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1. Haplotype analyses of the c.1027C>T and c.2167_2168delAT recurrent truncating mutations in the breast cancer-predisposing gene PALB2

Author

Catucci, I, Casadei, S, Ding, Y, Volorio, S, Ficarazzi, F, Falanga, A, Marchetti, M, Tondini, C, Franchi, M, Adamson, A, Mandell, J, Walsh, T, Olopade, O, Manoukian, S, Radice, P, Ricker, C, Weitzel, J, King, M, Peterlongo, P, Neuhausen, S, Catucci I., Casadei S., Ding Y. C., Volorio S., Ficarazzi F., Falanga A., Marchetti M., Tondini C., Franchi M., Adamson A., Mandell J., Walsh T., Olopade O. I., Manoukian S., Radice P., Ricker C., Weitzel J., King M. -C., Peterlongo P., Neuhausen S. L., Catucci, I, Casadei, S, Ding, Y, Volorio, S, Ficarazzi, F, Falanga, A, Marchetti, M, Tondini, C, Franchi, M, Adamson, A, Mandell, J, Walsh, T, Olopade, O, Manoukian, S, Radice, P, Ricker, C, Weitzel, J, King, M, Peterlongo, P, Neuhausen, S, Catucci I., Casadei S., Ding Y. C., Volorio S., Ficarazzi F., Falanga A., Marchetti M., Tondini C., Franchi M., Adamson A., Mandell J., Walsh T., Olopade O. I., Manoukian S., Radice P., Ricker C., Weitzel J., King M. -C., Peterlongo P., and Neuhausen S. L.

Abstract

Purpose: Breast cancer-predisposing mutations PALB2 c.1027C>T (p.Gln343*) and PALB2 c.2167_2168delAT have each been observed multiple times in breast cancer families of Italian ancestry. More recently, the c2167_2168delAT mutation was identified in unrelated breast cancer cases of various ancestries. For each mutation, we investigated whether the origin was multiple mutational events (a “hot-spot”) or a single event (a founder allele). Methods: We genotyped and reconstructed haplotypes for 36 participants of Italian, Italian-American, Hispanic, and Nigerian ancestries, using seven short tandem repeat (STR) markers that covered 3 Megabases within and flanking PALB2 on chromosome 16. Results: For PALB2 c.1027C>T, a shared haplotype with a minimum size of 150 kb was shared by all 19 carriers investigated, all of Italian ancestry. This result suggests that this allele arose as a single event in a shared ancestor. For PALB2 c.2167_2168delAT, all 12 carriers from American-Italian and Italian families shared a 1-Mb haplotype, the 3 Hispanic carriers shared a different haplotype of size 2 Mb, and the Nigerian carrier had different alleles at all 7 STR markers. These results suggest that PALB2 c.2167_2168delAT arose multiple times, but that within each population, PALB2 c.2167_2168delAT likely represents a single mutational event. Conclusion: We identified two PALB2 mutations that are founder alleles in Italian families, one of which is, independently, also a founder mutation in American-Hispanic breast cancers.

Published
2016

2. Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade

Author

Purrington, K.S., Slettedahl, S., Bolla, M.K., Michailidou, K., Czene, K., Nevanlinna, H., Bojesen, S.E., Andrulis, I.L., Cox, A., Hall, P., Carpenter, J., Yannoukakos, D., Haiman, C.A., Fasching, P.A., Mannermaa, A., Winqvist, R., Brenner, H., Lindblom, A., Chenevix-Trench, G., Benitez, J., Swerdlow, A., Kristensen, V., Guenel, P., Meindl, A., Darabi, H., Eriksson, M., Fagerholm, R., Aittomaki, K., Blomqvist, C., Nordestgaard, B.G., Nielsen, S.F., Flyger, H., Wang, X.S., Olswold, C., Olson, J.E., Mulligan, A.M., Knight, J.A., Tchatchou, S., Reed, M.W.R., Cross, S.S., Liu, J.J., Li, J.M., Humphreys, K., Clarke, C., Scott, R., Fostira, F., Fountzilas, G., Konstantopoulou, I., Henderson, B.E., Schumacher, F., Marchand, L. le, Ekici, A.B., Hartmann, A., Beckmann, M.W., Hartikainen, J.M., Kosma, V.M., Kataja, V., Jukkola-Vuorinen, A., Pylkas, K., Kauppila, S., Dieffenbach, A.K., Stegmaier, C., Arndt, V., Margolin, S., Balleine, R., Perez, J.I.A., Zamora, M.P., Menendez, P., Ashworth, A., Jones, M., Orr, N., Arveux, P., Kerbrat, P., Truong, T., Bugert, P., Toland, A.E., Ambrosone, C.B., Labreche, F., Goldberg, M.S., Dumont, M., Ziogas, A., Lee, E., Dite, G.S., Apicella, C., Southey, M.C., Long, J.R., Shrubsole, M., Deming-Halverson, S., Ficarazzi, F., Barile, M., Peterlongo, P., Durda, K., Jaworska-Bieniek, K., Tollenaar, R.A.E.M., Seynaeve, C., Bruning, T., Ko, Y.D., Deurzen, C.H.M. van, Martens, J.W.M., Kriege, M., Figueroa, J.D., Chanock, S.J., Lissowska, J., Tomlinson, I., Kerin, M.J., Miller, N., Schneeweiss, A., Tapper, W.J., Gerty, S.M., Durcan, L., Mclean, C., Milne, R.L., Baglietto, L., Silva, I.D., Fletcher, O., Johnson, N., Van'T Veer, L.J., Cornelissen, S., Forsti, A., Torres, D., Rudiger, T., Rudolph, A., Flesch-Janys, D., Nickels, S., Weltens, C., Floris, G., Moisse, M., Dennis, J., Wang, Q., Dunning, A.M., Shah, M., Brown, J., Simard, J., Anton-Culver, H., Neuhausen, S.L., Hopper, J.L., Bogdanova, N., Dork, T., Zheng, W., Radice, P., Jakubowska, A., Lubinski, J., Devillee, P., Brauch, H., Hooning, M., Garcia-Closas, M., Sawyer, E., Burwinkel, B., Marmee, F., Eccles, D.M., Giles, G.G., Peto, J., Schmidt, M., Broeks, A., Hamann, U., Chang-Claude, J., Lambrechts, D., Pharoah, P.D.P., Easton, D., Pankratz, V.S., Slager, S., Vachon, C.M., Couch, F.J., ABCTB Investigators, Australian Ovarian Canc Study Grp, kConFab Investigators, GENICA Network, Medical Oncology, Pathology, and Clinical Genetics

Subjects
Oncology, Candidate gene, Fibroblast Growth Factor, amplification, cancer susceptibility loci, Bioinformatics, medicine.disease_cause, Medical and Health Sciences, prostate-cancer, Prostate cancer, Risk Factors, Medizinische Fakultät, Genetics (clinical), Genetics & Heredity, tacc2, Association Studies Articles, Single Nucleotide, General Medicine, Biological Sciences, ddc, risk loci, cell-division, kConFab Investigators, Female, GENICA Network, Type 2, Receptor, Australian Ovarian Cancer Study Group, Breast Neoplasms, Carrier Proteins, Case-Control Studies, Haplotypes, Humans, Neoplasm Staging, Polymorphism, Single Nucleotide, Receptor, Fibroblast Growth Factor, Type 2, Tumor Suppressor Proteins, Genetic Variation, Molecular Biology, Genetics, medicine.medical_specialty, Mitotic index, ABCTB Investigators, Single-nucleotide polymorphism, Biology, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, ddc:610, Polymorphism, Lung cancer, Odds ratio, medicine.disease, genome-wide association, lung-cancer, progression, Carcinogenesis
Abstract

Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16-1.33, P = 4.2 × 10(-10)) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04-1.11, P = 8.7 × 10(-6)) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07-1.23, P = 7.9 × 10(-5)) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk (P = 2.1 × 10(-3)). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.

Published
2014
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3. Common germline polymorphisms\ud associated with breast cancer-specific survival

Author

Pirie, A., Guo, Q., Kraft, P., Canisius, S., Eccles, D.M., Rahman, N., Nevanlinna, H., Chen, C., Khan, S., Tyrer, J., Bolla, M.K., Wang, Q., Dennis, J., Michailidou, K., Lush, M., Dunning, A.M., Shah, M., Czene, K., Darabi, H., Eriksson, M., Lambrechts, D., Weltens, C., Leunen, K., van Ongeval, C., Nordestgaard, B.G., Nielsen, S.F., Flyger, H., Rudolph, A., Seibold, P., Flesch-Janys, D., Blomqvist, C., Aittomaki, K., Fagerholm, R., Muranen, T.A., Olsen, J.E., Hallberg, E., Vachon, C., Knight, J.A., Glendon, G., Mulligan, A.M., Broeks, A., Cornelissen, S., Haiman, C.A., Henderson, B.E., Schumacher, F., Le Marchand, L., Hopper, J.L., Tsimiklis, H., Apicella, C., Southey, M.C., Cross, S.S., Reed, M.W.R., Giles, G.G., Milne, R.L., McLean, C., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Hooning, M.J., Hollestelle, A., Martens, J.W.M., van den Ouweland, A.M.W., Marme, F., Schneeweiss, A., Yang, R., Burwinkel, B., Figueroa, J., Chanock, S.J., Lissowska, J., Sawyer, E.J., Tomlinson, I., Kerin, M.J., Miller, N., Brenner, H., Butterbach, K., Holleczek, B., Kataja, V., Kosma, V-M., Hartikainen, J.M., Li, J., Brand, J.S., Humphreys, K., Devilee, P., Tollenaar, R.A.E.M., Seynaeve, C., Radice, P., Peterlongo, P., Manoukian, S., Ficarazzi, F., Beckmann, M.W., Hein, A., Ekici, A.B., Balleine, R., Phillips, K-A., Benitez, J., Zamora, M.P., Perez, J.I.A., Menendez, P., Jakubowska, A., Lubinski, J., Gronwald, J., Durda, K., Hamann, U., Kabisch, M., Ulmer, H.U., Ruediger, T., Margolin, S., Kristensen, V., Nord, S., Evans, D.G., Abraham, J., Earl, H., Poole, C.J., Hiller, L., Dunn, J.A., Bowden, S., Campa, D., Diver, W.R., Gapstur, S.M., Gaudet, M.M., Hankinson, S., Hoover, R.N., Husing, A., Kaaks, R., Machiela, M.J., Willett, W., Barrdahl, M., Canzian, F., Chin, S-F., Caldas, C., Hunter, D.J., Lindstrom, S., Garcia-Closas, M., Couch, F.J., Investigators, kConFab, Chenevix-Trench, G., Mannermaa, A., Andrulis, I.L., Hall, P., Chang-Claude, J., Easton, D.F., Bojesen, S.E., Cox, A., Fasching, P.A., Pharoah, P.D.P., Schmidt, M.K., and Investigators, NBCS

Abstract

Introduction: Previous studies have identified common germline variants nominally associated with breast cancer\ud survival. These associations have not been widely replicated in further studies. The purpose of this study was to\ud evaluate the association of previously reported SNPs with breast cancer-specific survival using data from a pooled\ud analysis of eight breast cancer survival genome-wide association studies (GWAS) from the Breast Cancer Association\ud Consortium.\ud Methods: A literature review was conducted of all previously published associations between common germline\ud variants and three survival outcomes: breast cancer-specific survival, overall survival and disease-free survival.\ud All associations that reached the nominal significance level of P value

Published
2015

4. Candidate genetic modifiers for breast and ovarian cancer risk inBRCA1andBRCA2 mutation carriers

Author

Peterlongo, P, Chang-Claude, J, Moysich, KB, Rudolph, A, Schmutzler, RK, Simard, J, Soucy, P, Eeles, RA, Easton, DF, Hamann, U, Wilkening, S, Chen, B, Rookus, MA, Schmidt, MK, Van Der Baan, FH, Spurdle, AB, Walker, LC, Lose, F, Maia, AT, Montagna, M, Matricardi, L, Lubinski, J, Jakubowska, A, Garcia, EBG, Olopade, OI, Nussbaum, RL, Nathanson, KL, Domchek, SM, Rebbeck, TR, Arun, BK, Karlan, BY, Orsulic, S, Lester, J, Chung, WK, Miron, A, Southey, MC, Goldgar, DE, Buys, SS, Janavicius, R, Dorfling, CM, Van Rensburg, EJ, Ding, YC, Neuhausen, SL, Hansen, TVO, Gerdes, AM, Ejlertsen, B, Jønson, L, Osorio, A, Martínez-Bouzas, C, Benitez, J, Conway, EE, Blazer, KR, Weitzel, JN, Manoukian, S, Peissel, B, Zaffaroni, D, Scuvera, G, Barile, M, Ficarazzi, F, Mariette, F, Fortuzzi, S, Viel, A, Giannini, G, Papi, L, Martayan, A, Tibiletti, MG, Radice, P, Vratimos, A, Fostira, F, Garber, JE, Donaldson, A, Brewer, C, Foo, C, Evans, DGR, Frost, D, Eccles, D, Brady, A, Cook, J, Tischkowitz, M, Adlard, J, Barwell, J, Walker, L, Izatt, L, Side, LE, Kennedy, MJ, Rogers, MT, Porteous, ME, Morrison, PJ, Platte, R, Davidson, R, and Hodgson, SV

Subjects
endocrine system diseases, skin and connective tissue diseases
Abstract

© 2014 American Association for Cancer Research. Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants inmany candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysiswas performed within a retrospective cohort approach. Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.

Published
2015
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5. Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers

Author

Peterlongo, P., Chang-Claude, J., Moysich, K.B., Rudolph, A., Schmutzler, R.K., Simard, J., Soucy, P., Eeles, R.A., Easton, D.F., Hamann, U., Wilkening, S., Chen, B., Rookus, M.A., Schmidt, M.K., Baan, F.H. van der, Spurdle, A.B., Walker, L.C., Lose, F., Maia, A.T., Montagna, M., Matricardi, L., Lubinski, J., Jakubowska, A., Garcia, E.B., Olopade, O.I., Nussbaum, R.L., Nathanson, K.L., Domchek, S.M., Rebbeck, T.R., Arun, B.K., Karlan, B.Y., Orsulic, S., Lester, J., Chung, W.K., Miron, A., Southey, M.C., Goldgar, D.E., Buys, S.S., Janavicius, R., Dorfling, C.M., Rensburg, E.J. van, Ding, Y.C., Neuhausen, S.L., Hansen, T.V., Gerdes, A.M., Ejlertsen, B., Jonson, L., Osorio, A., Martinez-Bouzas, C., Benitez, J., Conway, E.E., Blazer, K.R., Weitzel, J.N., Manoukian, S., Peissel, B., Zaffaroni, D., Scuvera, G., Barile, M., Ficarazzi, F., Mariette, F., Fortuzzi, S., Viel, A., Giannini, G., Papi, L., Martayan, A., Tibiletti, M.G., Radice, P., Vratimos, A., Fostira, F., Garber, J.E., Donaldson, A., Brewer, C., Foo, C., Evans, D.G., Frost, D., Eccles, D., Brady, A., Cook, J., Tischkowitz, M., Adlard, J., Barwell, J., Izatt, L., Side, L.E., Kennedy, M.J., Rogers, M.T., Porteous, M.E., Morrison, P.J., Platte, R., Davidson, R., Hodgson, S.V., Ellis, S., Cole, T., Godwin, A.K., Claes, K., Maerken, T. Van, Meindl, A., Gehrig, A., Sutter, C., Engel, C., Hoogerbrugge, N., et al., Peterlongo, P., Chang-Claude, J., Moysich, K.B., Rudolph, A., Schmutzler, R.K., Simard, J., Soucy, P., Eeles, R.A., Easton, D.F., Hamann, U., Wilkening, S., Chen, B., Rookus, M.A., Schmidt, M.K., Baan, F.H. van der, Spurdle, A.B., Walker, L.C., Lose, F., Maia, A.T., Montagna, M., Matricardi, L., Lubinski, J., Jakubowska, A., Garcia, E.B., Olopade, O.I., Nussbaum, R.L., Nathanson, K.L., Domchek, S.M., Rebbeck, T.R., Arun, B.K., Karlan, B.Y., Orsulic, S., Lester, J., Chung, W.K., Miron, A., Southey, M.C., Goldgar, D.E., Buys, S.S., Janavicius, R., Dorfling, C.M., Rensburg, E.J. van, Ding, Y.C., Neuhausen, S.L., Hansen, T.V., Gerdes, A.M., Ejlertsen, B., Jonson, L., Osorio, A., Martinez-Bouzas, C., Benitez, J., Conway, E.E., Blazer, K.R., Weitzel, J.N., Manoukian, S., Peissel, B., Zaffaroni, D., Scuvera, G., Barile, M., Ficarazzi, F., Mariette, F., Fortuzzi, S., Viel, A., Giannini, G., Papi, L., Martayan, A., Tibiletti, M.G., Radice, P., Vratimos, A., Fostira, F., Garber, J.E., Donaldson, A., Brewer, C., Foo, C., Evans, D.G., Frost, D., Eccles, D., Brady, A., Cook, J., Tischkowitz, M., Adlard, J., Barwell, J., Izatt, L., Side, L.E., Kennedy, M.J., Rogers, M.T., Porteous, M.E., Morrison, P.J., Platte, R., Davidson, R., Hodgson, S.V., Ellis, S., Cole, T., Godwin, A.K., Claes, K., Maerken, T. Van, Meindl, A., Gehrig, A., Sutter, C., Engel, C., Hoogerbrugge, N., and et al.

Abstract

Contains fulltext : 154702.pdf (publisher's version ) (Closed access), BACKGROUND: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. METHODS: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. RESULTS: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. CONCLUSION: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. IMPACT: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.

Published
2015

6. Common germline polymorphisms associated with breast cancer-specific survival

Author

Pirie, A. (Ailith), Guo, Q. (Qi), Kraft, P. (Peter), Canisius, S. (Sander), Eccles, D. (Diana), Rahman, N. (Nazneen), Nevanlinna, H. (Heli), Chen, C. (Constance), Khan, S. (Sofia), Tyrer, J.P. (Jonathan), Bolla, M.K. (Manjeet), Wang, Q. (Qing), Dennis, J. (Joe), Michailidou, K. (Kyriaki), Lush, M. (Michael), Dunning, A.M. (Alison), Shah, M. (Mitul), Czene, K. (Kamila), Darabi, H. (Hatef), Eriksson, M. (Mats), Lambrechts, D. (Diether), Weltens, C. (Caroline), Leunen, K., van Ongeval, C. (Chantal), Nordestgaard, B.G. (Børge), Nielsen, S.F. (Sune), Flyger, H. (Henrik), Rudolph, A. (Anja), Seibold, P. (Petra), Flesch-Janys, D. (Dieter), Blomqvist, C. (Carl), Aittomäki, K. (Kristiina), Fagerholm, R. (Rainer), Muranen, T.A. (Taru), Olsen, J.E. (Janet E.), Hallberg, B. (Boubou), Vachon, C. (Celine), Knight, J.A. (Julia), Glendon, G. (Gord), Mulligan, A.M. (Anna Marie), Broeks, A. (Annegien), Cornelissen, S. (Sten), Haiman, C.A. (Christopher), Henderson, B.E. (Brian), Schumacher, F. (Frederick), Le Marchand, L. (Loic), Hopper, J.L. (John), Tsimiklis, H. (Helen), Apicella, C. (Carmel), Southey, M.C. (Melissa), Cross, S.S. (Simon), Reed, M.W.R. (Malcolm), Giles, G.G. (Graham), Milne, R.L. (Roger), McLean, C.A. (Catriona Ann), Winqvist, R. (Robert), Pykäs, K. (Katri), Jukkola-Vuorinen, A. (Arja), Grip, M. (Mervi), Hooning, M.J. (Maartje), Hollestelle, A. (Antoinette), Martens, J.W.M. (John), Ouweland, A.M.W. (Ans) van den, Marme, F. (Federick), Schneeweiss, A. (Andreas), Yang, R. (Rongxi), Burwinkel, B. (Barbara), Figueroa, J.D. (Jonine), Chanock, S.J. (Stephen), Lissowska, J. (Jolanta), Sawyer, E.J. (Elinor), Tomlinson, I.P. (Ian), Kerin, M. (Michael), Miller, N. (Nicola), Brenner, H. (Hermann), Butterbach, K. (Katja), Holleczek, B. (B.), Kataja, V. (Vesa), Kosma, V-M. (Veli-Matti), Hartikainen, J.M. (J.), Li, J. (Jingmei), Brand, J.S. (Judith S.), Humphreys, M.K. (Manjeet), Devilee, P. (Peter), Tollenaar, R.A.E.M. (Rob), Seynaeve, C.M. (Caroline), Radice, P. (Paolo), Peterlongo, P. (Paolo), Manoukian, S. (Siranoush), Ficarazzi, F. (Filomena), Beckmann, M.W. (Matthias), Hein, R. (Rebecca), Ekici, A.B. (Arif), Balleine, R. (Rosemary), Phillips, K.-A. (Kelly-Anne), Benítez, J. (Javier), Zamora, M.P. (Pilar), Perez, J.I.A. (Jose Ignacio Arias), Menéndez, P. (Primitiva), Jakubowska, A. (Anna), Lubinski, J. (Jan), Gronwald, J. (Jacek), Durda, K. (Katarzyna), Hamann, U. (Ute), Kabisch, M. (Maria), Ulmer, H.U. (Hans), Rud̈iger, T. (Thomas), Margolin, S. (Sara), Kristensen, V. (Vessela), Nord, S. (Siljie), Evans, D.G. (Gareth), Abraham, J. (Jean), Earl, H. (Helena), Poole, C.J. (Christopher J.), Hiller, L. (Louise), Dunn, J.A. (J.), Bowden, S. (Sarah), Yang, R. (Rose), Campa, D. (Daniele), Diver, W.R. (Ryan), Gapstur, S.M. (Susan M.), Gaudet, M.M. (Mia), Hankinson, S.E. (Susan), Hoover, R.N. (Robert), Hüsing, A. (Anika), Kaaks, R. (Rudolf), Machiela, M.J. (Mitchell J.), Willett, W.C. (Walter C.), Barrdahl, M. (Myrto), Canzian, F. (Federico), Chin, S.-F. (Suet-Feung), Caldas, C. (Carlos), Hunter, D. (David), Lindstrom, S. (Stephen), García-Closas, M. (Montserrat), Couch, F.J. (Fergus), Chenevix-Trench, G. (Georgia), Mannermaa, A. (Arto), Andrulis, I.L. (Irene), Hall, P. (Per), Chang-Claude, J. (Jenny), Easton, D.F. (Douglas), Bojesen, S.E. (Stig), Cox, A. (Angela), Fasching, P.A. (Peter), Pharoah, P.D.P. (Paul), Schmidt, M.K. (Marjanka), Pirie, A. (Ailith), Guo, Q. (Qi), Kraft, P. (Peter), Canisius, S. (Sander), Eccles, D. (Diana), Rahman, N. (Nazneen), Nevanlinna, H. (Heli), Chen, C. (Constance), Khan, S. (Sofia), Tyrer, J.P. (Jonathan), Bolla, M.K. (Manjeet), Wang, Q. (Qing), Dennis, J. (Joe), Michailidou, K. (Kyriaki), Lush, M. (Michael), Dunning, A.M. (Alison), Shah, M. (Mitul), Czene, K. (Kamila), Darabi, H. (Hatef), Eriksson, M. (Mats), Lambrechts, D. (Diether), Weltens, C. (Caroline), Leunen, K., van Ongeval, C. (Chantal), Nordestgaard, B.G. (Børge), Nielsen, S.F. (Sune), Flyger, H. (Henrik), Rudolph, A. (Anja), Seibold, P. (Petra), Flesch-Janys, D. (Dieter), Blomqvist, C. (Carl), Aittomäki, K. (Kristiina), Fagerholm, R. (Rainer), Muranen, T.A. (Taru), Olsen, J.E. (Janet E.), Hallberg, B. (Boubou), Vachon, C. (Celine), Knight, J.A. (Julia), Glendon, G. (Gord), Mulligan, A.M. (Anna Marie), Broeks, A. (Annegien), Cornelissen, S. (Sten), Haiman, C.A. (Christopher), Henderson, B.E. (Brian), Schumacher, F. (Frederick), Le Marchand, L. (Loic), Hopper, J.L. (John), Tsimiklis, H. (Helen), Apicella, C. (Carmel), Southey, M.C. (Melissa), Cross, S.S. (Simon), Reed, M.W.R. (Malcolm), Giles, G.G. (Graham), Milne, R.L. (Roger), McLean, C.A. (Catriona Ann), Winqvist, R. (Robert), Pykäs, K. (Katri), Jukkola-Vuorinen, A. (Arja), Grip, M. (Mervi), Hooning, M.J. (Maartje), Hollestelle, A. (Antoinette), Martens, J.W.M. (John), Ouweland, A.M.W. (Ans) van den, Marme, F. (Federick), Schneeweiss, A. (Andreas), Yang, R. (Rongxi), Burwinkel, B. (Barbara), Figueroa, J.D. (Jonine), Chanock, S.J. (Stephen), Lissowska, J. (Jolanta), Sawyer, E.J. (Elinor), Tomlinson, I.P. (Ian), Kerin, M. (Michael), Miller, N. (Nicola), Brenner, H. (Hermann), Butterbach, K. (Katja), Holleczek, B. (B.), Kataja, V. (Vesa), Kosma, V-M. (Veli-Matti), Hartikainen, J.M. (J.), Li, J. (Jingmei), Brand, J.S. (Judith S.), Humphreys, M.K. (Manjeet), Devilee, P. (Peter), Tollenaar, R.A.E.M. (Rob), Seynaeve, C.M. (Caroline), Radice, P. (Paolo), Peterlongo, P. (Paolo), Manoukian, S. (Siranoush), Ficarazzi, F. (Filomena), Beckmann, M.W. (Matthias), Hein, R. (Rebecca), Ekici, A.B. (Arif), Balleine, R. (Rosemary), Phillips, K.-A. (Kelly-Anne), Benítez, J. (Javier), Zamora, M.P. (Pilar), Perez, J.I.A. (Jose Ignacio Arias), Menéndez, P. (Primitiva), Jakubowska, A. (Anna), Lubinski, J. (Jan), Gronwald, J. (Jacek), Durda, K. (Katarzyna), Hamann, U. (Ute), Kabisch, M. (Maria), Ulmer, H.U. (Hans), Rud̈iger, T. (Thomas), Margolin, S. (Sara), Kristensen, V. (Vessela), Nord, S. (Siljie), Evans, D.G. (Gareth), Abraham, J. (Jean), Earl, H. (Helena), Poole, C.J. (Christopher J.), Hiller, L. (Louise), Dunn, J.A. (J.), Bowden, S. (Sarah), Yang, R. (Rose), Campa, D. (Daniele), Diver, W.R. (Ryan), Gapstur, S.M. (Susan M.), Gaudet, M.M. (Mia), Hankinson, S.E. (Susan), Hoover, R.N. (Robert), Hüsing, A. (Anika), Kaaks, R. (Rudolf), Machiela, M.J. (Mitchell J.), Willett, W.C. (Walter C.), Barrdahl, M. (Myrto), Canzian, F. (Federico), Chin, S.-F. (Suet-Feung), Caldas, C. (Carlos), Hunter, D. (David), Lindstrom, S. (Stephen), García-Closas, M. (Montserrat), Couch, F.J. (Fergus), Chenevix-Trench, G. (Georgia), Mannermaa, A. (Arto), Andrulis, I.L. (Irene), Hall, P. (Per), Chang-Claude, J. (Jenny), Easton, D.F. (Douglas), Bojesen, S.E. (Stig), Cox, A. (Angela), Fasching, P.A. (Peter), Pharoah, P.D.P. (Paul), and Schmidt, M.K. (Marjanka)

Abstract

Introduction: Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with breast cancer-specific survival using data from a pooled analysis of eight breast cancer survival genome-wide association studies (GWAS) from the Breast Cancer Association Consortium. Methods: A literature review was conducted of all previously published associations between common germline variants and three survival outcomes: breast cancer-specific survival, overall survival and disease-free survival. All associations that reached the nominal significance level of P value <0.05 were included. Single nucleotide polymorphisms that had been previously reported as nominally associated with at least one survival outcome were evaluated in the pooled analysis of over 37,000 breast cancer cases for association with breast cancer-specific survival. Previous associations were evaluated using a one-sided test based on the reported direction of effect. Results: Fifty-six variants from 45 previous publications were evaluated in the meta-analysis. Fifty-four of these were evaluated in the full set of 37,954 breast cancer cases with 2,900 events and the two additional variants were evaluated in a reduced sample size of 30,000 samples in order to ensure independence from the previously published studies. Five variants reached nominal significance (P <0.05) in the pooled GWAS data compared to 2.8 expected under the null hypothesis. Seven additional variants were associated (P <0.05) with ER-positive disease. Conclusions: Although no variants reached genome-wide significance (P <5 x 10-8), these results suggest that there is some evidence of association between candidate common germline variants an

Published
2015
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7. Candidate genetic modifiers for breast and ovarian cancer risk inBRCA1andBRCA2 mutation carriers

Author

Peterlongo, P. (Paolo), Chang-Claude, J. (Jenny), Moysich, K.B. (Kirsten), Rudolph, A. (Anja), Schmutzler, R.K. (Rita), Simard, J. (Jacques), Soucy, P. (Penny), Eeles, R. (Rosalind), Easton, D.F. (Douglas), Hamann, U. (Ute), Wilkening, S. (Stefan), Chen, B. (Bowang), Rookus, M.A. (Matti), Schmidt, M.K. (Marjanka), Baan, F.H. (Frederieke) van der, Spurdle, A.B. (Amanda), Walker, L.C. (Logan), Lose, F. (Felicity), Maia, A.-T. (Ana-Teresa), Montagna, M. (Marco), Matricardi, L. (Laura), Lubinski, J. (Jan), Jakubowska, A. (Anna), Garcia, E.B.G., Olopade, O.I. (Olofunmilayo), Nussbaum, R.L. (Robert L.), Nathanson, K.L. (Katherine), Domchek, S.M. (Susan), Rebbeck, R. (Timothy), Arun, B.K. (Banu), Karlan, B.Y. (Beth), Orsulic, S. (Sandra), Lester, K.J. (Kathryn), Chung, W.K. (Wendy K.), Miron, A. (Alexander), Southey, M.C. (Melissa), Goldgar, D. (David), Buys, S.S. (Saundra), Janavicius, R. (Ramunas), Dorfling, C.M. (Cecilia), Rensburg, E.J. (Elizabeth) van, Ding, Y.C. (Yuan Chun), Neuhausen, S.L. (Susan), Hansen, T.V.O. (Thomas), Gerdes, A.-M. (Anne-Marie), Ejlertsen, B. (Bent), Jønson, L. (Lars), Osorio, A. (Ana), Martínez-Bouzas, C. (Cristina), Benítez, J. (Javier), Conway, E.E. (Edye E.), Blazer, K.R. (Kathleen R.), Weitzel, J.N. (Jeffrey), Manoukian, S. (Siranoush), Peissel, B. (Bernard), Zaffaroni, D. (Daniela), Scuvera, G. (Giulietta), Barile, M. (Monica), Ficarazzi, F. (Filomena), Mariette, F. (F.), Fortuzzi, S. (S.), Viel, A. (Alessandra), Giannini, G. (Giuseppe), Papi, L. (Laura), Martayan, A. (Aline), Tibiletti, M.G. (Maria Grazia), Radice, P. (Paolo), Vratimos, A. (Athanassios), Fostira, F. (Florentia), Garber, J. (Judy), Donaldson, A. (Alan), Brewer, C. (Carole), Foo, C. (Claire), Evans, D.G. (Gareth), Frost, D. (Debra), Eccles, D. (Diana), Brady, A. (A.), Cook, J. (Jackie), Tischkowitz, M. (Marc), Adlard, L., Barwell, J. (Julian), Walker, L.J. (Lisa), Izatt, L. (Louise), Side, L. (Lucy), Kennedy, M.J. (John), Rogers, M.T. (Mark), Porteous, M.E. (Mary), Morrison, P.J. (Patrick), Platte, R. (Radka), Davidson, R. (Rosemarie), Hodgson, S. (Shirley), Ellis, S.D. (Steve), Cole, T. (Trevor), Godwin, A.K. (Andrew), Claes, K.B.M. (Kathleen B.M.), Van Maerken, T. (Tom), Meindl, A. (Alfons), Gehrig, P.A. (Paola A.), Sutter, C. (Christian), Engel, C. (Christoph), Niederacher, D. (Dieter), Steinemann, D. (Doris), Plendl, H. (Hansjoerg), Kast, K. (Karin), Rhiem, K. (Kerstin), Ditsch, N. (Nina), Arnold, N. (Norbert), Varon-Mateeva, R. (Raymonda), Wapenschmidt, B. (Barbara), Wang-Gohrke, S. (Shan), Bressac-de Paillerets, B. (Brigitte), Buecher, B. (Bruno), Delnatte, C.D. (Capucine), Houdayer, C. (Claude), Stoppa-Lyonnet, D. (Dominique), Damiola, F. (Francesca), Coupier, I. (Isabelle), Barjhoux, L. (Laure), Vénat-Bouvet, L. (Laurence), Golmard, L. (Lisa), Boutry-Kryza, N. (N.), Sinilnikova, O. (Olga), Caron, O. (Olivier), Pujol, P. (Pascal), Mazoyer, S. (Sylvie), Belotti, M. (Muriel), Piedmonte, M. (Marion), Friedlander, M.L. (Michael L.), Rodriguez, G. (Gustavo), Copeland, L.J. (Larry J.), Hoya, M. (Miguel) de La, Perez-Segura, P. (Pedro), Nevanlinna, H. (Heli), Aittomäki, K. (Kristiina), Os, T.A.M. (Theo) van, Meijers-Heijboer, E.J. (Hanne), Hout, A.H. (Annemarie) van der, Vreeswijk, M.P. (Maaike), Hoogerbrugge, N. (Nicoline), Ausems, M.G.E.M. (Margreet), Doorn, H.C. (Lena) van, Collée, J.M. (Margriet), Olah, E., Díez, O. (Orland), Blanco, I. (Ignacio), Lázaro, C. (Conxi), Brunet, J. (Joan), Feliubadaló, L. (L.), Cybulski, C. (Cezary), Gronwald, J. (Jacek), Durda, K. (Katarzyna), Jaworska-Bieniek, K. (Katarzyna), Sukiennicki, G. (Grzegorz), Arason, A. (Adalgeir), Chiquette, J. (Jocelyne), Teixeira, P.J., Olswold, C. (Curtis), Couch, F.J. (Fergus), Lindor, N.M. (Noralane), Wang, X. (X.), Szabo, C. (Csilla), Offit, K. (Kenneth), Corines, M. (Marina), Jacobs, L. (Lauren), Robson, M.E. (Mark E.), Zhang, L. (Lingling), Joseph, V. (Vijai), Berger, A. (Andreas), Singer, C.F. (Christian), Rappaport, C. (Christine), Kaulich, D.G. (Daphne Gschwantler), Pfeiler, G. (Georg), Tea, M.-K., Phelan, C. (Catherine), Greene, M.H. (Mark), Mai, P.L. (Phuong), Rennert, G. (Gad), Mulligan, A.-M. (Anna-Marie), Glendon, G. (Gord), Tchatchou, S. (Sandrine), Andrulis, I.L. (Irene), Toland, A.E. (Amanda), Bojesen, A. (Anders), Pedersen, I.S. (Inge Sokilde), Thomassen, M. (Mads), Jensen, U.B., Laitman, Y. (Yael), Rantala, J. (Johanna), Wachenfeldt, A. (Anna) von, Ehrencrona, H. (Hans), Askmalm, M.S. (Marie), Borg, Å. (Åke), Kuchenbaecker, K.B. (Karoline), McGuffog, L. (Lesley), Barrowdale, D. (Daniel), Healey, S. (Sue), Lee, A. (Andrew), Pharoah, P.D.P. (Paul D.P.), Chenevix-Trench, G. (Georgia), Antoniou, A.C. (Antonis), Friedman, E. (Eitan), Peterlongo, P. (Paolo), Chang-Claude, J. (Jenny), Moysich, K.B. (Kirsten), Rudolph, A. (Anja), Schmutzler, R.K. (Rita), Simard, J. (Jacques), Soucy, P. (Penny), Eeles, R. (Rosalind), Easton, D.F. (Douglas), Hamann, U. (Ute), Wilkening, S. (Stefan), Chen, B. (Bowang), Rookus, M.A. (Matti), Schmidt, M.K. (Marjanka), Baan, F.H. (Frederieke) van der, Spurdle, A.B. (Amanda), Walker, L.C. (Logan), Lose, F. (Felicity), Maia, A.-T. (Ana-Teresa), Montagna, M. (Marco), Matricardi, L. (Laura), Lubinski, J. (Jan), Jakubowska, A. (Anna), Garcia, E.B.G., Olopade, O.I. (Olofunmilayo), Nussbaum, R.L. (Robert L.), Nathanson, K.L. (Katherine), Domchek, S.M. (Susan), Rebbeck, R. (Timothy), Arun, B.K. (Banu), Karlan, B.Y. (Beth), Orsulic, S. (Sandra), Lester, K.J. (Kathryn), Chung, W.K. (Wendy K.), Miron, A. (Alexander), Southey, M.C. (Melissa), Goldgar, D. (David), Buys, S.S. (Saundra), Janavicius, R. (Ramunas), Dorfling, C.M. (Cecilia), Rensburg, E.J. (Elizabeth) van, Ding, Y.C. (Yuan Chun), Neuhausen, S.L. (Susan), Hansen, T.V.O. (Thomas), Gerdes, A.-M. (Anne-Marie), Ejlertsen, B. (Bent), Jønson, L. (Lars), Osorio, A. (Ana), Martínez-Bouzas, C. (Cristina), Benítez, J. (Javier), Conway, E.E. (Edye E.), Blazer, K.R. (Kathleen R.), Weitzel, J.N. (Jeffrey), Manoukian, S. (Siranoush), Peissel, B. (Bernard), Zaffaroni, D. (Daniela), Scuvera, G. (Giulietta), Barile, M. (Monica), Ficarazzi, F. (Filomena), Mariette, F. (F.), Fortuzzi, S. (S.), Viel, A. (Alessandra), Giannini, G. (Giuseppe), Papi, L. (Laura), Martayan, A. (Aline), Tibiletti, M.G. (Maria Grazia), Radice, P. (Paolo), Vratimos, A. (Athanassios), Fostira, F. (Florentia), Garber, J. (Judy), Donaldson, A. (Alan), Brewer, C. (Carole), Foo, C. (Claire), Evans, D.G. (Gareth), Frost, D. (Debra), Eccles, D. (Diana), Brady, A. (A.), Cook, J. (Jackie), Tischkowitz, M. (Marc), Adlard, L., Barwell, J. (Julian), Walker, L.J. (Lisa), Izatt, L. (Louise), Side, L. (Lucy), Kennedy, M.J. (John), Rogers, M.T. (Mark), Porteous, M.E. (Mary), Morrison, P.J. (Patrick), Platte, R. (Radka), Davidson, R. (Rosemarie), Hodgson, S. (Shirley), Ellis, S.D. (Steve), Cole, T. (Trevor), Godwin, A.K. (Andrew), Claes, K.B.M. (Kathleen B.M.), Van Maerken, T. (Tom), Meindl, A. (Alfons), Gehrig, P.A. (Paola A.), Sutter, C. (Christian), Engel, C. (Christoph), Niederacher, D. (Dieter), Steinemann, D. (Doris), Plendl, H. (Hansjoerg), Kast, K. (Karin), Rhiem, K. (Kerstin), Ditsch, N. (Nina), Arnold, N. (Norbert), Varon-Mateeva, R. (Raymonda), Wapenschmidt, B. (Barbara), Wang-Gohrke, S. (Shan), Bressac-de Paillerets, B. (Brigitte), Buecher, B. (Bruno), Delnatte, C.D. (Capucine), Houdayer, C. (Claude), Stoppa-Lyonnet, D. (Dominique), Damiola, F. (Francesca), Coupier, I. (Isabelle), Barjhoux, L. (Laure), Vénat-Bouvet, L. (Laurence), Golmard, L. (Lisa), Boutry-Kryza, N. (N.), Sinilnikova, O. (Olga), Caron, O. (Olivier), Pujol, P. (Pascal), Mazoyer, S. (Sylvie), Belotti, M. (Muriel), Piedmonte, M. (Marion), Friedlander, M.L. (Michael L.), Rodriguez, G. (Gustavo), Copeland, L.J. (Larry J.), Hoya, M. (Miguel) de La, Perez-Segura, P. (Pedro), Nevanlinna, H. (Heli), Aittomäki, K. (Kristiina), Os, T.A.M. (Theo) van, Meijers-Heijboer, E.J. (Hanne), Hout, A.H. (Annemarie) van der, Vreeswijk, M.P. (Maaike), Hoogerbrugge, N. (Nicoline), Ausems, M.G.E.M. (Margreet), Doorn, H.C. (Lena) van, Collée, J.M. (Margriet), Olah, E., Díez, O. (Orland), Blanco, I. (Ignacio), Lázaro, C. (Conxi), Brunet, J. (Joan), Feliubadaló, L. (L.), Cybulski, C. (Cezary), Gronwald, J. (Jacek), Durda, K. (Katarzyna), Jaworska-Bieniek, K. (Katarzyna), Sukiennicki, G. (Grzegorz), Arason, A. (Adalgeir), Chiquette, J. (Jocelyne), Teixeira, P.J., Olswold, C. (Curtis), Couch, F.J. (Fergus), Lindor, N.M. (Noralane), Wang, X. (X.), Szabo, C. (Csilla), Offit, K. (Kenneth), Corines, M. (Marina), Jacobs, L. (Lauren), Robson, M.E. (Mark E.), Zhang, L. (Lingling), Joseph, V. (Vijai), Berger, A. (Andreas), Singer, C.F. (Christian), Rappaport, C. (Christine), Kaulich, D.G. (Daphne Gschwantler), Pfeiler, G. (Georg), Tea, M.-K., Phelan, C. (Catherine), Greene, M.H. (Mark), Mai, P.L. (Phuong), Rennert, G. (Gad), Mulligan, A.-M. (Anna-Marie), Glendon, G. (Gord), Tchatchou, S. (Sandrine), Andrulis, I.L. (Irene), Toland, A.E. (Amanda), Bojesen, A. (Anders), Pedersen, I.S. (Inge Sokilde), Thomassen, M. (Mads), Jensen, U.B., Laitman, Y. (Yael), Rantala, J. (Johanna), Wachenfeldt, A. (Anna) von, Ehrencrona, H. (Hans), Askmalm, M.S. (Marie), Borg, Å. (Åke), Kuchenbaecker, K.B. (Karoline), McGuffog, L. (Lesley), Barrowdale, D. (Daniel), Healey, S. (Sue), Lee, A. (Andrew), Pharoah, P.D.P. (Paul D.P.), Chenevix-Trench, G. (Georgia), Antoniou, A.C. (Antonis), and Friedman, E. (Eitan)

Abstract

Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants inmany candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysiswas performed within a retrospective cohort approach. Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.

Published
2015
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8. Common germline polymorphisms associated with breast cancer-specific survival

Author

Pirie, A, Guo, Q, Kraft, P, Canisius, S, Eccles, DM, Rahman, N, Nevanlinna, H, Chen, C, Khan, S, Tyrer, J, Bolla, MK, Wang, Q, Dennis, J, Michailidou, K, Lush, M, Dunning, AM, Shah, M, Czene, K, Darabi, H, Eriksson, M, Lambrechts, D, Weltens, C, Leunen, K, van Ongeval, C, Nordestgaard, BG, Nielsen, SF, Flyger, H, Rudolph, A, Seibold, P, Flesch-Janys, D, Blomqvist, C, Aittomaki, K, Fagerholm, R, Muranen, TA, Olsen, JE, Hallberg, E, Vachon, C, Knight, JA, Glendon, G, Mulligan, AM, Broeks, A, Cornelissen, S, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Hopper, JL, Tsimiklis, H, Apicella, C, Southey, MC, Cross, SS, Reed, MWR, Giles, GG, Milne, RL, McLean, C, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Hooning, MJ, Hollestelle, A, Martens, JWM, van den Ouweland, AMW, Marme, F, Schneeweiss, A, Yang, R, Burwinkel, B, Figueroa, J, Chanock, SJ, Lissowska, J, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Brenner, H, Butterbach, K, Holleczek, B, Kataja, V, Kosma, V-M, Hartikainen, JM, Li, J, Brand, JS, Humphreys, K, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Radice, P, Peterlongo, P, Manoukian, S, Ficarazzi, F, Beckmann, MW, Hein, A, Ekici, AB, Balleine, R, Phillips, K-A, Benitez, J, Zamora, MP, Perez, JIA, Menendez, P, Jakubowska, A, Lubinski, J, Gronwald, J, Durda, K, Hamann, U, Kabisch, M, Ulmer, HU, Ruediger, T, Margolin, S, Kristensen, V, Nord, S, Evans, DG, Abraham, J, Earl, H, Poole, CJ, Hiller, L, Dunn, JA, Bowden, S, Campa, D, Diver, WR, Gapstur, SM, Gaudet, MM, Hankinson, S, Hoover, RN, Husing, A, Kaaks, R, Machiela, MJ, Willett, W, Barrdahl, M, Canzian, F, Chin, S-F, Caldas, C, Hunter, DJ, Lindstrom, S, Garcia-Closas, M, Couch, FJ, Chenevix-Trench, G, Mannermaa, A, Andrulis, IL, Hall, P, Chang-Claude, J, Easton, DF, Bojesen, SE, Cox, A, Fasching, PA, Pharoah, PDP, Schmidt, MK, Pirie, A, Guo, Q, Kraft, P, Canisius, S, Eccles, DM, Rahman, N, Nevanlinna, H, Chen, C, Khan, S, Tyrer, J, Bolla, MK, Wang, Q, Dennis, J, Michailidou, K, Lush, M, Dunning, AM, Shah, M, Czene, K, Darabi, H, Eriksson, M, Lambrechts, D, Weltens, C, Leunen, K, van Ongeval, C, Nordestgaard, BG, Nielsen, SF, Flyger, H, Rudolph, A, Seibold, P, Flesch-Janys, D, Blomqvist, C, Aittomaki, K, Fagerholm, R, Muranen, TA, Olsen, JE, Hallberg, E, Vachon, C, Knight, JA, Glendon, G, Mulligan, AM, Broeks, A, Cornelissen, S, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Hopper, JL, Tsimiklis, H, Apicella, C, Southey, MC, Cross, SS, Reed, MWR, Giles, GG, Milne, RL, McLean, C, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Hooning, MJ, Hollestelle, A, Martens, JWM, van den Ouweland, AMW, Marme, F, Schneeweiss, A, Yang, R, Burwinkel, B, Figueroa, J, Chanock, SJ, Lissowska, J, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Brenner, H, Butterbach, K, Holleczek, B, Kataja, V, Kosma, V-M, Hartikainen, JM, Li, J, Brand, JS, Humphreys, K, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Radice, P, Peterlongo, P, Manoukian, S, Ficarazzi, F, Beckmann, MW, Hein, A, Ekici, AB, Balleine, R, Phillips, K-A, Benitez, J, Zamora, MP, Perez, JIA, Menendez, P, Jakubowska, A, Lubinski, J, Gronwald, J, Durda, K, Hamann, U, Kabisch, M, Ulmer, HU, Ruediger, T, Margolin, S, Kristensen, V, Nord, S, Evans, DG, Abraham, J, Earl, H, Poole, CJ, Hiller, L, Dunn, JA, Bowden, S, Campa, D, Diver, WR, Gapstur, SM, Gaudet, MM, Hankinson, S, Hoover, RN, Husing, A, Kaaks, R, Machiela, MJ, Willett, W, Barrdahl, M, Canzian, F, Chin, S-F, Caldas, C, Hunter, DJ, Lindstrom, S, Garcia-Closas, M, Couch, FJ, Chenevix-Trench, G, Mannermaa, A, Andrulis, IL, Hall, P, Chang-Claude, J, Easton, DF, Bojesen, SE, Cox, A, Fasching, PA, Pharoah, PDP, and Schmidt, MK

Abstract

INTRODUCTION: Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with breast cancer-specific survival using data from a pooled analysis of eight breast cancer survival genome-wide association studies (GWAS) from the Breast Cancer Association Consortium. METHODS: A literature review was conducted of all previously published associations between common germline variants and three survival outcomes: breast cancer-specific survival, overall survival and disease-free survival. All associations that reached the nominal significance level of P value <0.05 were included. Single nucleotide polymorphisms that had been previously reported as nominally associated with at least one survival outcome were evaluated in the pooled analysis of over 37,000 breast cancer cases for association with breast cancer-specific survival. Previous associations were evaluated using a one-sided test based on the reported direction of effect. RESULTS: Fifty-six variants from 45 previous publications were evaluated in the meta-analysis. Fifty-four of these were evaluated in the full set of 37,954 breast cancer cases with 2,900 events and the two additional variants were evaluated in a reduced sample size of 30,000 samples in order to ensure independence from the previously published studies. Five variants reached nominal significance (P <0.05) in the pooled GWAS data compared to 2.8 expected under the null hypothesis. Seven additional variants were associated (P <0.05) with ER-positive disease. CONCLUSIONS: Although no variants reached genome-wide significance (P <5 x 10(-8)), these results suggest that there is some evidence of association between candidate common germline variants and breast cancer prognosis. Larger studies from multinational collaborations are necessary to increase the

Published
2015

9. The rs12975333 variant in the miR-125a and breast cancer risk in Germany, Italy, Australia and Spain

Author

Peterlongo, P., primary, Caleca, L., additional, Cattaneo, E., additional, Ravagnani, F., additional, Bianchi, T., additional, Galastri, L., additional, Bernard, L., additional, Ficarazzi, F., additional, Dall'olio, V., additional, Marme, F., additional, Langheinz, A., additional, Sohn, C., additional, Burwinkel, B., additional, Giles, G. G., additional, Baglietto, L., additional, Severi, G., additional, Odefrey, F. A., additional, Southey, M. C., additional, Osorio, A., additional, Fernandez, F., additional, Alonso, M. R., additional, Benitez, J., additional, Barile, M., additional, Peissel, B., additional, Manoukian, S., additional, and Radice, P., additional

Published
2011
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10. Haplotype analyses of the c.1027CT and c.2167_2168delAT recurrent truncating mutations in the breast cancer-predisposing gene PALB2

Author

Sara Volorio, Paolo Peterlongo, Jeffrey N. Weitzel, Susan L. Neuhausen, Carlo Tondini, Marina Marchetti, Tom Walsh, Silvia Casadei, Jessica B. Mandell, Aaron Adamson, Paolo Radice, Yuan Chun Ding, Siranoush Manoukian, Olufunmilayo I. Olopade, Filomena Ficarazzi, Anna Falanga, Charité Ricker, Irene Catucci, Mary Claire King, Michela Franchi, Catucci, I, Casadei, S, Ding, Y, Volorio, S, Ficarazzi, F, Falanga, A, Marchetti, M, Tondini, C, Franchi, M, Adamson, A, Mandell, J, Walsh, T, Olopade, O, Manoukian, S, Radice, P, Ricker, C, Weitzel, J, King, M, Peterlongo, P, and Neuhausen, S

Subjects
0301 basic medicine, Cancer Research, Heterozygote, PALB2, Population, Breast Neoplasms, Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Chromosome 16, Breast cancer, medicine, Humans, Genetic Predisposition to Disease, Allele, education, Alleles, Genetic Association Studies, Genetics, education.field_of_study, Haplotype, Breast cancer, Founder mutations, Haplotype, PALB2, Breast Neoplasms, Fanconi Anemia Complementation Group N Protein, Female, Founder Effect, Genetic Association Studies, Heterozygote, Humans, Italy, Microsatellite Repeats, Pedigree, Alleles, Genetic Predisposition to Disease, Haplotypes, Mutation, medicine.disease, Founder Effect, Pedigree, 030104 developmental biology, Oncology, Haplotypes, Italy, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), Mutation, Female, Fanconi Anemia Complementation Group N Protein, Founder effect, Microsatellite Repeats
Abstract

Purpose: Breast cancer-predisposing mutations PALB2 c.1027C>T (p.Gln343*) and PALB2 c.2167_2168delAT have each been observed multiple times in breast cancer families of Italian ancestry. More recently, the c2167_2168delAT mutation was identified in unrelated breast cancer cases of various ancestries. For each mutation, we investigated whether the origin was multiple mutational events (a “hot-spot”) or a single event (a founder allele). Methods: We genotyped and reconstructed haplotypes for 36 participants of Italian, Italian-American, Hispanic, and Nigerian ancestries, using seven short tandem repeat (STR) markers that covered 3 Megabases within and flanking PALB2 on chromosome 16. Results: For PALB2 c.1027C>T, a shared haplotype with a minimum size of 150kb was shared by all 19 carriers investigated, all of Italian ancestry. This result suggests that this allele arose as a single event in a shared ancestor. For PALB2 c.2167_2168delAT, all 12 carriers from American-Italian and Italian families shared a 1-Mb haplotype, the 3 Hispanic carriers shared a different haplotype of size 2Mb, and the Nigerian carrier had different alleles at all 7 STR markers. These results suggest that PALB2 c.2167_2168delAT arose multiple times, but that within each population, PALB2 c.2167_2168delAT likely represents a single mutational event. Conclusion: We identified two PALB2 mutations that are founder alleles in Italian families, one of which is, independently, also a founder mutation in American-Hispanic breast cancers.

Published
2016

11. Towards population-based genetic screenings for breast and ovarian cancer: A comprehensive review from economic evaluations to patient perspectives.

Author

Ficarazzi F, Vecchi M, Ferrari M, and Pierotti MA

Subjects
Cost-Benefit Analysis, Early Detection of Cancer, Female, Genetic Predisposition to Disease, Genetic Testing, Humans, Breast Neoplasms diagnosis, Breast Neoplasms genetics, Ovarian Neoplasms diagnosis, Ovarian Neoplasms genetics
Abstract

Genetic testing for hereditary breast and ovarian cancer following genetic counseling is based on guidelines that take into account particular features of the personal and family history, and clinical criteria conferring a probability of having a BRCA mutation greater than 10% as a threshold for accessing the test. However, besides reducing mortality and social impact, the extension of screening programs also for healthy family members would allow a huge saving of the rising costs associated with these pathologies, supporting the choice of the "Test" strategy versus a "No Test" one. Analyses of different health care systems show that by applying the "Test" strategy on patients and their families, a decrease in breast and ovarian cancer cases is achieved, as well as a substantial decrease in costs of economic resources, including the costs of the clinical management of early detected tumors. In this review, we analyzed the most recent papers published on this topic and we summarized the findings on the economic evaluations related to breast and ovarian cancer population screenings. These results proved and validated that the population-wide testing approach is a more accurate screening and preventive intervention than traditional guidelines based on personal/family history and clinical criteria to reduce breast and ovarian cancer risk., Competing Interests: Declaration of competing interest FF, MV and MAP are employees of Cogentech Ltd Benefit Corporation, MF is a consultant for Cogentech srl activities. Cogentech Ltd Benefit Corporation is a private limited company owned by the no-profit research institute IFOM (FIRC Institute of Molecular Oncology) whose mission is to provide technological services for the post-genomic era to researchers and clinicians. Cogentech services are dedicated to members of the international scientific community and clinicians who wish to use them for diagnostic purposes. Cogentech specifically, provides and develops genetic tests of susceptibility to various hereditary cancers including those related to the evaluation of BRCA gene mutations in patients with breast and ovarian cancer. In this perspective, the topic of the manuscript is related to general public benefits and a positive impact on cancer patients and society, at large, interests that are part of the mission of Cogentech Ltd Benefit Corporation activity. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2021
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12. Haplotype analyses of the c.1027C>T and c.2167&#95;2168delAT recurrent truncating mutations in the breast cancer-predisposing gene PALB2.

Author

Catucci I, Casadei S, Ding YC, Volorio S, Ficarazzi F, Falanga A, Marchetti M, Tondini C, Franchi M, Adamson A, Mandell J, Walsh T, Olopade OI, Manoukian S, Radice P, Ricker C, Weitzel J, King MC, Peterlongo P, and Neuhausen SL

Subjects
Female, Founder Effect, Genetic Association Studies, Heterozygote, Humans, Italy, Microsatellite Repeats, Pedigree, Alleles, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Fanconi Anemia Complementation Group N Protein genetics, Genetic Predisposition to Disease, Haplotypes, Mutation
Abstract

Purpose: Breast cancer-predisposing mutations PALB2 c.1027C>T (p.Gln343*) and PALB2 c.2167&#95;2168delAT have each been observed multiple times in breast cancer families of Italian ancestry. More recently, the c2167&#95;2168delAT mutation was identified in unrelated breast cancer cases of various ancestries. For each mutation, we investigated whether the origin was multiple mutational events (a "hot-spot") or a single event (a founder allele)., Methods: We genotyped and reconstructed haplotypes for 36 participants of Italian, Italian-American, Hispanic, and Nigerian ancestries, using seven short tandem repeat (STR) markers that covered 3 Megabases within and flanking PALB2 on chromosome 16., Results: For PALB2 c.1027C>T, a shared haplotype with a minimum size of 150 kb was shared by all 19 carriers investigated, all of Italian ancestry. This result suggests that this allele arose as a single event in a shared ancestor. For PALB2 c.2167&#95;2168delAT, all 12 carriers from American-Italian and Italian families shared a 1-Mb haplotype, the 3 Hispanic carriers shared a different haplotype of size 2 Mb, and the Nigerian carrier had different alleles at all 7 STR markers. These results suggest that PALB2 c.2167&#95;2168delAT arose multiple times, but that within each population, PALB2 c.2167&#95;2168delAT likely represents a single mutational event., Conclusion: We identified two PALB2 mutations that are founder alleles in Italian families, one of which is, independently, also a founder mutation in American-Hispanic breast cancers.

Published
2016
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13. Common germline polymorphisms associated with breast cancer-specific survival.

Author

Pirie A, Guo Q, Kraft P, Canisius S, Eccles DM, Rahman N, Nevanlinna H, Chen C, Khan S, Tyrer J, Bolla MK, Wang Q, Dennis J, Michailidou K, Lush M, Dunning AM, Shah M, Czene K, Darabi H, Eriksson M, Lambrechts D, Weltens C, Leunen K, van Ongeval C, Nordestgaard BG, Nielsen SF, Flyger H, Rudolph A, Seibold P, Flesch-Janys D, Blomqvist C, Aittomäki K, Fagerholm R, Muranen TA, Olsen JE, Hallberg E, Vachon C, Knight JA, Glendon G, Mulligan AM, Broeks A, Cornelissen S, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Hopper JL, Tsimiklis H, Apicella C, Southey MC, Cross SS, Reed MW, Giles GG, Milne RL, McLean C, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Hooning MJ, Hollestelle A, Martens JW, van den Ouweland AM, Marme F, Schneeweiss A, Yang R, Burwinkel B, Figueroa J, Chanock SJ, Lissowska J, Sawyer EJ, Tomlinson I, Kerin MJ, Miller N, Brenner H, Butterbach K, Holleczek B, Kataja V, Kosma VM, Hartikainen JM, Li J, Brand JS, Humphreys K, Devilee P, Tollenaar RA, Seynaeve C, Radice P, Peterlongo P, Manoukian S, Ficarazzi F, Beckmann MW, Hein A, Ekici AB, Balleine R, Phillips KA, Benitez J, Zamora MP, Perez JI, Menéndez P, Jakubowska A, Lubinski J, Gronwald J, Durda K, Hamann U, Kabisch M, Ulmer HU, Rüdiger T, Margolin S, Kristensen V, Nord S, Evans DG, Abraham J, Earl H, Poole CJ, Hiller L, Dunn JA, Bowden S, Yang R, Campa D, Diver WR, Gapstur SM, Gaudet MM, Hankinson S, Hoover RN, Hüsing A, Kaaks R, Machiela MJ, Willett W, Barrdahl M, Canzian F, Chin SF, Caldas C, Hunter DJ, Lindstrom S, Garcia-Closas M, Couch FJ, Chenevix-Trench G, Mannermaa A, Andrulis IL, Hall P, Chang-Claude J, Easton DF, Bojesen SE, Cox A, Fasching PA, Pharoah PD, and Schmidt MK

Subjects
Female, Genetic Association Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Prognosis, Breast Neoplasms genetics, Breast Neoplasms mortality, Germ Cells metabolism, Polymorphism, Single Nucleotide
Abstract

Introduction: Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with breast cancer-specific survival using data from a pooled analysis of eight breast cancer survival genome-wide association studies (GWAS) from the Breast Cancer Association Consortium., Methods: A literature review was conducted of all previously published associations between common germline variants and three survival outcomes: breast cancer-specific survival, overall survival and disease-free survival. All associations that reached the nominal significance level of P value <0.05 were included. Single nucleotide polymorphisms that had been previously reported as nominally associated with at least one survival outcome were evaluated in the pooled analysis of over 37,000 breast cancer cases for association with breast cancer-specific survival. Previous associations were evaluated using a one-sided test based on the reported direction of effect., Results: Fifty-six variants from 45 previous publications were evaluated in the meta-analysis. Fifty-four of these were evaluated in the full set of 37,954 breast cancer cases with 2,900 events and the two additional variants were evaluated in a reduced sample size of 30,000 samples in order to ensure independence from the previously published studies. Five variants reached nominal significance (P <0.05) in the pooled GWAS data compared to 2.8 expected under the null hypothesis. Seven additional variants were associated (P <0.05) with ER-positive disease., Conclusions: Although no variants reached genome-wide significance (P <5 x 10(-8)), these results suggest that there is some evidence of association between candidate common germline variants and breast cancer prognosis. Larger studies from multinational collaborations are necessary to increase the power to detect associations, between common variants and prognosis, at more stringent significance levels.

Published
2015
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14. Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.

Author

Peterlongo P, Chang-Claude J, Moysich KB, Rudolph A, Schmutzler RK, Simard J, Soucy P, Eeles RA, Easton DF, Hamann U, Wilkening S, Chen B, Rookus MA, Schmidt MK, van der Baan FH, Spurdle AB, Walker LC, Lose F, Maia AT, Montagna M, Matricardi L, Lubinski J, Jakubowska A, Gómez Garcia EB, Olopade OI, Nussbaum RL, Nathanson KL, Domchek SM, Rebbeck TR, Arun BK, Karlan BY, Orsulic S, Lester J, Chung WK, Miron A, Southey MC, Goldgar DE, Buys SS, Janavicius R, Dorfling CM, van Rensburg EJ, Ding YC, Neuhausen SL, Hansen TV, Gerdes AM, Ejlertsen B, Jønson L, Osorio A, Martínez-Bouzas C, Benitez J, Conway EE, Blazer KR, Weitzel JN, Manoukian S, Peissel B, Zaffaroni D, Scuvera G, Barile M, Ficarazzi F, Mariette F, Fortuzzi S, Viel A, Giannini G, Papi L, Martayan A, Tibiletti MG, Radice P, Vratimos A, Fostira F, Garber JE, Donaldson A, Brewer C, Foo C, Evans DG, Frost D, Eccles D, Brady A, Cook J, Tischkowitz M, Adlard J, Barwell J, Walker L, Izatt L, Side LE, Kennedy MJ, Rogers MT, Porteous ME, Morrison PJ, Platte R, Davidson R, Hodgson SV, Ellis S, Cole T, Godwin AK, Claes K, Van Maerken T, Meindl A, Gehrig A, Sutter C, Engel C, Niederacher D, Steinemann D, Plendl H, Kast K, Rhiem K, Ditsch N, Arnold N, Varon-Mateeva R, Wappenschmidt B, Wang-Gohrke S, Bressac-de Paillerets B, Buecher B, Delnatte C, Houdayer C, Stoppa-Lyonnet D, Damiola F, Coupier I, Barjhoux L, Venat-Bouvet L, Golmard L, Boutry-Kryza N, Sinilnikova OM, Caron O, Pujol P, Mazoyer S, Belotti M, Piedmonte M, Friedlander ML, Rodriguez GC, Copeland LJ, de la Hoya M, Segura PP, Nevanlinna H, Aittomäki K, van Os TA, Meijers-Heijboer HE, van der Hout AH, Vreeswijk MP, Hoogerbrugge N, Ausems MG, van Doorn HC, Collée JM, Olah E, Diez O, Blanco I, Lazaro C, Brunet J, Feliubadalo L, Cybulski C, Gronwald J, Durda K, Jaworska-Bieniek K, Sukiennicki G, Arason A, Chiquette J, Teixeira MR, Olswold C, Couch FJ, Lindor NM, Wang X, Szabo CI, Offit K, Corines M, Jacobs L, Robson ME, Zhang L, Joseph V, Berger A, Singer CF, Rappaport C, Kaulich DG, Pfeiler G, Tea MK, Phelan CM, Greene MH, Mai PL, Rennert G, Mulligan AM, Glendon G, Tchatchou S, Andrulis IL, Toland AE, Bojesen A, Pedersen IS, Thomassen M, Jensen UB, Laitman Y, Rantala J, von Wachenfeldt A, Ehrencrona H, Askmalm MS, Borg Å, Kuchenbaecker KB, McGuffog L, Barrowdale D, Healey S, Lee A, Pharoah PD, Chenevix-Trench G, Antoniou AC, and Friedman E

Subjects
Adult, Cohort Studies, Female, Humans, Mutation, Polymorphism, Single Nucleotide, Retrospective Studies, Young Adult, Breast Neoplasms genetics, Genes, BRCA1 physiology, Genes, BRCA2 physiology, Ovarian Neoplasms genetics
Abstract

Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes., Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach., Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments., Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers., Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies., (©2014 American Association for Cancer Research.)

Published
2015
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15. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.

Author

Bojesen SE, Pooley KA, Johnatty SE, Beesley J, Michailidou K, Tyrer JP, Edwards SL, Pickett HA, Shen HC, Smart CE, Hillman KM, Mai PL, Lawrenson K, Stutz MD, Lu Y, Karevan R, Woods N, Johnston RL, French JD, Chen X, Weischer M, Nielsen SF, Maranian MJ, Ghoussaini M, Ahmed S, Baynes C, Bolla MK, Wang Q, Dennis J, McGuffog L, Barrowdale D, Lee A, Healey S, Lush M, Tessier DC, Vincent D, Bacot F, Vergote I, Lambrechts S, Despierre E, Risch HA, González-Neira A, Rossing MA, Pita G, Doherty JA, Alvarez N, Larson MC, Fridley BL, Schoof N, Chang-Claude J, Cicek MS, Peto J, Kalli KR, Broeks A, Armasu SM, Schmidt MK, Braaf LM, Winterhoff B, Nevanlinna H, Konecny GE, Lambrechts D, Rogmann L, Guénel P, Teoman A, Milne RL, Garcia JJ, Cox A, Shridhar V, Burwinkel B, Marme F, Hein R, Sawyer EJ, Haiman CA, Wang-Gohrke S, Andrulis IL, Moysich KB, Hopper JL, Odunsi K, Lindblom A, Giles GG, Brenner H, Simard J, Lurie G, Fasching PA, Carney ME, Radice P, Wilkens LR, Swerdlow A, Goodman MT, Brauch H, Garcia-Closas M, Hillemanns P, Winqvist R, Dürst M, Devilee P, Runnebaum I, Jakubowska A, Lubinski J, Mannermaa A, Butzow R, Bogdanova NV, Dörk T, Pelttari LM, Zheng W, Leminen A, Anton-Culver H, Bunker CH, Kristensen V, Ness RB, Muir K, Edwards R, Meindl A, Heitz F, Matsuo K, du Bois A, Wu AH, Harter P, Teo SH, Schwaab I, Shu XO, Blot W, Hosono S, Kang D, Nakanishi T, Hartman M, Yatabe Y, Hamann U, Karlan BY, Sangrajrang S, Kjaer SK, Gaborieau V, Jensen A, Eccles D, Høgdall E, Shen CY, Brown J, Woo YL, Shah M, Azmi MA, Luben R, Omar SZ, Czene K, Vierkant RA, Nordestgaard BG, Flyger H, Vachon C, Olson JE, Wang X, Levine DA, Rudolph A, Weber RP, Flesch-Janys D, Iversen E, Nickels S, Schildkraut JM, Silva Idos S, Cramer DW, Gibson L, Terry KL, Fletcher O, Vitonis AF, van der Schoot CE, Poole EM, Hogervorst FB, Tworoger SS, Liu J, Bandera EV, Li J, Olson SH, Humphreys K, Orlow I, Blomqvist C, Rodriguez-Rodriguez L, Aittomäki K, Salvesen HB, Muranen TA, Wik E, Brouwers B, Krakstad C, Wauters E, Halle MK, Wildiers H, Kiemeney LA, Mulot C, Aben KK, Laurent-Puig P, Altena AM, Truong T, Massuger LF, Benitez J, Pejovic T, Perez JI, Hoatlin M, Zamora MP, Cook LS, Balasubramanian SP, Kelemen LE, Schneeweiss A, Le ND, Sohn C, Brooks-Wilson A, Tomlinson I, Kerin MJ, Miller N, Cybulski C, Henderson BE, Menkiszak J, Schumacher F, Wentzensen N, Le Marchand L, Yang HP, Mulligan AM, Glendon G, Engelholm SA, Knight JA, Høgdall CK, Apicella C, Gore M, Tsimiklis H, Song H, Southey MC, Jager A, den Ouweland AM, Brown R, Martens JW, Flanagan JM, Kriege M, Paul J, Margolin S, Siddiqui N, Severi G, Whittemore AS, Baglietto L, McGuire V, Stegmaier C, Sieh W, Müller H, Arndt V, Labrèche F, Gao YT, Goldberg MS, Yang G, Dumont M, McLaughlin JR, Hartmann A, Ekici AB, Beckmann MW, Phelan CM, Lux MP, Permuth-Wey J, Peissel B, Sellers TA, Ficarazzi F, Barile M, Ziogas A, Ashworth A, Gentry-Maharaj A, Jones M, Ramus SJ, Orr N, Menon U, Pearce CL, Brüning T, Pike MC, Ko YD, Lissowska J, Figueroa J, Kupryjanczyk J, Chanock SJ, Dansonka-Mieszkowska A, Jukkola-Vuorinen A, Rzepecka IK, Pylkäs K, Bidzinski M, Kauppila S, Hollestelle A, Seynaeve C, Tollenaar RA, Durda K, Jaworska K, Hartikainen JM, Kosma VM, Kataja V, Antonenkova NN, Long J, Shrubsole M, Deming-Halverson S, Lophatananon A, Siriwanarangsan P, Stewart-Brown S, Ditsch N, Lichtner P, Schmutzler RK, Ito H, Iwata H, Tajima K, Tseng CC, Stram DO, van den Berg D, Yip CH, Ikram MK, Teh YC, Cai H, Lu W, Signorello LB, Cai Q, Noh DY, Yoo KY, Miao H, Iau PT, Teo YY, McKay J, Shapiro C, Ademuyiwa F, Fountzilas G, Hsiung CN, Yu JC, Hou MF, Healey CS, Luccarini C, Peock S, Stoppa-Lyonnet D, Peterlongo P, Rebbeck TR, Piedmonte M, Singer CF, Friedman E, Thomassen M, Offit K, Hansen TV, Neuhausen SL, Szabo CI, Blanco I, Garber J, Narod SA, Weitzel JN, Montagna M, Olah E, Godwin AK, Yannoukakos D, Goldgar DE, Caldes T, Imyanitov EN, Tihomirova L, Arun BK, Campbell I, Mensenkamp AR, van Asperen CJ, van Roozendaal KE, Meijers-Heijboer H, Collée JM, Oosterwijk JC, Hooning MJ, Rookus MA, van der Luijt RB, Os TA, Evans DG, Frost D, Fineberg E, Barwell J, Walker L, Kennedy MJ, Platte R, Davidson R, Ellis SD, Cole T, Bressac-de Paillerets B, Buecher B, Damiola F, Faivre L, Frenay M, Sinilnikova OM, Caron O, Giraud S, Mazoyer S, Bonadona V, Caux-Moncoutier V, Toloczko-Grabarek A, Gronwald J, Byrski T, Spurdle AB, Bonanni B, Zaffaroni D, Giannini G, Bernard L, Dolcetti R, Manoukian S, Arnold N, Engel C, Deissler H, Rhiem K, Niederacher D, Plendl H, Sutter C, Wappenschmidt B, Borg A, Melin B, Rantala J, Soller M, Nathanson KL, Domchek SM, Rodriguez GC, Salani R, Kaulich DG, Tea MK, Paluch SS, Laitman Y, Skytte AB, Kruse TA, Jensen UB, Robson M, Gerdes AM, Ejlertsen B, Foretova L, Savage SA, Lester J, Soucy P, Kuchenbaecker KB, Olswold C, Cunningham JM, Slager S, Pankratz VS, Dicks E, Lakhani SR, Couch FJ, Hall P, Monteiro AN, Gayther SA, Pharoah PD, Reddel RR, Goode EL, Greene MH, Easton DF, Berchuck A, Antoniou AC, Chenevix-Trench G, and Dunning AM

