Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores

Daniel R Barnes, Valentina Silvestri, Goska Leslie, Lesley McGuffog, Joe Dennis, Xin Yang, Julian Adlard, Bjarni A Agnarsson, Munaza Ahmed, Kristiina Aittomäki, Irene L Andrulis, Adalgeir Arason, Norbert Arnold, Bernd Auber, Jacopo Azzollini, Judith Balmaña, Rosa B Barkardottir, Daniel Barrowdale, Julian Barwell, Muriel Belotti, Javier Benitez, Pascaline Berthet, Susanne E Boonen, Åke Borg, Aniko Bozsik, Angela F Brady, Paul Brennan, Carole Brewer, Joan Brunet, Agostino Bucalo, Saundra S Buys, Trinidad Caldés, Maria A Caligo, Ian Campbell, Hayley Cassingham, Lise Lotte Christensen, Giulia Cini, Kathleen B M Claes, GEMO Study Collaborators, EMBRACE Collaborators, Jackie Cook, Anna Coppa, Laura Cortesi, Giuseppe Damante, Esther Darder, Rosemarie Davidson, Miguel de la Hoya, Kim De Leeneer, Robin de Putter, Jesús Del Valle, Orland Diez, Yuan Chun Ding, Susan M Domchek, Alan Donaldson, Jacqueline Eason, Ros Eeles, Christoph Engel, D Gareth Evans, Lidia Feliubadaló, Florentia Fostira, Megan Frone, Debra Frost, David Gallagher, Andrea Gehrig, Sophie Giraud, Gord Glendon, Andrew K Godwin, David E Goldgar, Mark H Greene, Helen Gregory, Eva Gross, Eric Hahnen, Ute Hamann, Thomas V O Hansen, Helen Hanson, Julia Hentschel, Judit Horvath, KConFab Investigators, HEBON Investigators, Louise Izatt, Angel Izquierdo, Paul A James, Ramunas Janavicius, Uffe Birk Jensen, Oskar Th Johannsson, Esther M John, Gero Kramer, Lone Kroeldrup, Torben A Kruse, Charlotte Lautrup, Conxi Lazaro, Fabienne Lesueur, Adria Lopez-Fernández, Phuong L Mai, Siranoush Manoukian, Zoltan Matrai, Laura Matricardi, Kara N Maxwell, Noura Mebirouk, Alfons Meindl, Marco Montagna, Alvaro N Monteiro, Patrick J Morrison, Taru A Muranen, Alex Murray, Katherine L Nathanson, Susan L Neuhausen, Heli Nevanlinna, Tu Nguyen-Dumont, Dieter Niederacher, Edith Olah, Olufunmilayo I Olopade, Domenico Palli, Michael T Parsons, Inge Sokilde Pedersen, Bernard Peissel, Pedro Perez-Segura, Paolo Peterlongo, Annabeth H Petersen, Pedro Pinto, Mary E Porteous, Caroline Pottinger, Miquel Angel Pujana, Paolo Radice, Juliane Ramser, Johanna Rantala, Mark Robson, Mark T Rogers, Karina Rønlund, Andreas Rump, Ana María Sánchez de Abajo, Payal D Shah, Saba Sharif, Lucy E Side, Christian F Singer, Zsofia Stadler, Linda Steele, Dominique Stoppa-Lyonnet, Christian Sutter, Yen Yen Tan, Manuel R Teixeira, Alex Teulé, Darcy L Thull, Marc Tischkowitz, Amanda E Toland, Stefania Tommasi, Angela Toss, Alison H Trainer, Vishakha Tripathi, Virginia Valentini, Christi J van Asperen, Marta Venturelli, Alessandra Viel, Joseph Vijai, Lisa Walker, Shan Wang-Gohrke, Barbara Wappenschmidt, Anna Whaite, Ines Zanna, Kenneth Offit, Mads Thomassen, Fergus J Couch, Rita K Schmutzler, Jacques Simard, Douglas F Easton, Georgia Chenevix-Trench, Antonis C Antoniou, Laura Ottini, Consortium of Investigators of Modifiers of BRCA1 and BRCA2, Daniel R Barnes, Valentina Silvestri, Goska Leslie, Lesley McGuffog, Joe Dennis, Xin Yang, Julian Adlard, Bjarni A Agnarsson, Munaza Ahmed, Kristiina Aittomäki, Irene L Andrulis, Adalgeir Arason, Norbert Arnold, Bernd Auber, Jacopo Azzollini, Judith Balmaña, Rosa B Barkardottir, Daniel Barrowdale, Julian Barwell, Muriel Belotti, Javier Benitez, Pascaline Berthet, Susanne E Boonen, Åke Borg, Aniko Bozsik, Angela F Brady, Paul Brennan, Carole Brewer, Joan Brunet, Agostino Bucalo, Saundra S Buys, Trinidad Caldés, Maria A Caligo, Ian Campbell, Hayley Cassingham, Lise Lotte Christensen, Giulia Cini, Kathleen B M Claes, GEMO Study Collaborators, EMBRACE Collaborators, Jackie Cook, Anna Coppa, Laura Cortesi, Giuseppe Damante, Esther Darder, Rosemarie Davidson, Miguel de la Hoya, Kim De Leeneer, Robin de Putter, Jesús Del Valle, Orland Diez, Yuan Chun Ding, Susan M Domchek, Alan Donaldson, Jacqueline Eason, Ros Eeles, Christoph Engel, D Gareth Evans, Lidia Feliubadaló, Florentia Fostira, Megan Frone, Debra Frost, David Gallagher, Andrea Gehrig, Sophie Giraud, Gord Glendon, Andrew K Godwin, David E Goldgar, Mark H Greene, Helen Gregory, Eva Gross, Eric Hahnen, Ute Hamann, Thomas V O Hansen, Helen Hanson, Julia Hentschel, Judit Horvath, KConFab Investigators, HEBON Investigators, Louise Izatt, Angel Izquierdo, Paul A James, Ramunas Janavicius, Uffe Birk Jensen, Oskar Th Johannsson, Esther M John, Gero Kramer, Lone Kroeldrup, Torben A Kruse, Charlotte Lautrup, Conxi Lazaro, Fabienne Lesueur, Adria Lopez-Fernández, Phuong L Mai, Siranoush Manoukian, Zoltan Matrai, Laura Matricardi, Kara N Maxwell, Noura Mebirouk, Alfons Meindl, Marco Montagna, Alvaro N Monteiro, Patrick J Morrison, Taru A Muranen, Alex Murray, Katherine L Nathanson, Susan L Neuhausen, Heli Nevanlinna, Tu Nguyen-Dumont, Dieter Niederacher, Edith Olah, Olufunmilayo I Olopade, Domenico Palli, Michael T Parsons, Inge Sokilde Pedersen, Bernard Peissel, Pedro Perez-Segura, Paolo Peterlongo, Annabeth H Petersen, Pedro Pinto, Mary E Porteous, Caroline Pottinger, Miquel Angel Pujana, Paolo Radice, Juliane Ramser, Johanna Rantala, Mark Robson, Mark T Rogers, Karina Rønlund, Andreas Rump, Ana María Sánchez de Abajo, Payal D Shah, Saba Sharif, Lucy E Side, Christian F Singer, Zsofia Stadler, Linda Steele, Dominique Stoppa-Lyonnet, Christian Sutter, Yen Yen Tan, Manuel R Teixeira, Alex Teulé, Darcy L Thull, Marc Tischkowitz, Amanda E Toland, Stefania Tommasi, Angela Toss, Alison H Trainer, Vishakha Tripathi, Virginia Valentini, Christi J van Asperen, Marta Venturelli, Alessandra Viel, Joseph Vijai, Lisa Walker, Shan Wang-Gohrke, Barbara Wappenschmidt, Anna Whaite, Ines Zanna, Kenneth Offit, Mads Thomassen, Fergus J Couch, Rita K Schmutzler, Jacques Simard, Douglas F Easton, Georgia Chenevix-Trench, Antonis C Antoniou, Laura Ottini, Consortium of Investigators of Modifiers of BRCA1 and BRCA2

Abstract

Background: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers.

Methods: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)-negative (PRSER-), or ER-positive (PRSER+) breast cancer risk.

Results: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions.

Conclusions: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.

© The Author(s) 2021. Published by Oxford University Press.

Figures

Figure 1.
Figure 1.
The predicted absolute risks of developing breast cancer and prostate cancer by PRS percentile. Risks were calculated assuming the per standard deviation ratio estimates in the combined sample of BRCA1 and BRCA2 carriers (Supplementary Tables 6 and 7). (A) The absolute risks of developing breast cancer for BRCA2 carriers by PRSER+ percentiles. (B) The absolute risks of developing prostate cancer for BRCA1 carriers by PRSPC percentiles. (C) The absolute risks of developing prostate cancer for BRCA2 carriers by PRSPC percentiles. PRS = polygenic risk scores; PRSER+ = ER-positive breast cancer PRS.
Figure 2.
Figure 2.
The predicted 10-year risks of developing breast cancer and prostate cancer by PRS percentile. Ten-year risks were calculated from the absolute risks of developing breast cancer or prostate cancer (Figure 1). (A) The 10-year risks of developing breast cancer for BRCA2 carriers by PRSER+ percentiles. (B) The 10-year risks of developing prostate cancer for BRCA1 pathogenic variant carriers by PRSPC percentiles. (C) The 10-year risks of developing prostate cancer for BRCA2 pathogenic variant carriers by PRSPC percentiles. PRS = polygenic risk scores PRSER+ = ER-positive breast cancer PRS.

References

    1. Castro E, Eeles R.. The role of BRCA1 and BRCA2 in prostate cancer. Asian J Androl. 2012;14(3):409–414.
    1. Rizzolo P, Silvestri V, Tommasi S, et al.Male breast cancer: genetics, epigenetics, and ethical aspects. Ann Oncol. 2013;24(suppl 8):viii75–viii82.
    1. Leongamornlert D, Mahmud N, Tymrakiewicz M, et al.; for the UKGPCS Collaborators. Germline BRCA1 mutations increase prostate cancer risk. Br J Cancer. 2012;106(10):1697–1701.
    1. Kote-Jarai Z, Leongamornlert D, Saunders E, et al.; for the UKGPCS Collaborators. BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. Br J Cancer. 2011;105(8):1230–1234.
    1. Nyberg T, Frost D, Barrowdale D, et al.Prostate cancer risks for male BRCA1 and BRCA2 mutation carriers: a prospective cohort study. Eur Urol. 2020;77(1):24–35.
    1. Liede A, Karlan BY, Narod SA.. Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol. 2004;22(4):735–742.
    1. Weiss JR, Moysich KB, Swede H.. Epidemiology of male breast cancer. Cancer Epidemiol Biomarkers Prev. 2005;14(1):20–26.
    1. Basham VM, Lipscombe JM, Ward JM, et al.BRCA1 and BRCA2 mutations in a population-based study of male breast cancer. Breast Cancer Res. 2002;4(1):R2.
    1. Ottini L, Masala G, D’Amico C, et al.BRCA1 and BRCA2 mutation status and tumor characteristics in male breast cancer: a population-based study in Italy. Cancer Res. 2003;63(2):342–347.
    1. Easton DF, Steele L, Fields P, et al.Cancer risks in two large breast cancer families linked to BRCA2 on chromosome 13q12-13. Am J Hum Genet. 1997;61(1):120–128.
    1. Thompson D, Easton D.. Breast cancer linkage C. variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet. 2001;68(2):410–419.
    1. Ferzoco RM, Ruddy KJ.. The epidemiology of male breast cancer. Curr Oncol Rep. 2016;18(1):1.
    1. Kwiatkowska E, Teresiak M, Filas V, Karczewska A, Breborowicz D, Mackiewicz A.. BRCA2 mutations and androgen receptor expression as independent predictors of outcome of male breast cancer patients. Clin Cancer Res. 2003;9(12):4452–4459.
    1. Mavaddat N, Pharoah PD, Michailidou K, et al.Prediction of breast cancer risk based on profiling with common genetic variants. J Natl Cancer Inst. 2015;107(5):djv036.
    1. Schumacher FR, Al Olama AA, Berndt SI, et al.; for the Genetic Associations and Mechanisms in Oncology (GAME-ON)/Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) Consortium. Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci. Nat Genet. 2018;50(7):928–936.
    1. Kuchenbaecker KB, McGuffog L, Barrowdale D, et al.Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst. 2017;109(7):djw302.
    1. Lecarpentier J, Silvestri V, Kuchenbaecker KB, et al.; for the KConFab Investigators. Prediction of breast and prostate cancer risks in male BRCA1 and BRCA2 mutation carriers using polygenic risk scores. J Clin Oncol. 2017;35(20):2240–2250.
    1. Barnes DR, Rookus MA, McGuffog L, et al.; for the Consortium of Investigators of Modifiers of BRCA and BRCA2. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants. Genet Med. 2020;22(10):1653–1666.
    1. Michailidou K, Lindstrom S, Dennis J, et al.; for the ConFab/AOCS Investigators. Association analysis identifies 65 new breast cancer risk loci. Nature. 2017;551(7678):92–94.
    1. Milne RL, Kuchenbaecker KB, Michailidou K, et al.; for the ABCTB Investigators. Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer. Nat Genet. 2017;49(12):1767–1778.
    1. Mavaddat N, Michailidou K, Dennis J, et al.; for the NBCS Collaborators. Polygenic risk scores for prediction of breast cancer and breast cancer subtypes. Am J Hum Genet. 2019;104(1):21–34.
    1. Maguire S, Perraki E, Tomczyk K, et al.Common susceptibility loci for male breast cancer. J Natl Cancer Inst. 2020;113(4):453–61.
    1. Gaddam S, Heller SL, Babb JS, Gao Y.. Male breast cancer risk assessment and screening recommendations in high-risk men who undergo genetic counseling and multigene panel testing. Clin Breast Cancer. 2021;21(1):74–79.
    1. Chenevix-Trench G, Milne RL, Antoniou AC, et al.; for CIMBA. An international initiative to identify genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA). Breast Cancer Res. 2007;9(2):104.
    1. Antoniou AC, Sinilnikova OM, Simard J, et al.; for the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). RAD51 135G–>C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies. Am J Hum Genet. 2007;81(6):1186–1200.
    1. Silvestri V, Barrowdale D, Mulligan AM, et al.; for EMBRACE. Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2. Breast Cancer Res. 2016;18(1):15.
    1. Huber PJ, The behavior of maximum likelihood estimates under nonstandard conditions. Paper presented at Proceedings of the Fifth Berkeley Symposium on Mathematical Statistics and Probability, Statistical Laboratory of the University of California, Berkeley, California, USA (June 21-July 18, 1965 and December 27, 1965-January 7, 1966); 1967.
    1. White H. A heteroskedasticity-consistent covariance matrix estimator and a direct test for heteroskedasticity. Econometrica. 1980;48(4):817–838.
    1. Kuchenbaecker KB, Hopper JL, Barnes DR, et al.; and the BRCA1 and BRCA2 Cohort Consortium. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017;317(23):2402–2416.
    1. Rebbeck TR, Mitra N, Wan F, et al.; for the CIMBA Consortium. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA. 2015;313(13):1347–1361.
    1. Patel VL, Busch EL, Friebel TM, et al.Association of genomic domains in BRCA1 and BRCA2 with prostate cancer risk and aggressiveness. Cancer Res. 2020;80(3):624–638.
    1. Antoniou AC, Beesley J, McGuffog L, et al.; for CIMBA. Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction. Cancer Res. 2010;70(23):9742–9754.
    1. Gallagher S, Hughes E, Wagner S, et al.Association of a polygenic risk score with breast cancer among women carriers of high- and moderate-risk breast cancer genes. JAMA Netw Open. 2020;3(7):e208501.
    1. Xiao R, Boehnke M.. Quantifying and correcting for the winner’s curse in genetic association studies. Genet Epidemiol. 2009;33(5):453–462.
    1. Sawyer S, Mitchell G, McKinley J, et al.A role for common genomic variants in the assessment of familial breast cancer. J Clin Oncol. 2012;30(35):4330–4336.
    1. Coignard J, Lush M, Beesley J, et al.; for the ABCTB Investigators. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers. Nat Commun. 2021;12(1):1078.
    1. Silvestri V, Leslie G, Barnes DR, et al.; and the CIMBA Group. Characterization of the cancer spectrum in men with germline BRCA1 and BRCA2 pathogenic variants: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). JAMA Oncol. 2020;6(8):1218.
    1. Daly MB, Pal T, Berry MP, et al. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2021;19(1):77–102.
    1. Paluch-Shimon S, Cardoso F, Sessa C, et al.; for the ESMO Guidelines Committee. Prevention and screening in BRCA mutation carriers and other breast/ovarian hereditary cancer syndromes: ESMO Clinical Practice Guidelines for cancer prevention and screening. Ann Oncol. 2016;27(suppl 5):v103–v110.
    1. American society of Clinical Oncology. Hereditary breast and ovarian cancer guidelines: screening for men with a BRCA1 or BRCA2 gene mutation; 2017. . Accessed September 30, 2019.
    1. Jia G, Lu Y, Wen W, et al.Evaluating the utility of polygenic risk scores in identifying high-risk individuals for eight common cancers. JNCI Cancer Spectr. 2020;4(3):pkaa021.
    1. Toland AE. Polygenic risk scores for prostate cancer: testing considerations. Can J Urol. 2019;26(5, suppl 2):17–18.
    1. Eeles RA, Raghallaigh H; for the Group TBS. BARCODE 1: a pilot study investigating the use of genetic profiling to identify men in the general population with the highest risk of prostate cancer to invite for targeted screening. J Clin Oncol. 2020;38(suppl 15):1505–1505.
    1. Institute of Cancer Research. BARCODE 1: The use of genetic profiling to guide prostate cancer targeted screening; 2020. . Accessed October 21, 2020.
    1. Castro E, Mikropoulos C, Bancroft EK, et al.; for the PROFILE Study Steering Committee. The PROFILE feasibility study: targeted screening of men with a family history of prostate cancer. Oncologist. 2016;21(6):716–722.
    1. Institute of Cancer Research. The PROFILE Study: germline genetic profiling: correlation with targeted prostate cancer screening and treatment; 2020. . Accessed October 21, 2020.
    1. Pashayan N, Antoniou AC, Ivanus U, et al.Personalized early detection and prevention of breast cancer: ENVISION consensus statement. Nat Rev Clin Oncol. 2020;17(11):687–705.
    1. Lee A, Mavaddat N, Wilcox AN, et al.BOADICEA: a comprehensive breast cancer risk prediction model incorporating genetic and nongenetic risk factors. Genet Med. 2019;21(8):1708–1718.
    1. IBIS. IBIS breast cancer risk evaluation tool; 2017. . Accessed May 21, 2020.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner