Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations.We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/2 mutations and implications for cancer risk prediction. Materials and Methods Wegenotyped 1,802male carriers ofBRCA1/2mutations fromthe Consortiumof Investigators ofModifiers 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 formale 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 variantswas associatedwith breast cancer risk (odds ratio per standard deviation of PRS, 1.36;95%CI, 1.19 to 1.56; P = 8.6 3 1026). 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=3.23 1029). 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.

Prediction of breast and prostate cancer risks in male BRCA1 and BRCA2 mutation carriers using polygenic risk scores / Lecarpentier, J.; Kuchenbaecker, K. B.; Barrowdale, D.; Dennis, J.; McGuffog, L.; Leslie, G.; Lee, A.; Al Olama, A. A.; Tyrer, J. P.; Frost, D.; Ellis, S.; Easton, D. F.; Antoniou, A. C.; Tischkowitz, M.; Evans, D. G.; Henderson, A.; Brewer, C.; Eccles, D.; Cook, J.; Ong, K. -R.; Walker, L.; Side, L. E.; Hodgson, S.; Izatt, L.; Eeles, R.; Orr, N.; Porteous, M. E.; Davidson, R.; Adlard, J.; Silvestri, V.; Rizzolo, P.; Navazio, A. S.; Valentini, V.; Zelli, V.; Ottini, L.; Toss, A.; Medici, V.; Cortesi, L.; Zanna, I.; Palli, D.; Radice, P.; Manoukian, S.; Peissel, B.; Azzollini, J.; Peterlongo, P.; Viel, A.; Cini, G.; Damante, G.; Tommasi, S.; Alducci, E.; Tognazzo, S.; Montagna, M.; Caligo, M. A.; Soucy, P.; Simard, J.; Mulligan, A. M.; Andrulis, I. L.; Glendon, G.; Southey, M.; Campbell, I.; James, P.; Mitchell, G.; Spurdle, A. B.; Holland, H.; Chenevix-Trench, G.; John, E. M.; Steele, L.; Ding, Y. C.; Neuhausen, S. L.; Weitzel, J. N.; Conner, T. A.; Buys, S. S.; Goldgar, D. E.; Godwin, A. K.; Sharma, P.; Rebbeck, T. R.; Vijai, J.; Robson, M.; Lincoln, A.; Musinsky, J.; Gaddam, P.; Offit, K.; Loud, J. T.; Greene, M. H.; Toland, A. E.; Senter, L.; Huo, D.; Nielsen, S. M.; Olopade, O. I.; Nathanson, K. L.; Domchek, S. M.; Lorenchick, C.; Jankowitz, R. C.; Couch, F. J.; Janavicius, R.; Hansen, T. V. O.; Bojesen, A.; Nielsen, H. R.; Skytte, A. -B.; Sunde, L.; Jensen, U. B.; Pedersen, I. S.; Krogh, L.; Kruse, T. A.; Thomassen, M.; Osorio, A.; De La Hoya, M.; Garcia-Barberan, V.; Caldes, T.; Segura, P. P.; Balmana, J.; Gutierrez-Enriquez, S.; Diez, O.; Teule, A.; Del Valle, J.; Feliubadalo, L.; Pujana, M. A.; Lazaro, C.; Izquierdo, A.; Darder, E.; Brunet, J.; Fostira, F.; Hamann, U.; Sutter, C.; Meindl, A.; Ditsch, N.; Gehrig, A.; Dworniczak, B.; Engel, C.; Wand, D.; Niederacher, D.; Steinemann, D.; Hahnen, E.; Hauke, J.; Rhiem, K.; Wappenschmidt, B.; Schmutzler, R. K.; Kast, K.; Arnold, N.; Wang-Gohrke, S.; Lasset, C.; Damiola, F.; Barjhoux, L.; Mazoyer, S.; Stoppa-Lyonnet, D.; Belotti, M.; Van Heetvelde, M.; Poppe, B.; De Leeneer, K.; Claes, K. B. M.; Kiiski, J. I.; Khan, S.; Nevanlinna, H.; Aittomaki, K.; Vvan Asperen, C. J.; