Brunet, J, Buecher, B, Butzow, R, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Cannioto, R, Carney, ME, Cescon, T, Chan, SB, Chang-Claude, J, Chanock, S, Chen, XQ, Chiew, YE, Chiquette, J, Chung, WK, Claes, KBM, Conner, T, Cook, LS, Cook, J, Cramer, DW, Cunningham, JM, and D'Aloisio, AA
Subjects: endocrine system diseases, female genital diseases and pregnancy complications
Abstract: © 2017 Nature America, Inc., part of Springer Nature. All rights reserved. To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
Published: 2017

15. 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

16. Assessing associations between the AURKAHMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers

Author: Blanco, I, Kuchenbaecker, K, Cuadras, D, Wang, X, Barrowdale, D, De Garibay, GR, Librado, P, Sánchez-Gracia, A, Rozas, J, Bonifaci, N, McGuffog, L, Pankratz, VS, Islam, A, Mateo, F, Berenguer, A, Petit, A, Català, I, Brunet, J, Feliubadaló, L, Tornero, E, Benítez, J, Osorio, A, Teresa, R, Teresa, C, Nevanlinna, H, Aittomäki, K, Arun, BK, Toland, AE, Karlan, BY, Walsh, C, Lester, J, Greene, MH, Mai, PL, Nussbaum, RL, Andrulis, IL, Domchek, SM, Nathanson, KL, Rebbeck, TR, Barkardottir, RB, Jakubowska, A, Lubinski, J, Durda, K, Jaworska-Bieniek, K, Claes, K, Van Maerken, T, Díez, O, Hansen, TV, Jønson, L, Gerdes, AM, Ejlertsen, B, De La Hoya, M, Caldés, T, Dunning, AM, 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, KR, Teixeira, MR, Teixeira, T, Hogervorst, FBL, Van Der Hout, AH, Seynaeve, C, Van Der Luijt, RB, Ligtenberg, MJL, Devilee, P, Wijnen, JT, Rookus, MA, Meijers-Heijboer, HEJ, Blok, MJ, Van Den Ouweland, AMW, Aalfs, CM, Rodriguez, GC, Phillips, KAA, Piedmonte, M, Nerenstone, SR, Bae-Jump, VL, O'Malley, DM, Ratner, ES, Schmutzler, RK, Wappenschmidt, B, Rhiem, K, Engel, C, Meindl, A, Ditsch, N, Arnold, N, Plendl, HJ, Niederacher, D, Sutter, C, and Wang-Gohrke, S
Subjects: skin and connective tissue diseases
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 × 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 pinteractionvalues > 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.
Published: 2015

17. 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, XS, Barrowdale, D, Garibay, GR, Librado, P, Sanchez-Gracia, A, Rozas, J, Bonifaci, N, McGuffog, L, Pankratz, VS, Islam, A, Mateo, F, Berenguer, A, Petit, A, Catala, I, Brunet, J, Feliubadalo, L, Tornero, E, Benitez, J, Osorio, A, Cajal, TRY, Nevanlinna, H, Aittomaki, K, Arun, BK, Toland, AE, Karlan, BY, Walsh, C, Lester, J, Greene, MH, Mai, PL, Nussbaum, RL, Andrulis, IL, Domchek, SM, Nathanson, KL, Rebbeck, TR, Barkardottir, RB, Jakubowska, A, Lubinski, J, Durda, K, Jaworska-Bieniek, K, Claes, K, Van Maerken, T, Diez, O, Hansen, TV, Jonson, L, Gerdes, AM, Ejlertsen, B, de la Hoya, M, Caldees, T, Dunning, AM, 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, KR, Teixeira, MR, Teixeira, Hogervorst, FBL, van der Hout, AH, Seynaeve, Caroline, van der Luijt, RB, Ligtenberg, MJL, Devilee, P, Wijnen, JT, Rookus, MA, Meijers-Heijboer, HEJ, Blok, MJ, van den Ouweland, Ans, Aalfs, CM, Rodriguez, GC, Phillips, KAA, Piedmonte, M, Nerenstone, SR, Bae-Jump, VL, O'Malley, DM, Ratner, ES, Schmutzler, RK, Wappenschmidt, B, Rhiem, K, Engel, C, Meindl, A, Ditsch, N, Arnold, N, Plendl, HJ, Niederacher, D, Sutter, C, Wang-Gohrke, S, Steinemann, D, Preisler-Adams, S, Kast, K, Varon-Mateeva, R, Gehrig, A, Bojesen, A, Pedersen, IS, Sunde, L, Jensen, UB, Thomassen, Marga, Kruse, TA, 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, CF, Rappaport, C, Geschwantler-Kaulich, D, Tea, MK, Pfeiler, G, John, EM, Miron, A, Neuhausen, SL, Terry, MB, Chung, WK, Daly, MB, Goldgar, DE, Janavicius, R, Dorfling, CM, van Rensburg, EJ, Fostira, F, Konstantopoulou, I, Garber, J, Godwin, AK, Olah, E, Narod, SA, Rennert, G, Paluch, SS, Laitman, Y, Friedman, E, Liljegren, A, Rantala, J, Stenmark-Askmalm, M, Loman, N, Imyanitov, EN, Hamann, U, Spurdle, AB, Healey, S, Weitzel, JN, 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, de Pauw, A, Lasset, C, Ferrer, SF, Castera, L, Berthet, P, Cornelis, F, Bignon, YJ, Damiola, F, Mazoyer, S, Sinilnikova, OM, Maxwell, CA, Vijai, J, Robson, M, Kauff, N, Corines, MJ, Villano, D, Cunningham, J, van der Lee, A, Lindor, N, Lazaro, C (Conxi), Easton, DF, Offit, K, Chenevix-Trench, G, Couch, FJ, Antoniou, AC, Pujana, MA, Blanco, I, Kuchenbaecker, K, Cuadras, D, Wang, XS, Barrowdale, D, Garibay, GR, Librado, P, Sanchez-Gracia, A, Rozas, J, Bonifaci, N, McGuffog, L, Pankratz, VS, Islam, A, Mateo, F, Berenguer, A, Petit, A, Catala, I, Brunet, J, Feliubadalo, L, Tornero, E, Benitez, J, Osorio, A, Cajal, TRY, Nevanlinna, H, Aittomaki, K, Arun, BK, Toland, AE, Karlan, BY, Walsh, C, Lester, J, Greene, MH, Mai, PL, Nussbaum, RL, Andrulis, IL, Domchek, SM, Nathanson, KL, Rebbeck, TR, Barkardottir, RB, Jakubowska, A, Lubinski, J, Durda, K, Jaworska-Bieniek, K, Claes, K, Van Maerken, T, Diez, O, Hansen, TV, Jonson, L, Gerdes, AM, Ejlertsen, B, de la Hoya, M, Caldees, T, Dunning, AM, 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, KR, Teixeira, MR, Teixeira, Hogervorst, FBL, van der Hout, AH, Seynaeve, Caroline, van der Luijt, RB, Ligtenberg, MJL, Devilee, P, Wijnen, JT, Rookus, MA, Meijers-Heijboer, HEJ, Blok, MJ, van den Ouweland, Ans, Aalfs, CM, Rodriguez, GC, Phillips, KAA, Piedmonte, M, Nerenstone, SR, Bae-Jump, VL, O'Malley, DM, Ratner, ES, Schmutzler, RK, Wappenschmidt, B, Rhiem, K, Engel, C, Meindl, A, Ditsch, N, Arnold, N, Plendl, HJ, Niederacher, D, Sutter, C, Wang-Gohrke, S, Steinemann, D, Preisler-Adams, S, Kast, K, Varon-Mateeva, R, Gehrig, A, Bojesen, A, Pedersen, IS, Sunde, L, Jensen, UB, Thomassen, Marga, Kruse, TA, 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, CF, Rappaport, C, Geschwantler-Kaulich, D, Tea, MK, Pfeiler, G, John, EM, Miron, A, Neuhausen, SL, Terry, MB, Chung, WK, Daly, MB, Goldgar, DE, Janavicius, R, Dorfling, CM, van Rensburg, EJ, Fostira, F, Konstantopoulou, I, Garber, J, Godwin, AK, Olah, E, Narod, SA, Rennert, G, Paluch, SS, Laitman, Y, Friedman, E, Liljegren, A, Rantala, J, Stenmark-Askmalm, M, Loman, N, Imyanitov, EN, Hamann, U, Spurdle, AB, Healey, S, Weitzel, JN, 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, de Pauw, A, Lasset, C, Ferrer, SF, Castera, L, Berthet, P, Cornelis, F, Bignon, YJ, Damiola, F, Mazoyer, S, Sinilnikova, OM, Maxwell, CA, Vijai, J, Robson, M, Kauff, N, Corines, MJ, Villano, D, Cunningham, J, van der Lee, A, Lindor, N, Lazaro, C (Conxi), Easton, DF, Offit, K, Chenevix-Trench, G, Couch, FJ, Antoniou, AC, and Pujana, MA
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 > 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.
Published: 2015

18. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

Author: Couch, FJ, Wang, X, McGuffog, L, Lee, A, Olswold, C, Kuchenbaecker, KB, Soucy, P, Fredericksen, Z, Barrowdale, D, Dennis, J, Gaudet, MM, Dicks, E, Kosel, M, Healey, S, Sinilnikova, OM, Bacot, F, Vincent, D, Hogervorst, FBL, Peock, S, Stoppa-Lyonnet, D, Jakubowska, A, Radice, P, Schmutzler, RK, Domchek, SM, Piedmonte, M, Singer, CF, Friedman, E, Thomassen, M, Hansen, TVO, Neuhausen, SL, Szabo, CI, Blanco, I, Greene, MH, Karlan, BY, Garber, J, Phelan, CM, Weitzel, JN, Montagna, M, Olah, E, Andrulis, IL, Godwin, AK, Yannoukakos, D, Goldgar, DE, Caldes, T, Nevanlinna, H, Osorio, A, Terry, MB, Daly, MB, van Rensburg, EJ, Hamann, U, Ramus, SJ, Ewart Toland, A, Caligo, MA, Olopade, OI, Tung, N, Claes, K, Beattie, MS, Southey, MC, Imyanitov, EN, Tischkowitz, M, Janavicius, R, John, EM, Kwong, A, Diez, O, Balmaña, J, Barkardottir, RB, Arun, BK, Rennert, G, Teo, SH, Ganz, PA, Campbell, I, van der Hout, AH, van Deurzen, CHM, Seynaeve, C, Gómez Garcia, EB, van Leeuwen, FE, Meijers-Heijboer, HEJ, Gille, JJP, Ausems, MGEM, Blok, MJ, Ligtenberg, MJL, Rookus, MA, Devilee, P, Verhoef, S, van Os, TAM, Wijnen, JT, Frost, D, Ellis, S, Fineberg, E, Platte, R, and Evans, DG
Subjects: endocrine system diseases, skin and connective tissue diseases
Abstract: BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10-4). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers. © 2013 Couch et al.
Published: 2013

19. ENIGMA - Evidence-based Network for the Interpretation of Germline Mutant Alleles: An international initiative to evaluate risk and clinical significance associated with sequence variation in BRCA1 and BRCA2 genes

Author: Spurdle, Ab, Healey, S, Devereau, A, Hogervorst, Fb, Monteiro, An, Nathanson, Kl, Radice, P, Stoppa Lyonnet, D, Tavtigian, S, Wappenschmidt, B, Couch, Fj, Goldgar, De, ENIGMA: Goldgar, D, Couch, F, Fackenthal, Jd, Thomassen, M, Teo, Sh, Hansen, Tv, Borg, Å, Eeles, R, Toland, A, Rogan, P, Guidugli, L, Brody, Lc, Brown, M, Kwong, A, Lei po CW, Nevanlinna, H, Garber, J, Foretova, L, Singer, Cf, Blok, Mj, Osorio, A, Kote Jarai, Z, Baralle, D, Vega, A, Blanco, A, Santamariña, M, Fachal, L, Nederlof, P, Peock, S, Pasini, Barbara, Tommasi, S, Lafferty, A, Ansari, A, Konstantopoulou, I, Pal, T, Simard, J, Bonetti, A, Varesco, L, Peissel, B, Evans, Dg, Foulkes, W, Szabo, C, van Asperen, C, Jonkers, J, Walker, L, Mitchell, G, Gutiérrez Enríquez, S, Diez, O, Millot, G, Fostira, F, Selkirk, C, Antoniou, A, Monteiro, A, Carvalho, M, Rubinstein, Ws, de la Hoya, M, Domchek, S, Caputo, S, Houdayer, C, Blanco, I, Lázaro, C, Whiley, P, Becker, A, Aretini, P, Eccles, D, Caldes, T, Viel, A, Izatt, L, Hogervorst, F, Nathanson, K, Pedersen, Is, Vreeswijk, M, Neuhausen, S, Yannoukakos, K, Tucker, K, Southey, M, Leary, J, Caligo, Ma, Gomez Garcia, E, Brandao, R, Lidereau, R, Montagna, M, Pertesi, M, Cornell, M, Rouleau, E, Sharan, S, Rahman, N, Lalloo, F, Weitzel, J, Campbell, J, Cummings, Machakova, E, Olopade, F, Godwin, A, Ozcelik, H, Seminara, D., Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Genetica & Celbiologie, and RS: GROW - School for Oncology and Reproduction
Subjects: Evidence-based practice, unclassified variant, RNA Splicing, Genes, BRCA2, Genes, BRCA1, consortium, Breast Neoplasms, Biology, Article, Germline mutation, breast cancer, Risk Factors, Genetic variation, Genetics, medicine, Humans, Clinical significance, Genetic Predisposition to Disease, BRCA1/BRCA2, Genetic Testing, Allele, unclassified variants, Gene, Genetics (clinical), Alleles, Germ-Line Mutation, Genetic testing, Ovarian Neoplasms, medicine.diagnostic_test, Mechanism (biology), Genetic Variation, BRCA1, BRCA2, ovarian cancer, Germ Cells, Organization and Administration, Data Interpretation, Statistical, international collaboration, Practice Guidelines as Topic, Female, Algorithms
Abstract: As genetic testing for predisposition to human diseases has become an increasingly common practice in medicine, the need for clear interpretation of the test results is apparent. However, for many disease genes, including the breast cancer susceptibility genes BRCA1 and BRCA2, a significant fraction of tests results in the detection of a genetic variant for which disease association is not known. The finding of an "unclassified" variant (UV)/variant of uncertain significance (VUS) complicates genetic test reporting and counseling. As these variants are individually rare, a large collaboration of researchers and clinicians will facilitate studies to assess their association with cancer predisposition. It was with this in mind that the ENIGMA consortium (www.enigmaconsortium.org) was initiated in 2009. The membership is both international and interdisciplinary, and currently includes more than 100 research scientists and clinicians from 19 countries. Within ENIGMA, there are presently six working groups focused on the following topics: analysis, clinical, database, functional, tumor histopathology, and mRNA splicing. ENIGMA provides a mechanism to pool resources, exchange methods and data, and coordinately develop and apply algorithms for classification of variants in BRCA1 and BRCA2. It is envisaged that the research and clinical application of models developed by ENIGMA will be relevant to the interpretation of sequence variants in other disease genes. Hum Mutat 00:1-6, 2011. © 2011 Wiley Periodicals, Inc.
Published: 2011

20. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

Author: Hunter, KW, Couch, FJ, Wang, X, McGuffog, L, Lee, A, Olswold, C, Kuchenbaecker, KB, Soucy, P, Fredericksen, Z, Barrowdale, D, Dennis, J, Gaudet, MM, Dicks, E, Kosel, M, Healey, S, Sinilnikova, OM, Bacot, F, Vincent, D, Hogervorst, FBL, Peock, S, Stoppa-Lyonnet, D, Jakubowska, A, Radice, P, Schmutzler, RK, Domchek, SM, Piedmonte, M, Singer, CF, Friedman, E, Thomassen, M, Hansen, TVO, Neuhausen, SL, Szabo, CI, Blanco, I, Greene, MH, Karlan, BY, Garber, J, Phelan, CM, Weitzel, JN, Montagna, M, Olah, E, Andrulis, IL, Godwin, AK, Yannoukakos, D, Goldgar, DE, Caldes, T, Nevanlinna, H, Osorio, A, Terry, MB, Daly, MB, van Rensburg, EJ, Hamann, U, Ramus, SJ, Toland, AE, Caligo, MA, Olopade, OI, Tung, N, Claes, K, Beattie, MS, Southey, MC, Imyanitov, EN, Tischkowitz, M, Janavicius, R, John, EM, Kwong, A, Diez, O, Balmana, J, Barkardottir, RB, Arun, BK, Rennert, G, Teo, S-H, Ganz, PA, Campbell, I, van der Hout, AH, van Deurzen, CHM, Seynaeve, C, Garcia, EBG, van Leeuwen, FE, Meijers-Heijboer, HEJ, Gille, JJP, Ausems, MGEM, Blok, MJ, Ligtenberg, MJL, Rookus, MA, Devilee, P, Verhoef, S, van Os, TAM, Wijnen, JT, Frost, D, Ellis, S, Fineberg, E, Platte, R, Evans, DG, Izatt, L, Eeles, RA, Adlard, J, Eccles, DM, Cook, J, Brewer, C, Douglas, F, Hodgson, S, Morrison, PJ, Side, LE, Donaldson, A, Houghton, C, Rogers, MT, Dorkins, H, Eason, J, Gregory, H, McCann, E, Murray, A, Calender, A, Hardouin, A, Berthet, P, Delnatte, C, Nogues, C, Lasset, C, Houdayer, C, Leroux, D, Rouleau, E, Prieur, F, Damiola, F, Sobol, H, Coupier, I, Venat-Bouvet, L, Castera, L, Gauthier-Villars, M, Leone, M, Pujol, P, Mazoyer, S, Bignon, Y-J, Zlowocka-Perlowska, E, Gronwald, J, Lubinski, J, Durda, K, Jaworska, K, Huzarski, T, Spurdle, AB, Viel, A, Peissel, B, Bonanni, B, Melloni, G, Ottini, L, Papi, L, Varesco, L, Tibiletti, MG, Peterlongo, P, Volorio, S, Manoukian, S, Pensotti, V, Arnold, N, Engel, C, Deissler, H, Gadzicki, D, Gehrig, A, Kast, K, Rhiem, K, Meindl, A, Niederacher, D, Ditsch, N, Plendl, H, Preisler-Adams, S, Engert, S, Sutter, C, Varon-Mateeva, R, Wappenschmidt, B, Weber, BHF, Arver, B, Stenmark-Askmalm, M, Loman, N, Rosenquist, R, Einbeigi, Z, Nathanson, KL, Rebbeck, TR, Blank, SV, Cohn, DE, Rodriguez, GC, Small, L, Friedlander, M, Bae-Jump, VL, Fink-Retter, A, Rappaport, C, Gschwantler-Kaulich, D, Pfeiler, G, Tea, M-K, Lindor, NM, Kaufman, B, Paluch, SS, Laitman, Y, Skytte, A-B, Gerdes, A-M, Pedersen, IS, Moeller, ST, Kruse, TA, Jensen, UB, Vijai, J, Sarrel, K, Robson, M, Kauff, N, Mulligan, AM, Glendon, G, Ozcelik, H, Ejlertsen, B, Nielsen, FC, Jonson, L, Andersen, MK, Ding, YC, Steele, L, Foretova, L, Teule, A, Lazaro, C, Brunet, J, Angel Pujana, M, Mai, PL, Loud, JT, Walsh, C, Lester, J, Orsulic, S, Narod, SA, Herzog, J, Sand, SR, Tognazzo, S, Agata, S, Vaszko, T, Weaver, J, Stavropoulou, AV, Buys, SS, Romero, A, de la Hoya, M, Aittomaki, K, Muranen, TA, Duran, M, Chung, WK, Lasa, A, Dorfling, CM, Miron, A, Benitez, J, Senter, L, Huo, D, Chan, SB, Sokolenko, AP, Chiquette, J, Tihomirova, L, Friebel, TM, Agnarsson, BA, Lu, KH, Lejbkowicz, F, James, PA, Hall, P, Dunning, AM, Tessier, D, Cunningham, J, Slager, SL, Wang, C, Hart, S, Stevens, K, Simard, J, Pastinen, T, Pankratz, VS, Offit, K, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Hunter, KW, Couch, FJ, Wang, X, McGuffog, L, Lee, A, Olswold, C, Kuchenbaecker, KB, Soucy, P, Fredericksen, Z, Barrowdale, D, Dennis, J, Gaudet, MM, Dicks, E, Kosel, M, Healey, S, Sinilnikova, OM, Bacot, F, Vincent, D, Hogervorst, FBL, Peock, S, Stoppa-Lyonnet, D, Jakubowska, A, Radice, P, Schmutzler, RK, Domchek, SM, Piedmonte, M, Singer, CF, Friedman, E, Thomassen, M, Hansen, TVO, Neuhausen, SL, Szabo, CI, Blanco, I, Greene, MH, Karlan, BY, Garber, J, Phelan, CM, Weitzel, JN, Montagna, M, Olah, E, Andrulis, IL, Godwin, AK, Yannoukakos, D, Goldgar, DE, Caldes, T, Nevanlinna, H, Osorio, A, Terry, MB, Daly, MB, van Rensburg, EJ, Hamann, U, Ramus, SJ, Toland, AE, Caligo, MA, Olopade, OI, Tung, N, Claes, K, Beattie, MS, Southey, MC, Imyanitov, EN, Tischkowitz, M, Janavicius, R, John, EM, Kwong, A, Diez, O, Balmana, J, Barkardottir, RB, Arun, BK, Rennert, G, Teo, S-H, Ganz, PA, Campbell, I, van der Hout, AH, van Deurzen, CHM, Seynaeve, C, Garcia, EBG, van Leeuwen, FE, Meijers-Heijboer, HEJ, Gille, JJP, Ausems, MGEM, Blok, MJ, Ligtenberg, MJL, Rookus, MA, Devilee, P, Verhoef, S, van Os, TAM, Wijnen, JT, Frost, D, Ellis, S, Fineberg, E, Platte, R, Evans, DG, Izatt, L, Eeles, RA, Adlard, J, Eccles, DM, Cook, J, Brewer, C, Douglas, F, Hodgson, S, Morrison, PJ, Side, LE, Donaldson, A, Houghton, C, Rogers, MT, Dorkins, H, Eason, J, Gregory, H, McCann, E, Murray, A, Calender, A, Hardouin, A, Berthet, P, Delnatte, C, Nogues, C, Lasset, C, Houdayer, C, Leroux, D, Rouleau, E, Prieur, F, Damiola, F, Sobol, H, Coupier, I, Venat-Bouvet, L, Castera, L, Gauthier-Villars, M, Leone, M, Pujol, P, Mazoyer, S, Bignon, Y-J, Zlowocka-Perlowska, E, Gronwald, J, Lubinski, J, Durda, K, Jaworska, K, Huzarski, T, Spurdle, AB, Viel, A, Peissel, B, Bonanni, B, Melloni, G, Ottini, L, Papi, L, Varesco, L, Tibiletti, MG, Peterlongo, P, Volorio, S, Manoukian, S, Pensotti, V, Arnold, N, Engel, C, Deissler, H, Gadzicki, D, Gehrig, A, Kast, K, Rhiem, K, Meindl, A, Niederacher, D, Ditsch, N, Plendl, H, Preisler-Adams, S, Engert, S, Sutter, C, Varon-Mateeva, R, Wappenschmidt, B, Weber, BHF, Arver, B, Stenmark-Askmalm, M, Loman, N, Rosenquist, R, Einbeigi, Z, Nathanson, KL, Rebbeck, TR, Blank, SV, Cohn, DE, Rodriguez, GC, Small, L, Friedlander, M, Bae-Jump, VL, Fink-Retter, A, Rappaport, C, Gschwantler-Kaulich, D, Pfeiler, G, Tea, M-K, Lindor, NM, Kaufman, B, Paluch, SS, Laitman, Y, Skytte, A-B, Gerdes, A-M, Pedersen, IS, Moeller, ST, Kruse, TA, Jensen, UB, Vijai, J, Sarrel, K, Robson, M, Kauff, N, Mulligan, AM, Glendon, G, Ozcelik, H, Ejlertsen, B, Nielsen, FC, Jonson, L, Andersen, MK, Ding, YC, Steele, L, Foretova, L, Teule, A, Lazaro, C, Brunet, J, Angel Pujana, M, Mai, PL, Loud, JT, Walsh, C, Lester, J, Orsulic, S, Narod, SA, Herzog, J, Sand, SR, Tognazzo, S, Agata, S, Vaszko, T, Weaver, J, Stavropoulou, AV, Buys, SS, Romero, A, de la Hoya, M, Aittomaki, K, Muranen, TA, Duran, M, Chung, WK, Lasa, A, Dorfling, CM, Miron, A, Benitez, J, Senter, L, Huo, D, Chan, SB, Sokolenko, AP, Chiquette, J, Tihomirova, L, Friebel, TM, Agnarsson, BA, Lu, KH, Lejbkowicz, F, James, PA, Hall, P, Dunning, AM, Tessier, D, Cunningham, J, Slager, SL, Wang, C, Hart, S, Stevens, K, Simard, J, Pastinen, T, Pankratz, VS, Offit, K, Easton, DF, Chenevix-Trench, G, and Antoniou, AC
Abstract: BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.
Published: 2013

21. Association of PHB 1630 C > T and MTHFR 677 C > T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study

Author: Jakubowska, A, Rozkrut, D, Antoniou, A, Hamann, U, Scott, RJ, McGuffog, L, Healy, S, Sinilnikova, OM, Rennert, G, Lejbkowicz, F, Flugelman, A, Andrulis, IL, Glendon, G, Ozcelik, H, Thomassen, Marga, Paligo, M, Aretini, P, Kantala, J, Aroer, B, von Wachenfeldt, A, Liljegren, A, Loman, N, Herbst, K, Kristoffersson, U, Rosenquist, R, Karlsson, P, Stenmark-Askmalm, M, Melin, B, Nathanson, KL, Domchek, SM, Byrski, T, Huzarski, T, Gronwald, J, Menkiszak, J, Cybulski, C, Serrano, P, Osorio, A, Cajal, TR, Tsitlaidou, M, Benitez, J, Gilbert, M, Rookus, M, Aalfs, CM, Kluijt, I, Boessenkool-Pape, JL, Meijers-Heijboer, HEJ, Oosterwijk, JC, van Asperen, CJ, Blok, MJ, Nelen, MR, van den Ouweland, Ans, Seynaeve, Caroline, van der Luijt, RB, Devilee, P, Easton, DF, Peock, S, Frost, D, Platte, R, Ellis, SD, Fineberg, E, Evans, DG, Lalloo, F, Eeles, R, Jacobs, C, Adlard, J, Davidson, R, Eccles, D, Cole, T, Cook, J, Godwin, A, Bove, B, Stoppa-Lyonnet, D, Caux-Moncoutier, V, Belotti, M, Tirapo, C, Mazoyer, S, Barjhoux, L, Boutry-Kryza, N, Pujol, P, Coupier, I, Peyrat, JP, Vennin, P, Muller, D, Fricker, JP, Venat-Bouvet, L, Johannsson, O, Isaacs, C, Schmutzler, R, Wappenschmidt, B, Meindl, A, Arnold, N, Varon-Mateeva, R, Niederacher, D, Sutter, C, Deissler, H, Preisler-Adams, S, Simard, J, Soucy, P, Durocher, F, Chenevix-Trench, G, Beesley, J, Chen, X, Rebbeck, T, Couch, F, Wang, X, Lindor, N, Fredericksen, Z, Pankratz, VS, Peterlongo, P, Bonanni, B, Fortuzzi, S, Peissel, B, Szabo, C, Mai, PL, Loud, JT, Lubinski, J, Jakubowska, A, Rozkrut, D, Antoniou, A, Hamann, U, Scott, RJ, McGuffog, L, Healy, S, Sinilnikova, OM, Rennert, G, Lejbkowicz, F, Flugelman, A, Andrulis, IL, Glendon, G, Ozcelik, H, Thomassen, Marga, Paligo, M, Aretini, P, Kantala, J, Aroer, B, von Wachenfeldt, A, Liljegren, A, Loman, N, Herbst, K, Kristoffersson, U, Rosenquist, R, Karlsson, P, Stenmark-Askmalm, M, Melin, B, Nathanson, KL, Domchek, SM, Byrski, T, Huzarski, T, Gronwald, J, Menkiszak, J, Cybulski, C, Serrano, P, Osorio, A, Cajal, TR, Tsitlaidou, M, Benitez, J, Gilbert, M, Rookus, M, Aalfs, CM, Kluijt, I, Boessenkool-Pape, JL, Meijers-Heijboer, HEJ, Oosterwijk, JC, van Asperen, CJ, Blok, MJ, Nelen, MR, van den Ouweland, Ans, Seynaeve, Caroline, van der Luijt, RB, Devilee, P, Easton, DF, Peock, S, Frost, D, Platte, R, Ellis, SD, Fineberg, E, Evans, DG, Lalloo, F, Eeles, R, Jacobs, C, Adlard, J, Davidson, R, Eccles, D, Cole, T, Cook, J, Godwin, A, Bove, B, Stoppa-Lyonnet, D, Caux-Moncoutier, V, Belotti, M, Tirapo, C, Mazoyer, S, Barjhoux, L, Boutry-Kryza, N, Pujol, P, Coupier, I, Peyrat, JP, Vennin, P, Muller, D, Fricker, JP, Venat-Bouvet, L, Johannsson, O, Isaacs, C, Schmutzler, R, Wappenschmidt, B, Meindl, A, Arnold, N, Varon-Mateeva, R, Niederacher, D, Sutter, C, Deissler, H, Preisler-Adams, S, Simard, J, Soucy, P, Durocher, F, Chenevix-Trench, G, Beesley, J, Chen, X, Rebbeck, T, Couch, F, Wang, X, Lindor, N, Fredericksen, Z, Pankratz, VS, Peterlongo, P, Bonanni, B, Fortuzzi, S, Peissel, B, Szabo, C, Mai, PL, Loud, JT, and Lubinski, J
Abstract: BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. RESULTS: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1 CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers. British Journal of Cancer (2012) 106, 2016-2024. doi:10.1038/bjc.2012.160 www.bjcancer.com Published online 15 May 2012 (C) 2012 Cancer Research UK
Published: 2012

22. Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers

Author: Ramus, S, Kartsonaki, C, Gayther, S, Pharoah, P, Sinilnikova, O, Beesley, J, Chen, X, Mcguffog, L, Healey, S, Couch, F, Wang, X, Fredericksen, Z, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Roversi, G, Barile, M, Viel, A, Allavena, A, Ottini, L, Papi, L, Gismondi, V, Capra, F, Radice, P, Greene, M, Mai, P, Andrulis, I, Glendon, G, Ozcelik, H, Thomassen, M, Gerdes, A, Kruse, T, Cruger, D, Jensen, U, Caligo, M, Olsson, H, Kristoffersson, U, Lindblom, A, Arver, B, Karlsson, P, Stenmark Askmalm, M, Borg, A, Neuhausen, S, Ding, Y, Nathanson, K, Domchek, S, Jakubowska, A, Lubiński, J, Huzarski, T, Byrski, T, Gronwald, J, Górski, B, Cybulski, C, Dębniak, T, Osorio, A, Durán, M, Tejada, M, Benítez, J, Hamann, U, Rookus, M, Verhoef, S, Tilanus Linthorst, M, Vreeswijk, M, Bodmer, D, Ausems, M, van Os, T, Asperen, C, Blok, M, Meijers Heijboer, H, Peock, S, Cook, M, Oliver, C, Frost, D, Dunning, A, Evans, D, Eeles, R, Pichert, G, Cole, T, Hodgson, S, Brewer, C, Morrison, P, Porteous, M, Kennedy, M, Rogers, M, Side, L, Donaldson, A, Gregory, H, Godwin, A, Stoppa Lyonnet, D, Moncoutier, V, Castera, L, Mazoyer, S, Barjhoux, L, Bonadona, V, Leroux, D, Faivre, L, Lidereau, R, Nogues, C, Bignon, Y, Prieur, F, Collonge Rame, M, Venat Bouvet, L, Fert Ferrer, S, Miron, A, Buys, S, Hopper, J, Daly, M, John, E, Terry, M, Goldgar, D, Hansen, T, Jønson, L, Ejlertsen, B, Agnarsson, B, Offit, K, Kirchhoff, T, Vijai, J, Dutra Clarke, A, Przybylo, J, Montagna, M, Casella, C, Imyanitov, E, Janavicius, R, Blanco, I, Lázaro, C, Moysich, K, Karlan, B, Gross, J, Beattie, M, Schmutzler, R, Wappenschmidt, B, Meindl, A, Ruehl, I, Fiebig, B, Sutter, C, Arnold, N, Deissler, H, Varon Mateeva, R, Kast, K, Niederacher, D, Gadzicki, D, Caldes, T, de la Hoya, M, Nevanlinna, H, Aittomäki, K, Simard, J, Soucy, P, Spurdle, A, Holland, H, Chenevix Trench, G, Easton, D, Antoniou, A, Ramus, SJ, Gayther, SA, Pharoah, PDP, Sinilnikova, OM, McGuffog, L, Couch, FJ, Greene, MH, Mai, PL, Andrulis, IL, Kruse, TA, Jensen, UB, Caligo, MA, Neuhausen, SL, Ding, YC, Nathanson, KL, Domchek, SM, Rookus, MA, Tilanus Linthorst, MA, Vreeswijk, MP, Ausems, MGEM, van Os, TA, Asperen, CJ, Blok, MJ, Meijers Heijboer, HEJ, Dunning, AM, Evans, DG, Morrison, PJ, Kennedy, MJ, Rogers, MT, Side, LE, Buys, SS, Hopper, JL, Daly, MB, John, EM, Terry, MB, Hansen, TvO, Agnarsson, BA, Dutra Clarke, AVC, Przybylo, JA, Imyanitov, EN, Moysich, KB, Karlan, BY, Beattie, MS, Spurdle, AB, Easton, DF, Antoniou, AC, ROVERSI, GAIA, Ramus, S, Kartsonaki, C, Gayther, S, Pharoah, P, Sinilnikova, O, Beesley, J, Chen, X, Mcguffog, L, Healey, S, Couch, F, Wang, X, Fredericksen, Z, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Roversi, G, Barile, M, Viel, A, Allavena, A, Ottini, L, Papi, L, Gismondi, V, Capra, F, Radice, P, Greene, M, Mai, P, Andrulis, I, Glendon, G, Ozcelik, H, Thomassen, M, Gerdes, A, Kruse, T, Cruger, D, Jensen, U, Caligo, M, Olsson, H, Kristoffersson, U, Lindblom, A, Arver, B, Karlsson, P, Stenmark Askmalm, M, Borg, A, Neuhausen, S, Ding, Y, Nathanson, K, Domchek, S, Jakubowska, A, Lubiński, J, Huzarski, T, Byrski, T, Gronwald, J, Górski, B, Cybulski, C, Dębniak, T, Osorio, A, Durán, M, Tejada, M, Benítez, J, Hamann, U, Rookus, M, Verhoef, S, Tilanus Linthorst, M, Vreeswijk, M, Bodmer, D, Ausems, M, van Os, T, Asperen, C, Blok, M, Meijers Heijboer, H, Peock, S, Cook, M, Oliver, C, Frost, D, Dunning, A, Evans, D, Eeles, R, Pichert, G, Cole, T, Hodgson, S, Brewer, C, Morrison, P, Porteous, M, Kennedy, M, Rogers, M, Side, L, Donaldson, A, Gregory, H, Godwin, A, Stoppa Lyonnet, D, Moncoutier, V, Castera, L, Mazoyer, S, Barjhoux, L, Bonadona, V, Leroux, D, Faivre, L, Lidereau, R, Nogues, C, Bignon, Y, Prieur, F, Collonge Rame, M, Venat Bouvet, L, Fert Ferrer, S, Miron, A, Buys, S, Hopper, J, Daly, M, John, E, Terry, M, Goldgar, D, Hansen, T, Jønson, L, Ejlertsen, B, Agnarsson, B, Offit, K, Kirchhoff, T, Vijai, J, Dutra Clarke, A, Przybylo, J, Montagna, M, Casella, C, Imyanitov, E, Janavicius, R, Blanco, I, Lázaro, C, Moysich, K, Karlan, B, Gross, J, Beattie, M, Schmutzler, R, Wappenschmidt, B, Meindl, A, Ruehl, I, Fiebig, B, Sutter, C, Arnold, N, Deissler, H, Varon Mateeva, R, Kast, K, Niederacher, D, Gadzicki, D, Caldes, T, de la Hoya, M, Nevanlinna, H, Aittomäki, K, Simard, J, Soucy, P, Spurdle, A, Holland, H, Chenevix Trench, G, Easton, D, Antoniou, A, Ramus, SJ, Gayther, SA, Pharoah, PDP, Sinilnikova, OM, McGuffog, L, Couch, FJ, Greene, MH, Mai, PL, Andrulis, IL, Kruse, TA, Jensen, UB, Caligo, MA, Neuhausen, SL, Ding, YC, Nathanson, KL, Domchek, SM, Rookus, MA, Tilanus Linthorst, MA, Vreeswijk, MP, Ausems, MGEM, van Os, TA, Asperen, CJ, Blok, MJ, Meijers Heijboer, HEJ, Dunning, AM, Evans, DG, Morrison, PJ, Kennedy, MJ, Rogers, MT, Side, LE, Buys, SS, Hopper, JL, Daly, MB, John, EM, Terry, MB, Hansen, TvO, Agnarsson, BA, Dutra Clarke, AVC, Przybylo, JA, Imyanitov, EN, Moysich, KB, Karlan, BY, Beattie, MS, Spurdle, AB, Easton, DF, Antoniou, AC, and ROVERSI, GAIA
Abstract: Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2.
Published: 2011

23. Exploring the link between MORF4L1 and risk of breast cancer

Author: Martrat, G, Maxwell, CA, Tominaga, E, Porta-de-la-Riva, M, Bonifaci, N, Gomez-Baldo, L, Bogliolo, M, Lazaro, C (Conxi), Blanco, I, Brunet, J, Aguilar, H, Fernandez-Rodriguez, J, Seal, S, Renwick, A, Rahman, N, Kuhl, J, Neveling, K, Schindler, D, Ramirez, MJ, Castella, M, Hernandez, G, Easton, DF, Peock, S, Cook, M, Oliver, CT, Frost, D, Platte, R, Evans, DG, Lalloo, F, Eeles, R, Izatt, L, Chu, C, Davidson, R, Ong, KR, Cook, J, Douglas, F, Hodgson, S, Brewer, C, Morrison, PJ, Porteous, M, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Roversi, G, Barile, M, Viel, A, pasini, B, Ottini, L, Putignano, AL, Savarese, A, Bernard, L, Radice, P, Healey, S, Spurdle, A, Chen, XQ, Beesley, J, Rookus, MA, Verhoef, S, Tilanus-Linthorst, MA, Vreeswijk, MP, van Asperen, CJ, Bodmer, D, Ausems, MGEM, van Os, TA, Blok, MJ, Meijers-Heijboer, HEJ, Hogervorst, FBL, Goldgar, DE, Buys, S, John, EM, Miron, A, Southey, M, Daly, MB, Harbst, K, Borg, A, Rantala, J, Barbany-Bustinza, G, Ehrencrona, H, Stenmark-Askmalm, M, Kaufman, B, Laitman, Y, Milgrom, R, Friedman, E, Domchek, SM, Nathanson, KL, Rebbeck, TR, Oskar, T, Couch, FJ, Wang, XS, Fredericksen, Z, Cuadras, D, Moreno, V, Pientka, FK, Depping, R, Caldes, T, Osorio, A, Benitez, J, Bueren, J, Heikkinen, T, Nevanlinna, H, Hamann, U, Torres, D, Caligo, MA, Godwin, AK, Imyanitov, EN, Janavicius, R, Sinilnikova, OM, Stoppa-Lyonnet, D, Mazoyer, S, Verny-Pierre, C, Castera, L, de Pauw, A, Bignon, YJ, Uhrhammer, N, Peyrat, JP, Vennin, P, Ferrer, SF, Collonge-Rame, MA, Mortemousque, I, McGuffog, L, Chenevix-Trench, G, Pereira-Smith, OM, Antoniou, AC, Ceron, J, Tominaga, K, Surralles, J, Pujana, MA, Martrat, G, Maxwell, CA, Tominaga, E, Porta-de-la-Riva, M, Bonifaci, N, Gomez-Baldo, L, Bogliolo, M, Lazaro, C (Conxi), Blanco, I, Brunet, J, Aguilar, H, Fernandez-Rodriguez, J, Seal, S, Renwick, A, Rahman, N, Kuhl, J, Neveling, K, Schindler, D, Ramirez, MJ, Castella, M, Hernandez, G, Easton, DF, Peock, S, Cook, M, Oliver, CT, Frost, D, Platte, R, Evans, DG, Lalloo, F, Eeles, R, Izatt, L, Chu, C, Davidson, R, Ong, KR, Cook, J, Douglas, F, Hodgson, S, Brewer, C, Morrison, PJ, Porteous, M, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Roversi, G, Barile, M, Viel, A, pasini, B, Ottini, L, Putignano, AL, Savarese, A, Bernard, L, Radice, P, Healey, S, Spurdle, A, Chen, XQ, Beesley, J, Rookus, MA, Verhoef, S, Tilanus-Linthorst, MA, Vreeswijk, MP, van Asperen, CJ, Bodmer, D, Ausems, MGEM, van Os, TA, Blok, MJ, Meijers-Heijboer, HEJ, Hogervorst, FBL, Goldgar, DE, Buys, S, John, EM, Miron, A, Southey, M, Daly, MB, Harbst, K, Borg, A, Rantala, J, Barbany-Bustinza, G, Ehrencrona, H, Stenmark-Askmalm, M, Kaufman, B, Laitman, Y, Milgrom, R, Friedman, E, Domchek, SM, Nathanson, KL, Rebbeck, TR, Oskar, T, Couch, FJ, Wang, XS, Fredericksen, Z, Cuadras, D, Moreno, V, Pientka, FK, Depping, R, Caldes, T, Osorio, A, Benitez, J, Bueren, J, Heikkinen, T, Nevanlinna, H, Hamann, U, Torres, D, Caligo, MA, Godwin, AK, Imyanitov, EN, Janavicius, R, Sinilnikova, OM, Stoppa-Lyonnet, D, Mazoyer, S, Verny-Pierre, C, Castera, L, de Pauw, A, Bignon, YJ, Uhrhammer, N, Peyrat, JP, Vennin, P, Ferrer, SF, Collonge-Rame, MA, Mortemousque, I, McGuffog, L, Chenevix-Trench, G, Pereira-Smith, OM, Antoniou, AC, Ceron, J, Tominaga, K, Surralles, J, and Pujana, MA
Abstract: Introduction: Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. Methods: Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. Results: A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to g-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, P(trend) = 0.45 and 0.05, P(2df) = 0.51 and 0.14, respectively; and rs10519219, P(trend) =
Published: 2011

24. A method to assess the clinical significance of unclassified variants in the BRCA1 and BRCA2 genes based on cancer family history

Author: Garcia, EBG, Oosterwijk, JC, Timmermans, M, van Asperen, CJ, Hogervorst, FBL, Hoogerbrugge, N, Oldenburg, Rogier, Verhoef, S, Dommering, CJ, Ausems, MGEM, van Os, TAM, van der Hout, AH, Ligtenberg, M, van den Ouweland, Ans, van der Luijt, RB, Wijnen, JT, Gille, JJP, Lindsey, PJ, Devilee, P, Blok, MJ, Vreeswijk, MPG, Garcia, EBG, Oosterwijk, JC, Timmermans, M, van Asperen, CJ, Hogervorst, FBL, Hoogerbrugge, N, Oldenburg, Rogier, Verhoef, S, Dommering, CJ, Ausems, MGEM, van Os, TAM, van der Hout, AH, Ligtenberg, M, van den Ouweland, Ans, van der Luijt, RB, Wijnen, JT, Gille, JJP, Lindsey, PJ, Devilee, P, Blok, MJ, and Vreeswijk, MPG
Abstract: Introduction Unclassified variants (UVs) in the BRCA1/BRCA2 genes are a frequent problem in counseling breast cancer and/or ovarian cancer families. Information about cancer family history is usually available, but has rarely been used to evaluate UVs. The aim of the present study was to identify which is the best combination of clinical parameters that can predict whether a UV is deleterious, to be used for the classification of UVs. Methods We developed logistic regression models with the best combination of clinical features that distinguished a positive control of BRCA pathogenic variants (115 families) from a negative control population of BRCA variants initially classified as UVs and later considered neutral (38 families). Results The models included a combination of BRCAPRO scores, Myriad scores, number of ovarian cancers in the family, the age at diagnosis, and the number of persons with ovarian tumors and/ or breast tumors. The areas under the receiver operating characteristic curves were respectively 0.935 and 0.836 for the BRCA1 and BRCA2 models. For each model, the minimum receiver operating characteristic distance (respectively 90% and 78% specificity for BRCA1 and BRCA2) was chosen as the cutoff value to predict which UVs are deleterious from a study population of 12 UVs, present in 59 Dutch families. The p. S1655F, p. R1699W, and p. R1699Q variants in BRCA1 and the p. Y2660D, p. R2784Q, and p. R3052W variants in BRCA2 are classified as deleterious according to our models. The predictions of the p. L246V variant in BRCA1 and of the p. Y42C, p. E462G, p. R2888C, and p. R3052Q variants in BRCA2 are in agreement with published information of them being neutral. The p. R2784W variant in BRCA2 remains uncertain. Conclusions The present study shows that these developed models are useful to classify UVs in clinical genetic practice.
Published: 2009

25. A simple method for co-segregation analysis to evaluate the pathogenicity of unclassified variants; BRCA1 and BRCA2 as an example

Author: Mohammadi, L, Vreeswijk, MP, Oldenburg, Rogier, van den Ouweland, Ans, Oosterwijk, JC, van der Hout, AH, Hoogerbrugge, N, Ligtenberg, M, Ausems, MG, van der Luijt, RB, Dommering, CJ, Gille, JJ, Verhoef, S, Hogervorst, FB, van Os, TA, Garcia, EG, Blok, MJ, Wijnen, JT, Helmer, Q, Devilee, P, van Asperen, CJ, van Houwelingen, HC, Mohammadi, L, Vreeswijk, MP, Oldenburg, Rogier, van den Ouweland, Ans, Oosterwijk, JC, van der Hout, AH, Hoogerbrugge, N, Ligtenberg, M, Ausems, MG, van der Luijt, RB, Dommering, CJ, Gille, JJ, Verhoef, S, Hogervorst, FB, van Os, TA, Garcia, EG, Blok, MJ, Wijnen, JT, Helmer, Q, Devilee, P, van Asperen, CJ, and van Houwelingen, HC
Abstract: Background: Assessment of the clinical significance of unclassified variants (UVs) identified in BRCA1 and BRCA2 is very important for genetic counselling. The analysis of co-segregation of the variant with the disease in families is a powerful tool for the classification of these variants. Statistical methods have been described in literature but these methods are not always easy to apply in a diagnostic setting. Methods: We have developed an easy to use method which calculates the likelihood ratio (LR) of an UV being deleterious, with penetrance as a function of age of onset, thereby avoiding the use of liability classes. The application of this algorithm is publicly available http://www.msbi.nl/cosegregation. It can easily be used in a diagnostic setting since it requires only information on gender, genotype, present age and/or age of onset for breast and/or ovarian cancer. Results: We have used the algorithm to calculate the likelihood ratio in favour of causality for 3 UVs in BRCA1 (p.M18T, p.S1655F and p.R1699Q) and 5 in BRCA2 (p.E462G p.Y2660D, p.R2784Q, p.R3052W and p.R3052Q). Likelihood ratios varied from 0.097 (BRCA2, p.E462G) to 230.69 (BRCA2, p.Y2660D). Typing distantly related individuals with extreme phenotypes (i.e. very early onset cancer or old healthy individuals) are most informative and give the strongest likelihood ratios for or against causality. Conclusion: Although co-segregation analysis on itself is in most cases insufficient to prove pathogenicity of an UV, this method simplifies the use of co-segregation as one of the key features in a multifactorial approach considerably.
Published: 2009

26. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

Author: Phelan, CM, Kuchenbaecker, KB, Tyrer, JP, Kar, SP, Lawrenson, K, Winham, SJ, Dennis, J, Pirie, A, Riggan, MJ, Chornokur, G, Earp, MA, Lyra, PC, Lee, JM, Coetzee, S, Beesley, J, McGuffog, L, Soucy, P, Dicks, E, Lee, A, Barrowdale, D, Lecarpentier, J, Leslie, G, Aalfs, CM, Aben, KKH, Adams, M, Adlard, J, Andrulis, IL, Anton-Culver, H, Antonenkova, N, AOCS Study Group, Aravantinos, G, Arnold, N, Arun, BK, Arver, B, Azzollini, J, Balmaña, J, Banerjee, SN, Barjhoux, L, Barkardottir, RB, Bean, Y, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Bernardini, MQ, Birrer, MJ, Bjorge, L, Black, A, Blankstein, K, Blok, MJ, Bodelon, C, Bogdanova, N, Bojesen, A, Bonanni, B, Borg, Å, Bradbury, AR, Brenton, JD, Brewer, C, Brinton, L, Broberg, P, Brooks-Wilson, A, Bruinsma, F, Brunet, J, Buecher, B, Butzow, R, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Cannioto, R, Carney, ME, Cescon, T, Chan, SB, Chang-Claude, J, Chanock, S, Chen, XQ, Chiew, Y-E, Chiquette, J, Chung, WK, Claes, KBM, Conner, T, Cook, LS, Cook, J, Cramer, DW, Cunningham, JM, D'Aloisio, AA, Daly, MB, Damiola, F, Damirovna, SD, Dansonka-Mieszkowska, A, Dao, F, Davidson, R, DeFazio, A, Delnatte, C, Doheny, KF, Diez, O, Ding, YC, Doherty, JA, Domchek, SM, Dorfling, CM, Dörk, T, Dossus, L, Duran, M, Dürst, M, Dworniczak, B, Eccles, D, Edwards, T, Eeles, R, Eilber, U, Ejlertsen, B, Ekici, AB, Ellis, S, Elvira, M, EMBRACE Study, Eng, KH, Engel, C, Evans, DG, Fasching, PA, Ferguson, S, Ferrer, SF, Flanagan, JM, Fogarty, ZC, Fortner, RT, Fostira, F, Foulkes, WD, Fountzilas, G, Fridley, BL, Friebel, TM, Friedman, E, Frost, D, Ganz, PA, Garber, J, García, MJ, Garcia-Barberan, V, Gehrig, A, GEMO Study Collaborators, Gentry-Maharaj, A, Gerdes, A-M, Giles, GG, Glasspool, R, Glendon, G, Godwin, AK, Goldgar, DE, Goranova, T, Gore, M, Greene, MH, Gronwald, J, Gruber, S, Hahnen, E, Haiman, CA, Håkansson, N, Hamann, U, Hansen, TVO, Harrington, PA, Harris, HR, Hauke, J, HEBON Study, Hein, A, Henderson, A, Hildebrandt, MAT, Hillemanns, P, Hodgson, S, Høgdall, CK, Høgdall, E, Hogervorst, FBL, Holland, H, Hooning, MJ, Hosking, K, Huang, R-Y, Hulick, PJ, Hung, J, Hunter, DJ, Huntsman, DG, Huzarski, T, Imyanitov, EN, Isaacs, C, Iversen, ES, Izatt, L, Izquierdo, A, Jakubowska, A, James, P, Janavicius, R, Jernetz, M, Jensen, A, Jensen, UB, John, EM, Johnatty, S, Jones, ME, Kannisto, P, Karlan, BY, Karnezis, A, Kast, K, KConFab Investigators, Kennedy, CJ, Khusnutdinova, E, Kiemeney, LA, Kiiski, JI, Kim, S-W, Kjaer, SK, Köbel, M, Kopperud, RK, Kruse, TA, Kupryjanczyk, J, Kwong, A, Laitman, Y, Lambrechts, D, Larrañaga, N, Larson, MC, Lazaro, C, Le, ND, Le Marchand, L, Lee, JW, Lele, SB, Leminen, A, Leroux, D, Lester, J, Lesueur, F, Levine, DA, Liang, D, Liebrich, C, Lilyquist, J, Lipworth, L, Lissowska, J, Lu, KH, Lubinński, J, Luccarini, C, Lundvall, L, Mai, PL, Mendoza-Fandiño, G, Manoukian, S, Massuger, LFAG, May, T, Mazoyer, S, McAlpine, JN, McGuire, V, McLaughlin, McNeish, I, Meijers-Heijboer, H, Meindl, A, Menon, U, Mensenkamp, AR, Merritt, MA, Milne, RL, Mitchell, G, Modugno, F, Moes-Sosnowska, J, Moffitt, M, Montagna, M, Moysich, KB, Mulligan, AM, Musinsky, J, Nathanson, KL, Nedergaard, L, Ness, RB, Neuhausen, SL, Nevanlinna, H, Niederacher, D, Nussbaum, RL, Odunsi, K, Olah, E, Olopade, OI, Olsson, H, Olswold, C, O'Malley, DM, Ong, K-R, Onland-Moret, NC, OPAL Study Group, Orr, N, Orsulic, S, Osorio, A, Palli, D, Papi, L, Park-Simon, T-W, Paul, J, Pearce, CL, Pedersen, IS, Peeters, PHM, Peissel, B, Peixoto, A, Pejovic, T, Pelttari, LM, Permuth, JB, Peterlongo, P, Pezzani, L, Pfeiler, G, Phillips, K-A, Piedmonte, M, Pike, MC, Piskorz, AM, Poblete, Pocza, T, Poole, EM, Poppe, B, Porteous, ME, Prieur, F, Prokofyeva, D, Pugh, E, Pujana, MA, Pujol, P, Radice, P, Rantala, J, Rappaport-Fuerhauser, C, Rennert, G, Rhiem, K, Rice, P, Richardson, A, Robson, M, Rodriguez, GC, Rodríguez-Antona, C, Romm, J, Rookus, MA, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Salvesen, HB, Sandler, DP, Schoemaker, MJ, Senter, L, Setiawan, VW, Severi, G, Sharma, P, Shelford, T, Siddiqui, N, Side, LE, Sieh, W, Singer, CF, Sobol, H, Song, H, Southey, MC, Spurdle, AB, Stadler, Z, Steinemann, D, Stoppa-Lyonnet, D, Sucheston-Campbell, LE, Sukiennicki, G, Sutphen, R, Sutter, C, Swerdlow, AJ, Szabo, CI, Szafron, L, Tan, YY, Taylor, JA, Tea, M-K, Teixeira, MR, Teo, S-H, Terry, KL, Thompson, PJ, Thomsen, LCV, Thull, DL, Tihomirova, L, Tinker, AV, Tischkowitz, M, Tognazzo, S, Toland, AE, Tone, A, Trabert, B, Travis, RC, Trichopoulou, A, Tung, N, Tworoger, SS, Van Altena, AM, Van Den Berg, D, Van Der Hout, AH, Van Der Luijt, RB, Van Heetvelde, M, Van Nieuwenhuysen, E, Van Rensburg, EJ, Vanderstichele, A, Varon-Mateeva, R, Vega, A, Edwards, DV, Vergote, I, Vierkant, RA, Vijai, J, Vratimos, A, Walker, L, Walsh, C, Wand, D, Wang-Gohrke, S, Wappenschmidt, B, Webb, PM, Weinberg, CR, Weitzel, JN, Wentzensen, N, Whittemore, AS, Wijnen, JT, Wilkens, LR, Wolk, A, Woo, M, Wu, X, Wu, AH, Yang, H, Yannoukakos, D, Ziogas, A, Zorn, KK, Narod, SA, Easton, DF, Amos, CI, Schildkraut, JM, Ramus, SJ, Ottini, L, Goodman, MT, Park, SK, Kelemen, LE, Risch, HA, Thomassen, M, Offit, K, Simard, J, Schmutzler, RK, Hazelett, D, Monteiro, AN, Couch, FJ, Berchuck, A, Chenevix-Trench, G, Goode, EL, Sellers, TA, Gayther, SA, Antoniou, AC, and Pharoah, PDP
Subjects: ovarian cancer, endocrine system diseases, genome-wide association studies, epidemiology, female genital diseases and pregnancy complications, 3. Good health
Abstract: To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 $\textit{BRCA1}$ and $\textit{BRCA2}$ mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

27. Cohort profile: a nationwide study in Dutch CHEK2 c.1100delC families using the infrastructure of the HEreditary Breast and Ovarian cancer study Netherlands - Hebon-CHEK2.

Author: Schreurs MAC, Adank MA, Hollestelle A, de Groot R, Stommel-Jenner DJ, Van Asperen CJ, Ausems MGEM, Berger LPV, Blok MJ, van Engelen K, Hogervorst FBL, Geurts-Giele W, Gille JJP, Wevers MR, Schmidt MK, and Hooning MJ
Subjects: Humans, Female, Netherlands epidemiology, Middle Aged, Adult, Pedigree, Aged, Cohort Studies, Heterozygote, Checkpoint Kinase 2 genetics, Breast Neoplasms genetics, Genetic Predisposition to Disease, Ovarian Neoplasms genetics, Ovarian Neoplasms epidemiology
Abstract: Purpose: CHEK2 c.1100delC is associated with an increased breast cancer risk in women. While this variant is prevalent in the Netherlands (1% in the general population), knowledge of aetiology and prognosis of breast cancer and other tumours in CHEK2 c.1100delC carriers is lacking. The nationwide HEreditary Breast and Ovarian cancer study the Netherlands (Hebon) cohort aims to answer study questions in families with an increased risk of breast cancer and ovarian cancer. While initially focusing on BRCA1/2 -variant families, Hebon gradually expanded to include pathogenic variants in other genes associated with breast and/or ovarian cancer over time. This provides an excellent setting to establish a cohort to ultimately study the impact of CHEK2 c.1100delC on cancer risk prediction and surveillance, breast cancer treatment and prognosis., Participants: We invited all heterozygous and homozygous CHEK2 c.1100delC indexes and tested female relatives. 1802 women were included, of whom 1374 were heterozygotes and 938 were breast cancer cases. Pedigrees were collected from all clinical genetic departments. Furthermore, participants completed a detailed questionnaire on hormonal and lifestyle factors, family history, cancer diagnosis and treatment., Findings to Date: Mean age at study inclusion was 53 years. Linkage with the Netherlands Cancer Registry showed a younger age at diagnosis in homozygotes (mean age 41.7 years) and heterozygotes (47.9 years) than non-carriers (51.2 years). Furthermore, carriers were more often diagnosed with grade 2, oestrogen receptor-positive breast cancer and more often developed contralateral breast cancer than non-carriers. Most women consumed alcohol regularly and about half never smoked., Future Plans: Further data linkages with the Netherlands Cancer Registry will allow prospective follow-up and breast cancer risk assessment in unaffected women at the time of genetic testing, risk of contralateral breast cancer and survival in patients with breast cancer. Also, linkage with the nationwide network and registry of histopathology and cytopathology in The Netherlands (PALGA) allows us to retrieve tumour samples to study tumourigenesis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)
Published: 2024
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28. Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk.

Author: Barnes DR, Tyrer JP, Dennis J, Leslie G, Bolla MK, Lush M, Aeilts AM, Aittomäki K, Andrieu N, Andrulis IL, Anton-Culver H, Arason A, Arun BK, Balmaña J, Bandera EV, Barkardottir RB, Berger LPV, de Gonzalez AB, Berthet P, Białkowska K, Bjørge L, Blanco AM, Blok MJ, Bobolis KA, Bogdanova NV, Brenton JD, Butz H, Buys SS, Caligo MA, Campbell I, Castillo C, Claes KBM, Colonna SV, Cook LS, Daly MB, Dansonka-Mieszkowska A, de la Hoya M, deFazio A, DePersia A, Ding YC, Domchek SM, Dörk T, Einbeigi Z, Engel C, Evans DG, Foretova L, Fortner RT, Fostira F, Foti MC, Friedman E, Frone MN, Ganz PA, Gentry-Maharaj A, Glendon G, Godwin AK, González-Neira A, Greene MH, Gronwald J, Guerrieri-Gonzaga A, Hamann U, Hansen TVO, Harris HR, Hauke J, Heitz F, Hogervorst FBL, Hooning MJ, Hopper JL, Huff CD, Huntsman DG, Imyanitov EN, Izatt L, Jakubowska A, James PA, Janavicius R, John EM, Kar S, Karlan BY, Kennedy CJ, Kiemeney LALM, Konstantopoulou I, Kupryjanczyk J, Laitman Y, Lavie O, Lawrenson K, Lester J, Lesueur F, Lopez-Pleguezuelos C, Mai PL, Manoukian S, May T, McNeish IA, Menon U, Milne RL, Modugno F, Mongiovi JM, Montagna M, Moysich KB, Neuhausen SL, Nielsen FC, Noguès C, Oláh E, Olopade OI, Osorio A, Papi L, Pathak H, Pearce CL, Pedersen IS, Peixoto A, Pejovic T, Peng PC, Peshkin BN, Peterlongo P, Powell CB, Prokofyeva D, Pujana MA, Radice P, Rashid MU, Rennert G, Richenberg G, Sandler DP, Sasamoto N, Setiawan VW, Sharma P, Sieh W, Singer CF, Snape K, Sokolenko AP, Soucy P, Southey MC, Stoppa-Lyonnet D, Sutphen R, Sutter C, Teixeira MR, Terry KL, Thomsen LCV, Tischkowitz M, Toland AE, Van Gorp T, Vega A, Velez Edwards DR, Webb PM, Weitzel JN, Wentzensen N, Whittemore AS, Winham SJ, Wu AH, Yadav S, Yu Y, Ziogas A, Berchuck A, Couch FJ, Goode EL, Goodman MT, Monteiro AN, Offit K, Ramus SJ, Risch HA, Schildkraut JM, Thomassen M, Simard J, Easton DF, Jones MR, Chenevix-Trench G, Gayther SA, Antoniou AC, and Pharoah PDP
Abstract: Background: Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We used data from the Ovarian Cancer Association Consortium (OCAC), Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA), UK Biobank (UKBB), and FinnGen to identify novel HGSOC susceptibility loci and develop polygenic scores (PGS)., Methods: We analyzed >22 million variants for 398,238 women. Associations were assessed separately by consortium and meta-analysed. OCAC and CIMBA data were used to develop PGS which were trained on FinnGen data and validated in UKBB and BioBank Japan., Results: Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was finding that TP53 3'-UTR SNP rs78378222 was associated with HGSOC (per T allele relative risk (RR)=1.44, 95%CI:1.28-1.62, P=1.76×10 -9 ). The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95%CI:1.37-1.54) per standard deviation in the UKBB validation (AUROC curve=0.61, 95%CI:0.59-0.62)., Conclusions: This study represents the largest GWAS for HGSOC to date. The results highlight that improvements in imputation reference panels and increased sample sizes can identify HGSOC associated variants that previously went undetected, resulting in improved PGS. The use of updated PGS in cancer risk prediction algorithms will then improve personalized risk prediction for HGSOC.
Published: 2024
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29. Genome sequencing as a generic diagnostic strategy for rare disease.

Author: Schobers G, Derks R, den Ouden A, Swinkels H, van Reeuwijk J, Bosgoed E, Lugtenberg D, Sun SM, Corominas Galbany J, Weiss M, Blok MJ, Olde Keizer RACM, Hofste T, Hellebrekers D, de Leeuw N, Stegmann A, Kamsteeg EJ, Paulussen ADC, Ligtenberg MJL, Bradley XZ, Peden J, Gutierrez A, Pullen A, Payne T, Gilissen C, van den Wijngaard A, Brunner HG, Nelen M, Yntema HG, and Vissers LELM
Subjects: Humans, Whole Genome Sequencing, Base Sequence, Chromosome Mapping, Exome Sequencing, Rare Diseases diagnosis, Rare Diseases genetics, High-Throughput Nucleotide Sequencing
Abstract: Background: To diagnose the full spectrum of hereditary and congenital diseases, genetic laboratories use many different workflows, ranging from karyotyping to exome sequencing. A single generic high-throughput workflow would greatly increase efficiency. We assessed whether genome sequencing (GS) can replace these existing workflows aimed at germline genetic diagnosis for rare disease., Methods: We performed short-read GS (NovaSeq™6000; 150 bp paired-end reads, 37 × mean coverage) on 1000 cases with 1271 known clinically relevant variants, identified across different workflows, representative of our tertiary diagnostic centers. Variants were categorized into small variants (single nucleotide variants and indels < 50 bp), large variants (copy number variants and short tandem repeats) and other variants (structural variants and aneuploidies). Variant calling format files were queried per variant, from which workflow-specific true positive rates (TPRs) for detection were determined. A TPR of ≥ 98% was considered the threshold for transition to GS. A GS-first scenario was generated for our laboratory, using diagnostic efficacy and predicted false negative as primary outcome measures. As input, we modeled the diagnostic path for all 24,570 individuals referred in 2022, combining the clinical referral, the transition of the underlying workflow(s) to GS, and the variant type(s) to be detected., Results: Overall, 95% (1206/1271) of variants were detected. Detection rates differed per variant category: small variants in 96% (826/860), large variants in 93% (341/366), and other variants in 87% (39/45). TPRs varied between workflows (79-100%), with 7/10 being replaceable by GS. Models for our laboratory indicate that a GS-first strategy would be feasible for 84.9% of clinical referrals (750/883), translating to 71% of all individuals (17,444/24,570) receiving GS as their primary test. An estimated false negative rate of 0.3% could be expected., Conclusions: GS can capture clinically relevant germline variants in a 'GS-first strategy' for the majority of clinical indications in a genetics diagnostic lab., (© 2024. The Author(s).)
Published: 2024
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30. ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk.

Author: Stolarova L, Kleiblova P, Zemankova P, Stastna B, Janatova M, Soukupova J, Achatz MI, Ambrosone C, Apostolou P, Arun BK, Auer P, Barnard M, Bertelsen B, Blok MJ, Boddicker N, Brunet J, Burnside ES, Calvello M, Campbell I, Chan SH, Chen F, Chiang JB, Coppa A, Cortesi L, Crujeiras-González A, De Leeneer K, De Putter R, DePersia A, Devereux L, Domchek S, Efremidis A, Engel C, Ernst C, Evans DGR, Feliubadaló L, Fostira F, Fuentes-Ríos O, Gómez-García EB, González S, Haiman C, Hansen TVO, Hauke J, Hodge J, Hu C, Huang H, Ishak NDB, Iwasaki Y, Konstantopoulou I, Kraft P, Lacey J, Lázaro C, Li N, Lim WK, Lindstrom S, Lori A, Martinez E, Martins A, Matsuda K, Matullo G, McInerny S, Michailidou K, Montagna M, Monteiro ANA, Mori L, Nathanson K, Neuhausen SL, Nevanlinna H, Olson JE, Palmer J, Pasini B, Patel A, Piane M, Poppe B, Radice P, Renieri A, Resta N, Richardson ME, Rosseel T, Ruddy KJ, Santamariña M, Dos Santos ES, Teras L, Toland AE, Trentham-Dietz A, Vachon CM, Volk AE, Weber-Lassalle N, Weitzel JN, Wiesmuller L, Winham S, Yadav S, Yannoukakos D, Yao S, Zampiga V, Zethoven M, Zhang ZW, Zima T, Spurdle AB, Vega A, Rossing M, Del Valle J, De Nicolo A, Hahnen E, Claes KBM, Ngeow J, Momozawa Y, James PA, Couch FJ, Macurek L, and Kleibl Z
Subjects: Humans, Female, Genetic Predisposition to Disease, Checkpoint Kinase 2 genetics, Mutation, Missense, Germ-Line Mutation, Germ Cells, Breast Neoplasms epidemiology, Breast Neoplasms genetics
Abstract: Purpose: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT)., Experimental Design: We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case-control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls., Results: A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired (N = 102), functionally intermediate (N = 12), or functionally wild-type (WT)-like (N = 226). We then examined their association with breast cancer risk in the case-control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35-3.41), 1.57 (95% CI, 1.41-1.75), and 1.19 (95% CI, 1.08-1.31), respectively. The meta-analysis of population-specific datasets showed similar results., Conclusions: We determined the functional consequences for the majority of CHEK2 missense VUS found in patients with breast cancer (3,660/4,436; 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating CHEK2 variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers., (©2023 The Authors; Published by the American Association for Cancer Research.)
Published: 2023
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31. FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women.

Author: Figlioli G, Billaud A, Ahearn TU, Antonenkova NN, Becher H, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Blok MJ, Bogdanova NV, Bonanni B, Burwinkel B, Camp NJ, Campbell A, Castelao JE, Cessna MH, Chanock SJ, Czene K, Devilee P, Dörk T, Engel C, Eriksson M, Fasching PA, Figueroa JD, Gabrielson M, Gago-Dominguez M, García-Closas M, González-Neira A, Grassmann F, Guénel P, Gündert M, Hadjisavvas A, Hahnen E, Hall P, Hamann U, Harrington PA, He W, Hillemanns P, Hollestelle A, Hooning MJ, Hoppe R, Howell A, Humphreys K, Jager A, Jakubowska A, Khusnutdinova EK, Ko YD, Kristensen VN, Lindblom A, Lissowska J, Lubiński J, Mannermaa A, Manoukian S, Margolin S, Mavroudis D, Newman WG, Obi N, Panayiotidis MI, Rashid MU, Rhenius V, Rookus MA, Saloustros E, Sawyer EJ, Schmutzler RK, Shah M, Sironen R, Southey MC, Suvanto M, Tollenaar RAEM, Tomlinson I, Truong T, van der Kolk LE, van Veen EM, Wappenschmidt B, Yang XR, Bolla MK, Dennis J, Dunning AM, Easton DF, Lush M, Michailidou K, Pharoah PDP, Wang Q, Adank MA, Schmidt MK, Andrulis IL, Chang-Claude J, Nevanlinna H, Chenevix-Trench G, Evans DG, Milne RL, Radice P, and Peterlongo P
Subjects: Humans, Female, Triple Negative Breast Neoplasms genetics, Genetic Predisposition to Disease, Breast Neoplasms genetics, DNA Helicases genetics
Abstract: Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) in FANCM confer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association between FANCM missense variants (MVs) and breast cancer risk has been postulated. In this study, we further used the BRIDGES study to test 689 FANCM MVs for association with breast cancer risk, overall and in ER-negative and TNBC subtypes, in 39,885 cases (7566 selected for family history) and 35,271 controls of European ancestry. Sixteen common MVs were tested individually; the remaining rare 673 MVs were tested by burden analyses considering their position and pathogenicity score. We also conducted a meta-analysis of our results and those from published studies. We did not find evidence for association for any of the 16 variants individually tested. The rare MVs were significantly associated with increased risk of ER-negative breast cancer by burden analysis comparing familial cases to controls (OR = 1.48; 95% CI 1.07-2.04; P = 0.017). Higher ORs were found for the subgroup of MVs located in functional domains or predicted to be pathogenic. The meta-analysis indicated that FANCM MVs overall are associated with breast cancer risk (OR = 1.22; 95% CI 1.08-1.38; P = 0.002). Our results support the definition from previous analyses of FANCM as a moderate-risk breast cancer gene and provide evidence that FANCM MVs could be low/moderate risk factors for ER-negative and TNBC subtypes. Further genetic and functional analyses are necessary to clarify better the increased risks due to FANCM MVs., (© 2023. The Author(s).)
Published: 2023
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32. Molecular characterization of an embryonal rhabdomyosarcoma occurring in a patient with Kabuki syndrome: report and literature review in the light of tumor predisposition syndromes.

Author: Aukema SM, Glaser S, van den Hout MFCM, Dahlum S, Blok MJ, Hillmer M, Kolarova J, Sciot R, Schott DA, Siebert R, and Stumpel CTRM
Subjects: Humans, Child, Female, Phenotype, DNA, Mutation, Rhabdomyosarcoma, Embryonal genetics, Abnormalities, Multiple genetics, Abnormalities, Multiple pathology
Abstract: Kabuki syndrome is a well-recognized syndrome characterized by facial dysmorphism and developmental delay/intellectual disability and in the majority of patients a germline variant in KMT2D is found. As somatic KMT2D variants can be found in 5-10% of tumors a tumor predisposition in Kabuki syndrome is discussed. So far less than 20 patients with Kabuki syndrome and a concomitant malignancy have been published. Here we report on a female patient with Kabuki syndrome and a c.2558_2559delCT germline variant in KMT2D who developed an embryonal rhabdomyosarcoma (ERMS) at 10 years. On tumor tissue we performed DNA-methylation profiling and exome sequencing (ES). Copy number analyses revealed aneuploidies typical for ERMS including (partial) gains of chromosomes 2, 3, 7, 8, 12, 15, and 20 and 3 focal deletions of chromosome 11p. DNA methylation profiling mapped the case to ERMS by a DNA methylation-based sarcoma classifier. Sequencing suggested gain of the wild-type KMT2D allele in the trisomy 12. Including our patient literature review identified 18 patients with Kabuki syndrome and a malignancy. Overall, the landscape of malignancies in patients with Kabuki syndrome was reminiscent of that of the pediatric population in general. Histopathological and molecular data were only infrequently reported and no report included next generation sequencing and/or DNA-methylation profiling. Although we found no strong arguments pointing towards KS as a tumor predisposition syndrome, based on the small numbers any relation cannot be fully excluded. Further planned studies including profiling of additional tumors and long term follow-up of KS-patients into adulthood could provide further insights., (© 2022. The Author(s).)
Published: 2023
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33. STS pathogenic variants in a Dutch patient cohort clinically suspected for X-linked ichthyosis show genetic heterogeneity.

Author: Nagtzaam IF, van Leersum FS, Kouwenberg LCM, Blok MJ, Vreeburg M, Steijlen PM, Gostyński A, and van Geel M
Subjects: Humans, Steryl-Sulfatase genetics, Cohort Studies, Genetic Heterogeneity, Ichthyosis, X-Linked diagnosis, Ichthyosis, X-Linked genetics
Published: 2022
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34. Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers.

Author: Hakkaart C, Pearson JF, Marquart L, Dennis J, Wiggins GAR, Barnes DR, Robinson BA, Mace PD, Aittomäki K, Andrulis IL, Arun BK, Azzollini J, Balmaña J, Barkardottir RB, Belhadj S, Berger L, Blok MJ, Boonen SE, Borde J, Bradbury AR, Brunet J, Buys SS, Caligo MA, Campbell I, Chung WK, Claes KBM, Collonge-Rame MA, Cook J, Cosgrove C, Couch FJ, Daly MB, Dandiker S, Davidson R, de la Hoya M, de Putter R, Delnatte C, Dhawan M, Diez O, Ding YC, Domchek SM, Donaldson A, Eason J, Easton DF, Ehrencrona H, Engel C, Evans DG, Faust U, Feliubadaló L, Fostira F, Friedman E, Frone M, Frost D, Garber J, Gayther SA, Gehrig A, Gesta P, Godwin AK, Goldgar DE, Greene MH, Hahnen E, Hake CR, Hamann U, Hansen TVO, Hauke J, Hentschel J, Herold N, Honisch E, Hulick PJ, Imyanitov EN, Isaacs C, Izatt L, Izquierdo A, Jakubowska A, James PA, Janavicius R, John EM, Joseph V, Karlan BY, Kemp Z, Kirk J, Konstantopoulou I, Koudijs M, Kwong A, Laitman Y, Lalloo F, Lasset C, Lautrup C, Lazaro C, Legrand C, Leslie G, Lesueur F, Mai PL, Manoukian S, Mari V, Martens JWM, McGuffog L, Mebirouk N, Meindl A, Miller A, Montagna M, Moserle L, Mouret-Fourme E, Musgrave H, Nambot S, Nathanson KL, Neuhausen SL, Nevanlinna H, Yie JNY, Nguyen-Dumont T, Nikitina-Zake L, Offit K, Olah E, Olopade OI, Osorio A, Ott CE, Park SK, Parsons MT, Pedersen IS, Peixoto A, Perez-Segura P, Peterlongo P, Pocza T, Radice P, Ramser J, Rantala J, Rodriguez GC, Rønlund K, Rosenberg EH, Rossing M, Schmutzler RK, Shah PD, Sharif S, Sharma P, Side LE, Simard J, Singer CF, Snape K, Steinemann D, Stoppa-Lyonnet D, Sutter C, Tan YY, Teixeira MR, Teo SH, Thomassen M, Thull DL, Tischkowitz M, Toland AE, Trainer AH, Tripathi V, Tung N, van Engelen K, van Rensburg EJ, Vega A, Viel A, Walker L, Weitzel JN, Wevers MR, Chenevix-Trench G, Spurdle AB, Antoniou AC, and Walker LC
Subjects: BRCA1 Protein genetics, BRCA2 Protein genetics, DNA Copy Number Variations, Female, Genetic Predisposition to Disease, Heterozygote, Humans, RNA, Messenger, Breast Neoplasms genetics, Breast Neoplasms pathology
Abstract: The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers., (© 2022. The Author(s).)
Published: 2022
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35. Pathogenic neurofibromatosis type 1 (NF1) RNA splicing resolved by targeted RNAseq.

Author: Koster R, Brandão RD, Tserpelis D, van Roozendaal CEP, van Oosterhoud CN, Claes KBM, Paulussen ADC, Sinnema M, Vreeburg M, van der Schoot V, Stumpel CTRM, Broen MPG, Spruijt L, Jongmans MCJ, Lesnik Oberstein SAJ, Plomp AS, Misra-Isrie M, Duijkers FA, Louwers MJ, Szklarczyk R, Derks KWJ, Brunner HG, van den Wijngaard A, van Geel M, and Blok MJ
Abstract: Neurofibromatosis type 1 (NF1) is caused by loss-of-function variants in the NF1 gene. Approximately 10% of these variants affect RNA splicing and are either missed by conventional DNA diagnostics or are misinterpreted by in silico splicing predictions. Therefore, a targeted RNAseq-based approach was designed to detect pathogenic RNA splicing and associated pathogenic DNA variants. For this method RNA was extracted from lymphocytes, followed by targeted RNAseq. Next, an in-house developed tool (QURNAs) was used to calculate the enrichment score (ERS) for each splicing event. This method was thoroughly tested using two different patient cohorts with known pathogenic splice-variants in NF1. In both cohorts all 56 normal reference transcript exon splice junctions, 24 previously described and 45 novel non-reference splicing events were detected. Additionally, all expected pathogenic splice-variants were detected. Eleven patients with NF1 symptoms were subsequently tested, three of which have a known NF1 DNA variant with a putative effect on RNA splicing. This effect could be confirmed for all 3. The other eight patients were previously without any molecular confirmation of their NF1-diagnosis. A deep-intronic pathogenic splice variant could now be identified for two of them (25%). These results suggest that targeted RNAseq can be successfully used to detect pathogenic RNA splicing variants in NF1., (© 2021. The Author(s).)
Published: 2021
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36. Prevalence of Germline Pathogenic Variants in Cancer Predisposing Genes in Czech and Belgian Pancreatic Cancer Patients.

Author: Wieme G, Kral J, Rosseel T, Zemankova P, Parton B, Vocka M, Van Heetvelde M, Kleiblova P, Blaumeiser B, Soukupova J, van den Ende J, Nehasil P, Tejpar S, Borecka M, Gómez García EB, Blok MJ, Safarikova M, Kalousova M, Geboes K, De Putter R, Poppe B, De Leeneer K, Kleibl Z, Janatova M, and Claes KBM
Abstract: (1) Background: The proportion and spectrum of germline pathogenic variants (PV) associated with an increased risk for pancreatic ductal adenocarcinoma (PDAC) varies among populations. (2) Methods: We analyzed 72 Belgian and 226 Czech PDAC patients by multigene panel testing. The prevalence of pathogenic variants (PV) in relation to personal/family cancer history were evaluated. PDAC risks were calculated using both gnomAD-NFE and population-matched controls. (3) Results: In 35/298 (11.7%) patients a PV in an established PDAC-predisposition gene was found. BRCA1/2 PV conferred a high risk in both populations, ATM and Lynch genes only in the Belgian subgroup. PV in other known PDAC-predisposition genes were rarer. Interestingly, a high frequency of CHEK2 PV was observed in both patient populations. PV in PDAC-predisposition genes were more frequent in patients with (i) multiple primary cancers (12/38; 32%), (ii) relatives with PDAC (15/56; 27%), (iii) relatives with breast/ovarian/colorectal cancer or melanoma (15/86; 17%) but more rare in sporadic PDAC (5/149; 3.4%). PV in homologous recombination genes were associated with improved overall survival (HR = 0.51; 95% CI 0.34-0.77). (4) Conclusions: Our analysis emphasizes the value of multigene panel testing in PDAC patients, especially in individuals with a positive family cancer history, and underlines the importance of population-matched controls for risk assessment.
Published: 2021
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37. Generation and initial characterization of novel tumour organoid models to study human pancreatic cancer-induced cachexia.

Author: Vaes RDW, van Dijk DPJ, Welbers TTJ, Blok MJ, Aberle MR, Heij L, Boj SF, Olde Damink SWM, and Rensen SS
Subjects: Aged, Aged, 80 and over, Female, Hand Strength, Humans, Interleukin-6, Male, Middle Aged, Cachexia etiology, Organoids, Pancreatic Neoplasms complications
Abstract: Background: The majority of patients with pancreatic cancer develops cachexia. The mechanisms underlying cancer cachexia development and progression remain elusive, although tumour-derived factors are considered to play a major role. Pancreatic tumour organoids are in vitro three-dimensional organ-like structures that retain many pathophysiological characteristics of the in vivo tumour. We aimed to establish a pancreatic tumour organoid biobank from well-phenotyped cachectic and non-cachectic patients to enable identification of tumour-derived factors driving cancer cachexia., Methods: Organoids were generated from tumour tissue of eight pancreatic cancer patients. A comprehensive pre-operative patient assessment of cachexia-related parameters including nutritional status, physical performance, body composition, and inflammation was performed. Tumour-related and cachexia-related characteristics of the organoids were analysed using histological stainings, targeted sequencing, and real-time-quantitative PCR. Cachexia-related factors present in the circulation of the patients and in the tumour organoid secretome were analysed by enzyme-linked immunosorbent assay., Results: The established human pancreatic tumour organoids presented typical features of malignancy corresponding to the primary tumour (i.e. nuclear enlargement, multiple nucleoli, mitosis, apoptosis, and mutated KRAS and/or TP53). These tumour organoids also expressed variable levels of many known cachexia-related genes including interleukin-6 (IL-6), TNF-α, IL-8, IL-1α, IL-1β, Mcp-1, GDF15, and LIF. mRNA expression of IL-1α and IL-1β was significantly reduced in organoids from cachectic vs. non-cachectic patients (IL-1α: -3.8-fold, P = 0.009, and IL-1β: -4.7-fold, P = 0.004). LIF, IL-8, and GDF15 mRNA expression levels were significantly higher in organoids from cachectic vs. non-cachectic patients (LIF: 1.6-fold, P = 0.003; IL-8: 1.4-fold, P = 0.01; GDF15: 2.3-fold, P < 0.001). In line with the GDF15 and IL-8 mRNA expression levels, tumour organoids from cachectic patients secreted more GDF15 and IL-8 compared with organoids from non-cachectic patients (5.4 vs. 1.5 ng/mL, P = 0.01, and 7.4 vs. 1.3 ng/mL, P = 0.07, respectively)., Conclusions: This novel human pancreatic tumour organoid biobank provides a valuable tool to increase our understanding of the mechanisms driving cancer cachexia. Our preliminary characterization of the secretome of these organoids supports their application in functional studies including conditioned medium approaches and in vivo transplantation models., (© 2020 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)
Published: 2020
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38. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants.

Author: Barnes DR, Rookus MA, McGuffog L, Leslie G, Mooij TM, Dennis J, Mavaddat N, Adlard J, Ahmed M, Aittomäki K, Andrieu N, Andrulis IL, Arnold N, Arun BK, Azzollini J, Balmaña J, Barkardottir RB, Barrowdale D, Benitez J, Berthet P, Białkowska K, Blanco AM, Blok MJ, Bonanni B, Boonen SE, Borg Å, Bozsik A, Bradbury AR, Brennan P, Brewer C, Brunet J, Buys SS, Caldés T, Caligo MA, Campbell I, Christensen LL, Chung WK, Claes KBM, Colas C, Collonge-Rame MA, Cook J, Daly MB, Davidson R, de la Hoya M, de Putter R, Delnatte C, Devilee P, Diez O, Ding YC, Domchek SM, Dorfling CM, Dumont M, Eeles R, Ejlertsen B, Engel C, Evans DG, Faivre L, Foretova L, Fostira F, Friedlander M, Friedman E, Frost D, Ganz PA, Garber J, Gehrig A, Gerdes AM, Gesta P, Giraud S, Glendon G, Godwin AK, Goldgar DE, González-Neira A, Greene MH, Gschwantler-Kaulich D, Hahnen E, Hamann U, Hanson H, Hentschel J, Hogervorst FBL, Hooning MJ, Horvath J, Hu C, Hulick PJ, Imyanitov EN, Isaacs C, Izatt L, Izquierdo A, Jakubowska A, James PA, Janavicius R, John EM, Joseph V, Karlan BY, Kast K, Koudijs M, Kruse TA, Kwong A, Laitman Y, Lasset C, Lazaro C, Lester J, Lesueur F, Liljegren A, Loud JT, Lubiński J, Mai PL, Manoukian S, Mari V, Mebirouk N, Meijers-Heijboer HEJ, Meindl A, Mensenkamp AR, Miller A, Montagna M, Mouret-Fourme E, Mukherjee S, Mulligan AM, Nathanson KL, Neuhausen SL, Nevanlinna H, Niederacher D, Nielsen FC, Nikitina-Zake L, Noguès C, Olah E, Olopade OI, Ong KR, O'Shaughnessy-Kirwan A, Osorio A, Ott CE, Papi L, Park SK, Parsons MT, Pedersen IS, Peissel B, Peixoto A, Peterlongo P, Pfeiler G, Phillips KA, Prajzendanc K, Pujana MA, Radice P, Ramser J, Ramus SJ, Rantala J, Rennert G, Risch HA, Robson M, Rønlund K, Salani R, Schuster H, Senter L, Shah PD, Sharma P, Side LE, Singer CF, Slavin TP, Soucy P, Southey MC, Spurdle AB, Steinemann D, Steinsnyder Z, Stoppa-Lyonnet D, Sutter C, Tan YY, Teixeira MR, Teo SH, Thull DL, Tischkowitz M, Tognazzo S, Toland AE, Trainer AH, Tung N, van Engelen K, van Rensburg EJ, Vega A, Vierstraete J, Wagner G, Walker L, Wang-Gohrke S, Wappenschmidt B, Weitzel JN, Yadav S, Yang X, Yannoukakos D, Zimbalatti D, Offit K, Thomassen M, Couch FJ, Schmutzler RK, Simard J, Easton DF, Chenevix-Trench G, and Antoniou AC
Subjects: BRCA1 Protein genetics, BRCA2 Protein genetics, Carcinoma, Ovarian Epithelial genetics, Female, Genetic Predisposition to Disease, Heterozygote, Humans, Mutation, Prospective Studies, Retrospective Studies, Risk Factors, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Ovarian Neoplasms epidemiology, Ovarian Neoplasms genetics
Abstract: Purpose: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers., Methods: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort., Results: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10 -72 ). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10 -50 ). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10 -22 ) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10 -12 ) carriers. The associations in the prospective cohort were similar., Conclusion: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.
Published: 2020
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39. Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness.

Author: Patel VL, Busch EL, Friebel TM, Cronin A, Leslie G, McGuffog L, Adlard J, Agata S, Agnarsson BA, Ahmed M, Aittomäki K, Alducci E, Andrulis IL, Arason A, Arnold N, Artioli G, Arver B, Auber B, Azzollini J, Balmaña J, Barkardottir RB, Barnes DR, Barroso A, Barrowdale D, Belotti M, Benitez J, Bertelsen B, Blok MJ, Bodrogi I, Bonadona V, Bonanni B, Bondavalli D, Boonen SE, Borde J, Borg A, Bradbury AR, Brady A, Brewer C, Brunet J, Buecher B, Buys SS, Cabezas-Camarero S, Caldés T, Caliebe A, Caligo MA, Calvello M, Campbell IG, Carnevali I, Carrasco E, Chan TL, Chu ATW, Chung WK, Claes KBM, Collaborators GS, Collaborators E, Cook J, Cortesi L, Couch FJ, Daly MB, Damante G, Darder E, Davidson R, de la Hoya M, Puppa LD, Dennis J, Díez O, Ding YC, Ditsch N, Domchek SM, Donaldson A, Dworniczak B, Easton DF, Eccles DM, Eeles RA, Ehrencrona H, Ejlertsen B, Engel C, Evans DG, Faivre L, Faust U, Feliubadaló L, Foretova L, Fostira F, Fountzilas G, Frost D, García-Barberán V, Garre P, Gauthier-Villars M, Géczi L, Gehrig A, Gerdes AM, Gesta P, Giannini G, Glendon G, Godwin AK, Goldgar DE, Greene MH, Gutierrez-Barrera AM, Hahnen E, Hamann U, Hauke J, Herold N, Hogervorst FBL, Honisch E, Hopper JL, Hulick PJ, Investigators K, Investigators H, Izatt L, Jager A, James P, Janavicius R, Jensen UB, Jensen TD, Johannsson OT, John EM, Joseph V, Kang E, Kast K, Kiiski JI, Kim SW, Kim Z, Ko KP, Konstantopoulou I, Kramer G, Krogh L, Kruse TA, Kwong A, Larsen M, Lasset C, Lautrup C, Lazaro C, Lee J, Lee JW, Lee MH, Lemke J, Lesueur F, Liljegren A, Lindblom A, Llovet P, Lopez-Fernández A, Lopez-Perolio I, Lorca V, Loud JT, Ma ESK, Mai PL, Manoukian S, Mari V, Martin L, Matricardi L, Mebirouk N, Medici V, Meijers-Heijboer HEJ, Meindl A, Mensenkamp AR, Miller C, Gomes DM, Montagna M, Mooij TM, Moserle L, Mouret-Fourme E, Mulligan AM, Nathanson KL, Navratilova M, Nevanlinna H, Niederacher D, Nielsen FCC, Nikitina-Zake L, Offit K, Olah E, Olopade OI, Ong KR, Osorio A, Ott CE, Palli D, Park SK, Parsons MT, Pedersen IS, Peissel B, Peixoto A, Pérez-Segura P, Peterlongo P, Petersen AH, Porteous ME, Pujana MA, Radice P, Ramser J, Rantala J, Rashid MU, Rhiem K, Rizzolo P, Robson ME, Rookus MA, Rossing CM, Ruddy KJ, Santos C, Saule C, Scarpitta R, Schmutzler RK, Schuster H, Senter L, Seynaeve CM, Shah PD, Sharma P, Shin VY, Silvestri V, Simard J, Singer CF, Skytte AB, Snape K, Solano AR, Soucy P, Southey MC, Spurdle AB, Steele L, Steinemann D, Stoppa-Lyonnet D, Stradella A, Sunde L, Sutter C, Tan YY, Teixeira MR, Teo SH, Thomassen M, Tibiletti MG, Tischkowitz M, Tognazzo S, Toland AE, Tommasi S, Torres D, Toss A, Trainer AH, Tung N, van Asperen CJ, van der Baan FH, van der Kolk LE, van der Luijt RB, van Hest LP, Varesco L, Varon-Mateeva R, Viel A, Vierstraete J, Villa R, von Wachenfeldt A, Wagner P, Wang-Gohrke S, Wappenschmidt B, Weitzel JN, Wieme G, Yadav S, Yannoukakos D, Yoon SY, Zanzottera C, Zorn KK, D'Amico AV, Freedman ML, Pomerantz MM, Chenevix-Trench G, Antoniou AC, Neuhausen SL, Ottini L, Nielsen HR, and Rebbeck TR
Subjects: Adolescent, Adult, Aged, Aged, 80 and over, Genetic Association Studies, Heterozygote, Humans, Male, Middle Aged, Prognosis, Risk Factors, Young Adult, BRCA1 Protein genetics, BRCA2 Protein genetics, Genetic Predisposition to Disease, Genomics methods, Mutation, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology
Abstract: Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 ( BRCA1/2 ) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1 . These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual., (©2019 American Association for Cancer Research.)
Published: 2020
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40. Alcohol Consumption, Cigarette Smoking, and Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Results from The BRCA1 and BRCA2 Cohort Consortium.

Author: Li H, Terry MB, Antoniou AC, Phillips KA, Kast K, Mooij TM, Engel C, Noguès C, Stoppa-Lyonnet D, Lasset C, Berthet P, Mari V, Caron O, Barrowdale D, Frost D, Brewer C, Evans DG, Izatt L, Side L, Walker L, Tischkowitz M, Rogers MT, Porteous ME, Snape K, Meijers-Heijboer HEJ, Gille JJP, Blok MJ, Hoogerbrugge N, Daly MB, Andrulis IL, Buys SS, John EM, McLachlan SA, Friedlander M, Tan YY, Osorio A, Caldes T, Jakubowska A, Simard J, Singer CF, Olah E, Navratilova M, Foretova L, Gerdes AM, Roos-Blom MJ, Arver B, Olsson H, Schmutzler RK, Hopper JL, Milne RL, Easton DF, Van Leeuwen FE, Rookus MA, Andrieu N, and Goldgar DE
Subjects: Adult, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms genetics, Breast Neoplasms prevention & control, Female, Genetic Predisposition to Disease, Heterozygote, Humans, Middle Aged, Mutation, Prospective Studies, Reproductive History, Retrospective Studies, Risk Factors, Alcohol Drinking epidemiology, Breast Neoplasms epidemiology, Cigarette Smoking epidemiology, Life Style
Abstract: Background: Tobacco smoking and alcohol consumption have been intensively studied in the general population to assess their effects on the risk of breast cancer, but very few studies have examined these effects in BRCA1 and BRCA2 mutation carriers. Given the high breast cancer risk for mutation carriers and the importance of BRCA1 and BRCA2 in DNA repair, better evidence on the associations of these lifestyle factors with breast cancer risk is essential., Methods: Using a large international pooled cohort of BRCA1 and BRCA2 mutation carriers, we conducted retrospective (5,707 BRCA1 mutation carriers and 3,525 BRCA2 mutation carriers) and prospective (2,276 BRCA1 mutation carriers and 1,610 BRCA2 mutation carriers) analyses of alcohol and tobacco consumption using Cox proportional hazards models., Results: For both BRCA1 and BRCA2 mutation carriers, none of the smoking-related variables was associated with breast cancer risk, except smoking for more than 5 years before a first full-term pregnancy (FFTP) when compared with parous women who never smoked. For BRCA1 mutation carriers, the HR from retrospective analysis (HR R ) was 1.19 [95% confidence interval (CI), 1.02-1.39] and the HR from prospective analysis (HR P ) was 1.36 (95% CI, 0.99-1.87). For BRCA2 mutation carriers, smoking for more than 5 years before an FFTP showed an association of a similar magnitude, but the confidence limits were wider (HR R = 1.25; 95% CI, 1.01-1.55 and HR P = 1.30; 95% CI, 0.83-2.01). For both carrier groups, alcohol consumption was not associated with breast cancer risk., Conclusions: The finding that smoking during the prereproductive years increases breast cancer risk for mutation carriers warrants further investigation., Impact: This is the largest prospective study of BRCA mutation carriers to assess these important risk factors., (©2019 American Association for Cancer Research.)
Published: 2020
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41. Dutch genome diagnostic laboratories accelerated and improved variant interpretation and increased accuracy by sharing data.

Author: Fokkema IFAC, van der Velde KJ, Slofstra MK, Ruivenkamp CAL, Vogel MJ, Pfundt R, Blok MJ, Lekanne Deprez RH, Waisfisz Q, Abbott KM, Sinke RJ, Rahman R, Nijman IJ, de Koning B, Thijs G, Wieskamp N, Moritz RJG, Charbon B, Saris JJ, den Dunnen JT, Laros JFJ, Swertz MA, and van Gijn ME
Subjects: Data Accuracy, Databases, Genetic, Genetic Diseases, Inborn genetics, Guidelines as Topic, Humans, Laboratories, Netherlands, Sequence Analysis, DNA, Genetic Diseases, Inborn diagnosis, Genetic Variation, High-Throughput Nucleotide Sequencing methods, Information Dissemination methods
Abstract: Each year diagnostic laboratories in the Netherlands profile thousands of individuals for heritable disease using next-generation sequencing (NGS). This requires pathogenicity classification of millions of DNA variants on the standard 5-tier scale. To reduce time spent on data interpretation and increase data quality and reliability, the nine Dutch labs decided to publicly share their classifications. Variant classifications of nearly 100,000 unique variants were catalogued and compared in a centralized MOLGENIS database. Variants classified by more than one center were labeled as "consensus" when classifications agreed, and shared internationally with LOVD and ClinVar. When classifications opposed (LB/B vs. LP/P), they were labeled "conflicting", while other nonconsensus observations were labeled "no consensus". We assessed our classifications using the InterVar software to compare to ACMG 2015 guidelines, showing 99.7% overall consistency with only 0.3% discrepancies. Differences in classifications between Dutch labs or between Dutch labs and ACMG were mainly present in genes with low penetrance or for late onset disorders and highlight limitations of the current 5-tier classification system. The data sharing boosted the quality of DNA diagnostics in Dutch labs, an initiative we hope will be followed internationally. Recently, a positive match with a case from outside our consortium resulted in a more definite disease diagnosis., (© 2019 The Authors. Human Mutation Published by Wiley Periodicals, Inc.)
Published: 2019
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42. Survival after bilateral risk-reducing mastectomy in healthy BRCA1 and BRCA2 mutation carriers.

Author: Heemskerk-Gerritsen BAM, Jager A, Koppert LB, Obdeijn AI, Collée M, Meijers-Heijboer HEJ, Jenner DJ, Oldenburg HSA, van Engelen K, de Vries J, van Asperen CJ, Devilee P, Blok MJ, Kets CM, Ausems MGEM, Seynaeve C, Rookus MA, and Hooning MJ
Subjects: Breast Neoplasms mortality, Breast Neoplasms surgery, Female, Germ-Line Mutation, Humans, Mortality, Netherlands epidemiology, Prognosis, Public Health Surveillance, Risk Reduction Behavior, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms etiology, Breast Neoplasms prevention & control, Heterozygote, Mutation, Prophylactic Mastectomy methods
Abstract: Background: In healthy BRCA1/2 mutation carriers, bilateral risk-reducing mastectomy (BRRM) strongly reduces the risk of developing breast cancer (BC); however, no clear survival benefit of BRRM over BC surveillance has been reported yet., Methods: In this Dutch multicenter cohort study, we used multivariable Cox models with BRRM as a time-dependent covariable to estimate the associations between BRRM and the overall and BC-specific mortality rates, separately for BRCA1 and BRCA2 mutation carriers., Results: During a mean follow-up of 10.3 years, 722 out of 1712 BRCA1 (42%) and 406 out of 1145 BRCA2 (35%) mutation carriers underwent BRRM. For BRCA1 mutation carriers, we observed 52 deaths (20 from BC) in the surveillance group, and 10 deaths (one from BC) after BRRM. The hazard ratios were 0.40 (95% CI 0.20-0.90) for overall mortality and 0.06 (95% CI 0.01-0.46) for BC-specific mortality. BC-specific survival at age 65 was 93% for surveillance and 99.7% for BRRM. For BRCA2 mutation carriers, we observed 29 deaths (7 from BC) in the surveillance group, and 4 deaths (no BC) after BRRM. The hazard ratio for overall mortality was 0.45 (95% CI 0.15-1.36). BC-specific survival at age 65 was 98% for surveillance and 100% for BRRM., Conclusion: BRRM was associated with lower mortality than surveillance for BRCA1 mutation carriers, but for BRCA2 mutation carriers, BRRM may lead to similar BC-specific survival as surveillance. Our findings support a more individualized counseling based on BRCA mutation type.
Published: 2019
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43. Targeted RNA-seq successfully identifies normal and pathogenic splicing events in breast/ovarian cancer susceptibility and Lynch syndrome genes.

Author: Brandão RD, Mensaert K, López-Perolio I, Tserpelis D, Xenakis M, Lattimore V, Walker LC, Kvist A, Vega A, Gutiérrez-Enríquez S, Díez O, de la Hoya M, Spurdle AB, De Meyer T, and Blok MJ
Subjects: BRCA1 Protein genetics, BRCA2 Protein genetics, Cell Line, Tumor, DNA-Binding Proteins genetics, Electrophoresis, Capillary, Female, Genetic Predisposition to Disease, Humans, Mutation, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Hereditary Breast and Ovarian Cancer Syndrome genetics, RNA Splicing, Sequence Analysis, RNA methods
Abstract: A subset of genetic variants found through screening of patients with hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome impact RNA splicing. Through target enrichment of the transcriptome, it is possible to perform deep-sequencing and to identify the different and even rare mRNA isoforms. A targeted RNA-seq approach was used to analyse the naturally-occurring splicing events for a panel of 8 breast and/or ovarian cancer susceptibility genes (BRCA1, BRCA2, RAD51C, RAD51D, PTEN, STK11, CDH1, TP53), 3 Lynch syndrome genes (MLH1, MSH2, MSH6) and the fanconi anaemia SLX4 gene, in which monoallelic mutations were found in non-BRCA families. For BRCA1, BRCA2, RAD51C and RAD51D the results were validated by capillary electrophoresis and were compared to a non-targeted RNA-seq approach. We also compared splicing events from lymphoblastoid cell-lines with those from breast and ovarian fimbriae tissues. The potential of targeted RNA-seq to detect pathogenic changes in RNA-splicing was validated by the inclusion of samples with previously well characterized BRCA1/2 genetic variants. In our study, we update the catalogue of normal splicing events for BRCA1/2, provide an extensive catalogue of normal RAD51C and RAD51D alternative splicing, and list splicing events found for eight other genes. Additionally, we show that our approach allowed the identification of aberrant splicing events due to the presence of BRCA1/2 genetic variants and distinguished between complete and partial splicing events. In conclusion, targeted-RNA-seq can be very useful to classify variants based on their putative pathogenic impact on splicing., (© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
Published: 2019
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44. TP53 germline mutation testing in early-onset breast cancer: findings from a nationwide cohort.

Author: Bakhuizen JJ, Hogervorst FB, Velthuizen ME, Ruijs MW, van Engelen K, van Os TA, Gille JJ, Collée M, van den Ouweland AM, van Asperen CJ, Kets CM, Mensenkamp AR, Leter EM, Blok MJ, de Jong MM, and Ausems MG
Subjects: Adolescent, Adult, Age Factors, Age of Onset, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms diagnosis, Breast Neoplasms epidemiology, DNA Mutational Analysis, Female, Genetic Counseling statistics & numerical data, Genetic Predisposition to Disease, Genetic Testing statistics & numerical data, Germ-Line Mutation, Humans, Li-Fraumeni Syndrome diagnosis, Li-Fraumeni Syndrome epidemiology, Medical History Taking, Netherlands epidemiology, Practice Guidelines as Topic, Retrospective Studies, Young Adult, Breast Neoplasms genetics, Genetic Counseling standards, Genetic Testing standards, Li-Fraumeni Syndrome genetics, Tumor Suppressor Protein p53 genetics
Abstract: Early-onset breast cancer may be due to Li-Fraumeni Syndrome (LFS). Current national and international guidelines recommend that TP53 genetic testing should be considered for women with breast cancer diagnosed before the age of 31 years. However, large studies investigating TP53 mutation prevalence in this population are scarce. We collected nationwide laboratory records for all young breast cancer patients tested for TP53 mutations in the Netherlands. Between 2005 and 2016, 370 women diagnosed with breast cancer younger than 30 years of age were tested for TP53 germline mutations, and eight (2.2%) were found to carry a (likely) pathogenic TP53 sequence variant. Among BRCA1/BRCA2 mutation negative women without a family history suggestive of LFS or a personal history of multiple LFS-related tumours, the TP53 mutation frequency was < 1% (2/233). Taking into consideration that TP53 mutation prevalence was comparable or even higher in some studies selecting patients with breast cancer onset at older ages or HER2-positive breast cancers, raises the question of whether a very early age of onset is an appropriate single TP53 genetic testing criterion.
Published: 2019
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45. BRCA1 and BRCA2 5' noncoding region variants identified in breast cancer patients alter promoter activity and protein binding.

Author: Burke LJ, Sevcik J, Gambino G, Tudini E, Mucaki EJ, Shirley BC, Whiley P, Parsons MT, De Leeneer K, Gutiérrez-Enríquez S, Santamariña M, Caputo SM, Santana Dos Santos E, Soukupova J, Janatova M, Zemankova P, Lhotova K, Stolarova L, Borecka M, Moles-Fernández A, Manoukian S, Bonanni B, Edwards SL, Blok MJ, van Overeem Hansen T, Rossing M, Diez O, Vega A, Claes KBM, Goldgar DE, Rouleau E, Radice P, Peterlongo P, Rogan PK, Caligo M, Spurdle AB, and Brown MA
Subjects: 5' Untranslated Regions, Age of Onset, BRCA1 Protein chemistry, BRCA1 Protein metabolism, BRCA2 Protein chemistry, BRCA2 Protein metabolism, CCAAT-Binding Factor metabolism, Cell Line, Tumor, Female, Genetic Predisposition to Disease, Humans, MCF-7 Cells, PAX5 Transcription Factor metabolism, Protein Binding, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms genetics, Germ-Line Mutation, Promoter Regions, Genetic
Abstract: The widespread use of next generation sequencing for clinical testing is detecting an escalating number of variants in noncoding regions of the genome. The clinical significance of the majority of these variants is currently unknown, which presents a significant clinical challenge. We have screened over 6,000 early-onset and/or familial breast cancer (BC) cases collected by the ENIGMA consortium for sequence variants in the 5' noncoding regions of BC susceptibility genes BRCA1 and BRCA2, and identified 141 rare variants with global minor allele frequency < 0.01, 76 of which have not been reported previously. Bioinformatic analysis identified a set of 21 variants most likely to impact transcriptional regulation, and luciferase reporter assays detected altered promoter activity for four of these variants. Electrophoretic mobility shift assays demonstrated that three of these altered the binding of proteins to the respective BRCA1 or BRCA2 promoter regions, including NFYA binding to BRCA1:c.-287C>T and PAX5 binding to BRCA2:c.-296C>T. Clinical classification of variants affecting promoter activity, using existing prediction models, found no evidence to suggest that these variants confer a high risk of disease. Further studies are required to determine if such variation may be associated with a moderate or low risk of BC., (© 2018 The Authors. Human Mutation published by Wiley Periodicals, Inc.)
Published: 2018
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46. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

Author: Rebbeck TR, Friebel TM, Friedman E, Hamann U, Huo D, Kwong A, Olah E, Olopade OI, Solano AR, Teo SH, Thomassen M, Weitzel JN, Chan TL, Couch FJ, Goldgar DE, Kruse TA, Palmero EI, Park SK, Torres D, van Rensburg EJ, McGuffog L, Parsons MT, Leslie G, Aalfs CM, Abugattas J, Adlard J, Agata S, Aittomäki K, Andrews L, Andrulis IL, Arason A, Arnold N, Arun BK, Asseryanis E, Auerbach L, Azzollini J, Balmaña J, Barile M, Barkardottir RB, Barrowdale D, Benitez J, Berger A, Berger R, Blanco AM, Blazer KR, Blok MJ, Bonadona V, Bonanni B, Bradbury AR, Brewer C, Buecher B, Buys SS, Caldes T, Caliebe A, Caligo MA, Campbell I, Caputo SM, Chiquette J, Chung WK, Claes KBM, Collée JM, Cook J, Davidson R, de la Hoya M, De Leeneer K, de Pauw A, Delnatte C, Diez O, Ding YC, Ditsch N, Domchek SM, Dorfling CM, Velazquez C, Dworniczak B, Eason J, Easton DF, Eeles R, Ehrencrona H, Ejlertsen B, Engel C, Engert S, Evans DG, Faivre L, Feliubadaló L, Ferrer SF, Foretova L, Fowler J, Frost D, Galvão HCR, Ganz PA, Garber J, Gauthier-Villars M, Gehrig A, Gerdes AM, Gesta P, Giannini G, Giraud S, Glendon G, Godwin AK, Greene MH, Gronwald J, Gutierrez-Barrera A, Hahnen E, Hauke J, Henderson A, Hentschel J, Hogervorst FBL, Honisch E, Imyanitov EN, Isaacs C, Izatt L, Izquierdo A, Jakubowska A, James P, Janavicius R, Jensen UB, John EM, Vijai J, Kaczmarek K, Karlan BY, Kast K, Investigators K, Kim SW, Konstantopoulou I, Korach J, Laitman Y, Lasa A, Lasset C, Lázaro C, Lee A, Lee MH, Lester J, Lesueur F, Liljegren A, Lindor NM, Longy M, Loud JT, Lu KH, Lubinski J, Machackova E, Manoukian S, Mari V, Martínez-Bouzas C, Matrai Z, Mebirouk N, Meijers-Heijboer HEJ, Meindl A, Mensenkamp AR, Mickys U, Miller A, Montagna M, Moysich KB, Mulligan AM, Musinsky J, Neuhausen SL, Nevanlinna H, Ngeow J, Nguyen HP, Niederacher D, Nielsen HR, Nielsen FC, Nussbaum RL, Offit K, Öfverholm A, Ong KR, Osorio A, Papi L, Papp J, Pasini B, Pedersen IS, Peixoto A, Peruga N, Peterlongo P, Pohl E, Pradhan N, Prajzendanc K, Prieur F, Pujol P, Radice P, Ramus SJ, Rantala J, Rashid MU, Rhiem K, Robson M, Rodriguez GC, Rogers MT, Rudaitis V, Schmidt AY, Schmutzler RK, Senter L, Shah PD, Sharma P, Side LE, Simard J, Singer CF, Skytte AB, Slavin TP, Snape K, Sobol H, Southey M, Steele L, Steinemann D, Sukiennicki G, Sutter C, Szabo CI, Tan YY, Teixeira MR, Terry MB, Teulé A, Thomas A, Thull DL, Tischkowitz M, Tognazzo S, Toland AE, Topka S, Trainer AH, Tung N, van Asperen CJ, van der Hout AH, van der Kolk LE, van der Luijt RB, Van Heetvelde M, Varesco L, Varon-Mateeva R, Vega A, Villarreal-Garza C, von Wachenfeldt A, Walker L, Wang-Gohrke S, Wappenschmidt B, Weber BHF, Yannoukakos D, Yoon SY, Zanzottera C, Zidan J, Zorn KK, Hutten Selkirk CG, Hulick PJ, Chenevix-Trench G, Spurdle AB, Antoniou AC, and Nathanson KL
Subjects: Databases, Genetic, Family, Geography, Humans, BRCA1 Protein genetics, BRCA2 Protein genetics, Internationality, Mutation genetics
Abstract: The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations., (© 2018 Wiley Periodicals, Inc.)
Published: 2018
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47. The BRCA1 c. 5096G>A p.Arg1699Gln (R1699Q) intermediate risk variant: breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium.

Author: Moghadasi S, Meeks HD, Vreeswijk MP, Janssen LA, Borg Å, Ehrencrona H, Paulsson-Karlsson Y, Wappenschmidt B, Engel C, Gehrig A, Arnold N, Hansen TVO, Thomassen M, Jensen UB, Kruse TA, Ejlertsen B, Gerdes AM, Pedersen IS, Caputo SM, Couch F, Hallberg EJ, van den Ouweland AM, Collée MJ, Teugels E, Adank MA, van der Luijt RB, Mensenkamp AR, Oosterwijk JC, Blok MJ, Janin N, Claes KB, Tucker K, Viassolo V, Toland AE, Eccles DE, Devilee P, Van Asperen CJ, Spurdle AB, Goldgar DE, and García EG
Subjects: Chromosome Segregation, Female, Humans, Risk Factors, BRCA1 Protein genetics, Breast Neoplasms genetics, Genetic Predisposition to Disease, Mutation genetics, Ovarian Neoplasms genetics
Abstract: Background: We previously showed that the BRCA1 variant c.5096G>A p.Arg1699Gln (R1699Q) was associated with an intermediate risk of breast cancer (BC) and ovarian cancer (OC). This study aimed to assess these cancer risks for R1699Q carriers in a larger cohort, including follow-up of previously studied families, to further define cancer risks and to propose adjusted clinical management of female BRCA1 *R1699Q carriers., Methods: Data were collected from 129 BRCA1 *R1699Q families ascertained internationally by ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium members. A modified segregation analysis was used to calculate BC and OC risks. Relative risks were calculated under both monogenic model and major gene plus polygenic model assumptions., Results: In this cohort the cumulative risk of BC and OC by age 70 years was 20% and 6%, respectively. The relative risk for developing cancer was higher when using a model that included the effects of both the R1699Q variant and a residual polygenic component compared with monogenic model (for BC 3.67 vs 2.83, and for OC 6.41 vs 5.83)., Conclusion: Our results confirm that BRCA1 *R1699Q confers an intermediate risk for BC and OC. Breast surveillance for female carriers based on mammogram annually from age 40 is advised. Bilateral salpingo-oophorectomy should be considered based on family history., Competing Interests: Competing interests: EGG has received an honorarium in the past 3 years from AstraZeneca for giving a course and a lecture. HE (or rather, his department with him as primary contact) has received funding from Novartis Oncology (unrestricted grant) and AstraZeneca (invited speaker). KT has received an honorarium for chairing a mainstreaming genetic testing subcommittee and day seminar for AstraZeneca. AET declares to have received an honorarium from American Cancer Society for grant review, NIH NCI PDQ as editorial board, Italian Ministry of Health for grant review. DEE receives an honorarium from AstraZeneca via a contract with the university to provide consultancy advice from time to time (one or two advisory boards each year on average at the moment). DEG has received royalties from patents on the BRCA1 and BRCA2 genes from the University of Utah that are licensed to Myriad Genetics. All the other authors declare to have no conflicts of interest., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)
Published: 2018
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48. Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.

Author: Milne RL, Kuchenbaecker KB, Michailidou K, Beesley J, Kar S, Lindström S, Hui S, Lemaçon A, Soucy P, Dennis J, Jiang X, Rostamianfar A, Finucane H, Bolla MK, McGuffog L, Wang Q, Aalfs CM, Adams M, Adlard J, Agata S, Ahmed S, Ahsan H, Aittomäki K, Al-Ejeh F, Allen J, Ambrosone CB, Amos CI, Andrulis IL, Anton-Culver H, Antonenkova NN, Arndt V, Arnold N, Aronson KJ, Auber B, Auer PL, Ausems MGEM, Azzollini J, Bacot F, Balmaña J, Barile M, Barjhoux L, Barkardottir RB, Barrdahl M, Barnes D, Barrowdale D, Baynes C, Beckmann MW, Benitez J, Bermisheva M, Bernstein L, Bignon YJ, Blazer KR, Blok MJ, Blomqvist C, Blot W, Bobolis K, Boeckx B, Bogdanova NV, Bojesen A, Bojesen SE, Bonanni B, Børresen-Dale AL, Bozsik A, Bradbury AR, Brand JS, Brauch H, Brenner H, Bressac-de Paillerets B, Brewer C, Brinton L, Broberg P, Brooks-Wilson A, Brunet J, Brüning T, Burwinkel B, Buys SS, Byun J, Cai Q, Caldés T, Caligo MA, Campbell I, Canzian F, Caron O, Carracedo A, Carter BD, Castelao JE, Castera L, Caux-Moncoutier V, Chan SB, Chang-Claude J, Chanock SJ, Chen X, Cheng TD, Chiquette J, Christiansen H, Claes KBM, Clarke CL, Conner T, Conroy DM, Cook J, Cordina-Duverger E, Cornelissen S, Coupier I, Cox A, Cox DG, Cross SS, Cuk K, Cunningham JM, Czene K, Daly MB, Damiola F, Darabi H, Davidson R, De Leeneer K, Devilee P, Dicks E, Diez O, Ding YC, Ditsch N, Doheny KF, Domchek SM, Dorfling CM, Dörk T, Dos-Santos-Silva I, Dubois S, Dugué PA, Dumont M, Dunning AM, Durcan L, Dwek M, Dworniczak B, Eccles D, Eeles R, Ehrencrona H, Eilber U, Ejlertsen B, Ekici AB, Eliassen AH, Engel C, Eriksson M, Fachal L, Faivre L, Fasching PA, Faust U, Figueroa J, Flesch-Janys D, Fletcher O, Flyger H, Foulkes WD, Friedman E, Fritschi L, Frost D, Gabrielson M, Gaddam P, Gammon MD, Ganz PA, Gapstur SM, Garber J, Garcia-Barberan V, García-Sáenz JA, Gaudet MM, Gauthier-Villars M, Gehrig A, Georgoulias V, Gerdes AM, Giles GG, Glendon G, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Goodfellow P, Greene MH, Alnæs GIG, Grip M, Gronwald J, Grundy A, Gschwantler-Kaulich D, Guénel P, Guo Q, Haeberle L, Hahnen E, Haiman CA, Håkansson N, Hallberg E, Hamann U, Hamel N, Hankinson S, Hansen TVO, Harrington P, Hart SN, Hartikainen JM, Healey CS, Hein A, Helbig S, Henderson A, Heyworth J, Hicks B, Hillemanns P, Hodgson S, Hogervorst FB, Hollestelle A, Hooning MJ, Hoover B, Hopper JL, Hu C, Huang G, Hulick PJ, Humphreys K, Hunter DJ, Imyanitov EN, Isaacs C, Iwasaki M, Izatt L, Jakubowska A, James P, Janavicius R, Janni W, Jensen UB, John EM, Johnson N, Jones K, Jones M, Jukkola-Vuorinen A, Kaaks R, Kabisch M, Kaczmarek K, Kang D, Kast K, Keeman R, Kerin MJ, Kets CM, Keupers M, Khan S, Khusnutdinova E, Kiiski JI, Kim SW, Knight JA, Konstantopoulou I, Kosma VM, Kristensen VN, Kruse TA, Kwong A, Lænkholm AV, Laitman Y, Lalloo F, Lambrechts D, Landsman K, Lasset C, Lazaro C, Le Marchand L, Lecarpentier J, Lee A, Lee E, Lee JW, Lee MH, Lejbkowicz F, Lesueur F, Li J, Lilyquist J, Lincoln A, Lindblom A, Lissowska J, Lo WY, Loibl S, Long J, Loud JT, Lubinski J, Luccarini C, Lush M, MacInnis RJ, Maishman T, Makalic E, Kostovska IM, Malone KE, Manoukian S, Manson JE, Margolin S, Martens JWM, Martinez ME, Matsuo K, Mavroudis D, Mazoyer S, McLean C, Meijers-Heijboer H, Menéndez P, Meyer J, Miao H, Miller A, Miller N, Mitchell G, Montagna M, Muir K, Mulligan AM, Mulot C, Nadesan S, Nathanson KL, Neuhausen SL, Nevanlinna H, Nevelsteen I, Niederacher D, Nielsen SF, Nordestgaard BG, Norman A, Nussbaum RL, Olah E, Olopade OI, Olson JE, Olswold C, Ong KR, Oosterwijk JC, Orr N, Osorio A, Pankratz VS, Papi L, Park-Simon TW, Paulsson-Karlsson Y, Lloyd R, Pedersen IS, Peissel B, Peixoto A, Perez JIA, Peterlongo P, Peto J, Pfeiler G, Phelan CM, Pinchev M, Plaseska-Karanfilska D, Poppe B, Porteous ME, Prentice R, Presneau N, Prokofieva D, Pugh E, Pujana MA, Pylkäs K, Rack B, Radice P, Rahman N, Rantala J, Rappaport-Fuerhauser C, Rennert G, Rennert HS, Rhenius V, Rhiem K, Richardson A, Rodriguez GC, Romero A, Romm J, Rookus MA, Rudolph A, Ruediger T, Saloustros E, Sanders J, Sandler DP, Sangrajrang S, Sawyer EJ, Schmidt DF, Schoemaker MJ, Schumacher F, Schürmann P, Schwentner L, Scott C, Scott RJ, Seal S, Senter L, Seynaeve C, Shah M, Sharma P, Shen CY, Sheng X, Shimelis H, Shrubsole MJ, Shu XO, Side LE, Singer CF, Sohn C, Southey MC, Spinelli JJ, Spurdle AB, Stegmaier C, Stoppa-Lyonnet D, Sukiennicki G, Surowy H, Sutter C, Swerdlow A, Szabo CI, Tamimi RM, Tan YY, Taylor JA, Tejada MI, Tengström M, Teo SH, Terry MB, Tessier DC, Teulé A, Thöne K, Thull DL, Tibiletti MG, Tihomirova L, Tischkowitz M, Toland AE, Tollenaar RAEM, Tomlinson I, Tong L, Torres D, Tranchant M, Truong T, Tucker K, Tung N, Tyrer J, Ulmer HU, Vachon C, van Asperen CJ, Van Den Berg D, van den Ouweland AMW, van Rensburg EJ, Varesco L, Varon-Mateeva R, Vega A, Viel A, Vijai J, Vincent D, Vollenweider J, Walker L, Wang Z, Wang-Gohrke S, Wappenschmidt B, Weinberg CR, Weitzel JN, Wendt C, Wesseling J, Whittemore AS, Wijnen JT, Willett W, Winqvist R, Wolk A, Wu AH, Xia L, Yang XR, Yannoukakos D, Zaffaroni D, Zheng W, Zhu B, Ziogas A, Ziv E, Zorn KK, Gago-Dominguez M, Mannermaa A, Olsson H, Teixeira MR, Stone J, Offit K, Ottini L, Park SK, Thomassen M, Hall P, Meindl A, Schmutzler RK, Droit A, Bader GD, Pharoah PDP, Couch FJ, Easton DF, Kraft P, Chenevix-Trench G, García-Closas M, Schmidt MK, Antoniou AC, and Simard J
Subjects: Breast Neoplasms ethnology, Breast Neoplasms metabolism, Female, Genetic Predisposition to Disease ethnology, Genome-Wide Association Study methods, Heterozygote, Humans, Receptors, Estrogen metabolism, Risk Factors, White People genetics, BRCA1 Protein genetics, Breast Neoplasms genetics, Genetic Predisposition to Disease genetics, Mutation, Polymorphism, Single Nucleotide
Abstract: Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10 -8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.
Published: 2017
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49. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

Author: Phelan CM, Kuchenbaecker KB, Tyrer JP, Kar SP, Lawrenson K, Winham SJ, Dennis J, Pirie A, Riggan MJ, Chornokur G, Earp MA, Lyra PC Jr, Lee JM, Coetzee S, Beesley J, McGuffog L, Soucy P, Dicks E, Lee A, Barrowdale D, Lecarpentier J, Leslie G, Aalfs CM, Aben KKH, Adams M, Adlard J, Andrulis IL, Anton-Culver H, Antonenkova N, Aravantinos G, Arnold N, Arun BK, Arver B, Azzollini J, Balmaña J, Banerjee SN, Barjhoux L, Barkardottir RB, Bean Y, Beckmann MW, Beeghly-Fadiel A, Benitez J, Bermisheva M, Bernardini MQ, Birrer MJ, Bjorge L, Black A, Blankstein K, Blok MJ, Bodelon C, Bogdanova N, Bojesen A, Bonanni B, Borg Å, Bradbury AR, Brenton JD, Brewer C, Brinton L, Broberg P, Brooks-Wilson A, Bruinsma F, Brunet J, Buecher B, Butzow R, Buys SS, Caldes T, Caligo MA, Campbell I, Cannioto R, Carney ME, Cescon T, Chan SB, Chang-Claude J, Chanock S, Chen XQ, Chiew YE, Chiquette J, Chung WK, Claes KBM, Conner T, Cook LS, Cook J, Cramer DW, Cunningham JM, D'Aloisio AA, Daly MB, Damiola F, Damirovna SD, Dansonka-Mieszkowska A, Dao F, Davidson R, DeFazio A, Delnatte C, Doheny KF, Diez O, Ding YC, Doherty JA, Domchek SM, Dorfling CM, Dörk T, Dossus L, Duran M, Dürst M, Dworniczak B, Eccles D, Edwards T, Eeles R, Eilber U, Ejlertsen B, Ekici AB, Ellis S, Elvira M, Eng KH, Engel C, Evans DG, Fasching PA, Ferguson S, Ferrer SF, Flanagan JM, Fogarty ZC, Fortner RT, Fostira F, Foulkes WD, Fountzilas G, Fridley BL, Friebel TM, Friedman E, Frost D, Ganz PA, Garber J, García MJ, Garcia-Barberan V, Gehrig A, Gentry-Maharaj A, Gerdes AM, Giles GG, Glasspool R, Glendon G, Godwin AK, Goldgar DE, Goranova T, Gore M, Greene MH, Gronwald J, Gruber S, Hahnen E, Haiman CA, Håkansson N, Hamann U, Hansen TVO, Harrington PA, Harris HR, Hauke J, Hein A, Henderson A, Hildebrandt MAT, Hillemanns P, Hodgson S, Høgdall CK, Høgdall E, Hogervorst FBL, Holland H, Hooning MJ, Hosking K, Huang RY, Hulick PJ, Hung J, Hunter DJ, Huntsman DG, Huzarski T, Imyanitov EN, Isaacs C, Iversen ES, Izatt L, Izquierdo A, Jakubowska A, James P, Janavicius R, Jernetz M, Jensen A, Jensen UB, John EM, Johnatty S, Jones ME, Kannisto P, Karlan BY, Karnezis A, Kast K, Kennedy CJ, Khusnutdinova E, Kiemeney LA, Kiiski JI, Kim SW, Kjaer SK, Köbel M, Kopperud RK, Kruse TA, Kupryjanczyk J, Kwong A, Laitman Y, Lambrechts D, Larrañaga N, Larson MC, Lazaro C, Le ND, Le Marchand L, Lee JW, Lele SB, Leminen A, Leroux D, Lester J, Lesueur F, Levine DA, Liang D, Liebrich C, Lilyquist J, Lipworth L, Lissowska J, Lu KH, Lubinński J, Luccarini C, Lundvall L, Mai PL, Mendoza-Fandiño G, Manoukian S, Massuger LFAG, May T, Mazoyer S, McAlpine JN, McGuire V, McLaughlin JR, McNeish I, Meijers-Heijboer H, Meindl A, Menon U, Mensenkamp AR, Merritt MA, Milne RL, Mitchell G, Modugno F, Moes-Sosnowska J, Moffitt M, Montagna M, Moysich KB, Mulligan AM, Musinsky J, Nathanson KL, Nedergaard L, Ness RB, Neuhausen SL, Nevanlinna H, Niederacher D, Nussbaum RL, Odunsi K, Olah E, Olopade OI, Olsson H, Olswold C, O'Malley DM, Ong KR, Onland-Moret NC, Orr N, Orsulic S, Osorio A, Palli D, Papi L, Park-Simon TW, Paul J, Pearce CL, Pedersen IS, Peeters PHM, Peissel B, Peixoto A, Pejovic T, Pelttari LM, Permuth JB, Peterlongo P, Pezzani L, Pfeiler G, Phillips KA, Piedmonte M, Pike MC, Piskorz AM, Poblete SR, Pocza T, Poole EM, Poppe B, Porteous ME, Prieur F, Prokofyeva D, Pugh E, Pujana MA, Pujol P, Radice P, Rantala J, Rappaport-Fuerhauser C, Rennert G, Rhiem K, Rice P, Richardson A, Robson M, Rodriguez GC, Rodríguez-Antona C, Romm J, Rookus MA, Rossing MA, Rothstein JH, Rudolph A, Runnebaum IB, Salvesen HB, Sandler DP, Schoemaker MJ, Senter L, Setiawan VW, Severi G, Sharma P, Shelford T, Siddiqui N, Side LE, Sieh W, Singer CF, Sobol H, Song H, Southey MC, Spurdle AB, Stadler Z, Steinemann D, Stoppa-Lyonnet D, Sucheston-Campbell LE, Sukiennicki G, Sutphen R, Sutter C, Swerdlow AJ, Szabo CI, Szafron L, Tan YY, Taylor JA, Tea MK, Teixeira MR, Teo SH, Terry KL, Thompson PJ, Thomsen LCV, Thull DL, Tihomirova L, Tinker AV, Tischkowitz M, Tognazzo S, Toland AE, Tone A, Trabert B, Travis RC, Trichopoulou A, Tung N, Tworoger SS, van Altena AM, Van Den Berg D, van der Hout AH, van der Luijt RB, Van Heetvelde M, Van Nieuwenhuysen E, van Rensburg EJ, Vanderstichele A, Varon-Mateeva R, Vega A, Edwards DV, Vergote I, Vierkant RA, Vijai J, Vratimos A, Walker L, Walsh C, Wand D, Wang-Gohrke S, Wappenschmidt B, Webb PM, Weinberg CR, Weitzel JN, Wentzensen N, Whittemore AS, Wijnen JT, Wilkens LR, Wolk A, Woo M, Wu X, Wu AH, Yang H, Yannoukakos D, Ziogas A, Zorn KK, Narod SA, Easton DF, Amos CI, Schildkraut JM, Ramus SJ, Ottini L, Goodman MT, Park SK, Kelemen LE, Risch HA, Thomassen M, Offit K, Simard J, Schmutzler RK, Hazelett D, Monteiro AN, Couch FJ, Berchuck A, Chenevix-Trench G, Goode EL, Sellers TA, Gayther SA, Antoniou AC, and Pharoah PDP
Subjects: Alleles, BRCA1 Protein genetics, BRCA2 Protein genetics, Carcinoma, Ovarian Epithelial, Female, Genome-Wide Association Study, Genotype, Humans, Meta-Analysis as Topic, Mutation, Neoplasms, Glandular and Epithelial pathology, Ovarian Neoplasms pathology, Polymorphism, Single Nucleotide, Risk Factors, Telomere-Binding Proteins genetics, Genetic Loci genetics, Genetic Predisposition to Disease genetics, Neoplasms, Glandular and Epithelial genetics, Ovarian Neoplasms genetics
Abstract: To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
Published: 2017
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50. Novel BRCA1 and BRCA2 Tumor Test as Basis for Treatment Decisions and Referral for Genetic Counselling of Patients with Ovarian Carcinomas.

Author: Weren RD, Mensenkamp AR, Simons M, Eijkelenboom A, Sie AS, Ouchene H, van Asseldonk M, Gomez-Garcia EB, Blok MJ, de Hullu JA, Nelen MR, Hoischen A, Bulten J, Tops BB, Hoogerbrugge N, and Ligtenberg MJ
Subjects: Alleles, Amino Acid Substitution, DNA Copy Number Variations, DNA Mutational Analysis, Disease Management, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Testing methods, Genetic Testing standards, Genotype, Germ-Line Mutation, Humans, Loss of Heterozygosity, Ovarian Neoplasms diagnosis, Ovarian Neoplasms therapy, Reproducibility of Results, Clinical Decision-Making, Genes, BRCA1, Genes, BRCA2, Genetic Counseling, Ovarian Neoplasms genetics
Abstract: With the recent introduction of Poly(ADP-ribose) polymerase inhibitors, a promising novel therapy has become available for ovarian carcinoma (OC) patients with inactivating BRCA1 or BRCA2 mutations in their tumor. To select patients who may benefit from these treatments, assessment of the mutation status of BRCA1 and BRCA2 in the tumor is required. For reliable evaluation of germline and somatic mutations in these genes in DNA derived from formalin-fixed, paraffin-embedded (FFPE) tissue, we have developed a single-molecule molecular inversion probe (smMIP)-based targeted next-generation sequencing (NGS) approach. Our smMIP-based NGS approach provides analysis of both strands of the open reading frame of BRCA1 and BRCA2, enabling the discrimination between real variants and formalin-induced artefacts. The single molecule tag enables compilation of unique reads leading to a high analytical sensitivity and enabling assessment of the reliability of mutation-negative results. Multiplex ligation-dependent probe amplification (MLPA) and Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) were used to detect exon deletions of BRCA1 and methylation of the BRCA1 promoter, respectively. Here, we show that this combined approach allows the rapid and reliable detection of both germline and somatic aberrations affecting BRCA1 and BRCA2 in DNA derived from FFPE OCs, enabling improved hereditary cancer risk assessment and clinical treatment of ovarian cancer patients., (© 2016 The Authors. **Human Mutation published by Wiley Periodicals, Inc.)
Published: 2017
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