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Prediction of breast and prostate cancer risks in male BRCA1 and BRCA2 mutation carriers using polygenic risk scores

(2017) JOURNAL OF CLINICAL ONCOLOGY. 35(20). p.2240-2250
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Abstract
Purpose: BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigatedfor the first time to our knowledgeassociations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/2 mutations and implications for cancer risk prediction. Materials and Methods: We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results: In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 x 10(-6)). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 x 10(-9)). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion: PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.
Keywords
GENOME-WIDE ASSOCIATION, SUSCEPTIBILITY LOCI, FUNCTIONAL VARIANTS, GENETIC-VARIANTS, IDENTIFICATION, OVERDIAGNOSIS

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Citation

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Chicago
Lecarpentier, Julie, Valentina Silvestri, Karoline B Kuchenbaecker, Daniel Barrowdale, Joe Dennis, Lesley McGuffog, Penny Soucy, et al. 2017. “Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores.” Journal of Clinical Oncology 35 (20): 2240–2250.
APA
Lecarpentier, J., Silvestri, V., Kuchenbaecker, K. B., Barrowdale, D., Dennis, J., McGuffog, L., Soucy, P., et al. (2017). Prediction of breast and prostate cancer risks in male BRCA1 and BRCA2 mutation carriers using polygenic risk scores. JOURNAL OF CLINICAL ONCOLOGY, 35(20), 2240–2250.
Vancouver
1.
Lecarpentier J, Silvestri V, Kuchenbaecker KB, Barrowdale D, Dennis J, McGuffog L, et al. Prediction of breast and prostate cancer risks in male BRCA1 and BRCA2 mutation carriers using polygenic risk scores. JOURNAL OF CLINICAL ONCOLOGY. 2017;35(20):2240–50.
MLA
Lecarpentier, Julie, Valentina Silvestri, Karoline B Kuchenbaecker, et al. “Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores.” JOURNAL OF CLINICAL ONCOLOGY 35.20 (2017): 2240–2250. Print.
@article{8529878,
  abstract     = {Purpose: BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigatedfor the first time to our knowledgeassociations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/2 mutations and implications for cancer risk prediction.
Materials and Methods: We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights.
Results: In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95\% CI, 1.19 to 1.56; P = 8.6 x 10(-6)). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95\% CI, 1.35 to 1.81; P = 3.2 x 10(-9)). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7\% to 26\% for carriers of BRCA1 mutations and from 19\% to 61\% for carriers of BRCA2 mutations, respectively.
Conclusion: PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.},
  author       = {Lecarpentier, Julie and Silvestri, Valentina and Kuchenbaecker, Karoline B and Barrowdale, Daniel and Dennis, Joe and McGuffog, Lesley and Soucy, Penny and Leslie, Goska and Rizzolo, Piera and Navazio, Anna Sara and Valentini, Virginia and Zelli, Veronica and Lee, Andrew and Al Olama, Ali Amin and Tyrer, Jonathan P and Southey, Melissa and John, Esther M and Conner, Thomas A and Goldgar, David E and Buys, Saundra S and Janavicius, Ramunas and Steele, Linda and Ding, Yuan Chun and Neuhausen, Susan L and Hansen, Thomas VO and Osorio, Ana and Weitzel, Jeffrey N and Toss, Angela and Medici, Veronica and Cortesi, Laura and Zanna, Ines and Palli, Domenico and Radice, Paolo and Manoukian, Siranoush and Peissel, Bernard and Azzollini, Jacopo and Viel, Alessandra and Cini, Giulia and Damante, Giuseppe and Tommasi, Stefania and Peterlongo, Paolo and Fostira, Florentia and Hamann, Ute and Evans, D Gareth and Henderson, Alex and Brewer, Carole and Eccles, Diana and Cook, Jackie and Ong, Kai-ren and Walker, Lisa and Side, Lucy E and Porteous, Mary E and Davidson, Rosemarie and Hodgson, Shirley and Frost, Debra and Adlard, Julian and Izatt, Louise and Eeles, Ros and Ellis, Steve and Tischkowitz, Marc and Godwin, Andrew K and Meindl, Alfons and Gehrig, Andrea and Dworniczak, Bernd and Sutter, Christian and Engel, Christoph and Niederacher, Dieter and Steinemann, Doris and Hahnen, Eric and Hauke, Jan and Rhiem, Kerstin and Kast, Karin and Arnold, Norbert and Ditsch, Nina and Wang-Gohrke, Shan and Wappenschmidt, Barbara and Wand, Dorothea and Lasset, Christine and Stoppa-Lyonnet, Dominique and Belotti, Muriel and Damiola, Francesca and Barjhoux, Laure and Mazoyer, Sylvie and Van Heetvelde, Mattias and Poppe, Bruce and De Leeneer, Kim and Claes, Kathleen and de la Hoya, Miguel and Garcia-Barberan, Vanesa and Caldes, Trinidad and Perez Segura, Pedro and Kiiski, Johanna I and Aittomaeki, Kristiina and Khan, Sofia and Nevanlinna, Heli and van Asperen, Christi J and Vaszko, Tibor and Kasler, Miklos and Olah, Edith and Balmana, Judith and Gutierrez-Enriquez, Sara and Diez, Orland and Teule, Alex and Izquierdo, Angel and Darder, Esther and Brunet, Joan and Del Valle, Jesus and Feliubadalo, Lidia and Pujana, Miquel Angel and Lazaro, Conxi and Arason, Adalgeir and Agnarsson, Bjarni A and Johannsson, Oskar Th and Barkardottir, Rosa B and Alducci, Elisa and Tognazzo, Silvia and Montagna, Marco and Teixeira, Manuel R and Pinto, Pedro and Spurdle, Amanda B and Holland, Helene and Lee, Jong Won and Lee, Min Hyuk and Lee, Jihyoun and Kim, Sung-Won and Kang, Eunyoung and Kim, Zisun and Sharma, Priyanka and Rebbeck, Timothy R and Vijai, Joseph and Robson, Mark and Lincoln, Anne and Musinsky, Jacob and Gaddam, Pragna and Tan, Yen Y and Berger, Andreas and Singer, Christian F and Loud, Jennifer T and Greene, Mark H and Mulligan, Anna Marie and Glendon, Gord and Andrulis, Irene L and Toland, Amanda Ewart and Senter, Leigha and Bojesen, Anders and Nielsen, Henriette Roed and Skytte, Anne-Bine and Sunde, Lone and Jensen, Uffe Birk and Pedersen, Inge Sokilde and Krogh, Lotte and Kruse, Torben A and Caligo, Maria A and Yoon, Sook-Yee and Teo, Soo-Hwang and von Wachenfeldt, Anna and Huo, Dezheng and Nielsen, Sarah M and Olopade, Olufunmilayo I and Nathanson, Katherine L and Domchek, Susan M and Lorenchick, Christa and Jankowitz, Rachel C and Campbell, Ian and James, Paul and Mitchell, Gillian and Orr, Nick and Park, Sue Kyung and Thomassen, Mads and Offit, Kenneth and Couch, Fergus J and Simard, Jacques and Easton, Douglas F and Chenevix-Trench, Georgia and Schmutzler, Rita K and Antoniou, Antonis C and Ottini, Laura},
  issn         = {0732-183X},
  journal      = {JOURNAL OF CLINICAL ONCOLOGY},
  keyword      = {GENOME-WIDE ASSOCIATION,SUSCEPTIBILITY LOCI,FUNCTIONAL VARIANTS,GENETIC-VARIANTS,IDENTIFICATION,OVERDIAGNOSIS},
  language     = {eng},
  number       = {20},
  pages        = {2240--2250},
  title        = {Prediction of breast and prostate cancer risks in male BRCA1 and BRCA2 mutation carriers using polygenic risk scores},
  url          = {http://dx.doi.org/10.1200/JCO.2016.69.4935},
  volume       = {35},
  year         = {2017},
}

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