Subjects
Alternative Splicing, Breast Neoplasms pathology, Case-Control Studies, Chromatin genetics, DNA Methylation, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Luciferases metabolism, Oligonucleotide Array Sequence Analysis, Ovarian Neoplasms pathology, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Risk Factors, Biomarkers, Tumor genetics, Breast Neoplasms etiology, Genetic Loci genetics, Ovarian Neoplasms etiology, Polymorphism, Single Nucleotide genetics, Telomerase genetics, Telomere genetics
Abstract

TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.

Published
2013
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16. Comparative in vitro and in silico analyses of variants in splicing regions of BRCA1 and BRCA2 genes and characterization of novel pathogenic mutations.

Author

Colombo M, De Vecchi G, Caleca L, Foglia C, Ripamonti CB, Ficarazzi F, Barile M, Varesco L, Peissel B, Manoukian S, and Radice P

Subjects
Cell Line, Transformed, Humans, RNA, Messenger genetics, Reverse Transcriptase Polymerase Chain Reaction, Genes, BRCA1, Genes, BRCA2, Mutation, RNA Splicing
Abstract

Several unclassified variants (UVs) have been identified in splicing regions of disease-associated genes and their characterization as pathogenic mutations or benign polymorphisms is crucial for the understanding of their role in disease development. In this study, 24 UVs located at BRCA1 and BRCA2 splice sites were characterized by transcripts analysis. These results were used to evaluate the ability of nine bioinformatics programs in predicting genetic variants causing aberrant splicing (spliceogenic variants) and the nature of aberrant transcripts. Eleven variants in BRCA1 and 8 in BRCA2, including 8 not previously characterized at transcript level, were ascertained to affect mRNA splicing. Of these, 16 led to the synthesis of aberrant transcripts containing premature termination codons (PTCs), 2 to the up-regulation of naturally occurring alternative transcripts containing PTCs, and one to an in-frame deletion within the region coding for the DNA binding domain of BRCA2, causing the loss of the ability to bind the partner protein DSS1 and ssDNA. For each computational program, we evaluated the rate of non-informative analyses, i.e. those that did not recognize the natural splice sites in the wild-type sequence, and the rate of false positive predictions, i.e., variants incorrectly classified as spliceogenic, as a measure of their specificity, under conditions setting sensitivity of predictions to 100%. The programs that performed better were Human Splicing Finder and Automated Splice Site Analyses, both exhibiting 100% informativeness and specificity. For 10 mutations the activation of cryptic splice sites was observed, but we were unable to derive simple criteria to select, among the different cryptic sites predicted by the bioinformatics analyses, those actually used. Consistent with previous reports, our study provides evidences that in silico tools can be used for selecting splice site variants for in vitro analyses. However, the latter remain mandatory for the characterization of the nature of aberrant transcripts.

Published
2013
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17. Germline mutations in BRIP1 and PALB2 in Jewish high cancer risk families.

Author

Catucci I, Milgrom R, Kushnir A, Laitman Y, Paluch-Shimon S, Volorio S, Ficarazzi F, Bernard L, Radice P, Friedman E, and Peterlongo P

Subjects
Adult, Aged, Aged, 80 and over, Case-Control Studies, Exons, Fanconi Anemia Complementation Group N Protein, Fanconi Anemia Complementation Group Proteins, Female, Genetic Predisposition to Disease, Humans, Middle Aged, Breast Neoplasms genetics, DNA-Binding Proteins genetics, Germ-Line Mutation, Jews genetics, Nuclear Proteins genetics, Ovarian Neoplasms genetics, RNA Helicases genetics, Tumor Suppressor Proteins genetics
Abstract

Germline mutations in BRCA1 and BRCA2 account for ~30 % of inherited breast cancer. BRIP1 and PALB2 are likely genes for breast cancer susceptibility, based on their roles in maintaining cellular integrity. Indeed, few pathogenic germline mutations in both genes are reported in ethnically diverse breast cancer families. There is a paucity of data on the putative contribution of both genes to inherited breast cancer in Jewish high risk families. High risk Jewish women, none of whom was a carrier of the predominant Jewish mutations in BRCA1/BRCA2, were screened for BRIP1 germline mutations by combined denaturing gradient gel electrophoresis, high resolution melting and sequencing. Direct sequencing of exons and flanking intronic sequences was used for PALB2 mutational analysis. Overall, 149 women, all of high risk, cancer prone families of Ashkenazi origin, were genotyped for BRIP1 mutations: 127 with breast cancer, 22 with ovarian cancer. No truncating mutations were noted and one novel (p.Ala745Thr) and two previously described missense mutations were detected. For PALB2, 93 women were genotyped (87 with breast cancer) of Ashkenazi (n = 32) and non Ashkenazi Jewish origin. Fifteen sequence variants were detected, of these, none was truncating, four were not previously reported, and two (p.Asp871Gly and p.Leu1119Pro) were seemingly pathogenic based on the PolyPhen2 protein prediction algorithm. These missense mutations were not detected in any of 113 healthy Ashkenazi and 109 Moroccan, cancer free controls. In conclusion, germline mutations in BRIP1 and PALB2 contribute marginally to breast cancer susceptibility in ethnically diverse, Jewish high risk families.

Published
2012
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18. Sequencing analysis of SLX4/FANCP gene in Italian familial breast cancer cases.

Author

Catucci I, Colombo M, Verderio P, Bernard L, Ficarazzi F, Mariette F, Barile M, Peissel B, Cattaneo E, Manoukian S, Radice P, and Peterlongo P

Subjects
DNA Mutational Analysis, Family Health, Female, Gene Deletion, Genetic Predisposition to Disease, Humans, Italy, Models, Statistical, Mutation, Phylogeny, Breast Neoplasms genetics, Recombinases genetics, Sequence Analysis, DNA
Abstract

Breast cancer can be caused by germline mutations in several genes that are responsible for different hereditary cancer syndromes. Some of the genes causing the Fanconi anemia (FA) syndrome, such as BRCA2, BRIP1, PALB2, and RAD51C, are associated with high or moderate risk of developing breast cancer. Very recently, SLX4 has been established as a new FA gene raising the question of its implication in breast cancer risk. This study aimed at answering this question sequencing the entire coding region of SLX4 in 526 familial breast cancer cases from Italy. We found 81 different germline variants and none of these were clearly pathogenic. The statistical power of our sample size allows concluding that in Italy the frequency of carriers of truncating mutations of SLX4 may not exceed 0.6%. Our results indicate that testing for SLX4 germline mutations is unlikely to be relevant for the identification of individuals at risk of breast cancer, at least in the Italian population.

Published
2012
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19. A BRCA1 promoter variant (rs11655505) and breast cancer risk.

Author

Verderio P, Pizzamiglio S, Southey MC, Spurdle AB, Hopper JL, Chen X, Beesley J, Schmutzler RK, Engel C, Burwinkel B, Bugert P, Ficarazzi F, Manoukian S, Barile M, Wappenschmidt B, Chenevix-Trench G, Radice P, and Peterlongo P

Subjects
BRCA1 Protein genetics, Case-Control Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Logistic Models, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Breast Neoplasms genetics, Genes, BRCA1
Abstract

Background: A study of Chinese women recently suggested that the minor allele of rs11655505 in the BRCA1 promoter (c.-2265C-->T) increases promoter activity and has a protective effect on breast cancer risk., Methods: We genotyped rs11655505 in 2912 female breast cancer cases and 2783 unaffected female controls from four Caucasian breast cancer studies., Results: No evidence for an association between rs11655505 and breast cancer risk was found., Conclusions: Our study failed to confirm a role of rs11655505 in breast cancer risk. Larger studies are necessary to determine if there is a weak association between this SNP and breast cancer risk.

Published
2010
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20. Evaluation of SNPs in miR-146a, miR196a2 and miR-499 as low-penetrance alleles in German and Italian familial breast cancer cases.

Author

Catucci I, Yang R, Verderio P, Pizzamiglio S, Heesen L, Hemminki K, Sutter C, Wappenschmidt B, Dick M, Arnold N, Bugert P, Niederacher D, Meindl A, Schmutzler RK, Bartram CC, Ficarazzi F, Tizzoni L, Zaffaroni D, Manoukian S, Barile M, Pierotti MA, Radice P, Burwinkel B, and Peterlongo P

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Case-Control Studies, Female, Genetic Predisposition to Disease, Germany, Humans, Italy, Middle Aged, Young Adult, Alleles, Breast Neoplasms genetics, MicroRNAs genetics, Penetrance, Polymorphism, Single Nucleotide genetics
Abstract

Recently, the SNPs rs11614913 in hsa-mir-196a2 and rs3746444 in hsa-mir-499 were reported to be associated with increased breast cancer risk, and the SNP rs2910164 in hsa-mir-146a was shown to have an effect on age of breast cancer diagnosis. In order to further investigate the effect of these SNPs, we genotyped a total of 1894 breast cancer cases negative for disease-causing mutations or unclassified variants in BRCA1 and BRCA2, and 2760 controls from Germany and Italy. We compared the genotype and allele frequencies of rs2910164, rs11614913 and rs3746444 in cases versus controls of the German and Italian series, and of the two series combined; we also investigated the effect of the three SNPs on age at breast cancer diagnosis. None of the performed analyses showed statistically significant results. In conclusion, our data suggested lack of association between SNPs rs2910164, rs11614913 and rs3746444 and breast cancer risk, or age at breast cancer onset.

Published
2010
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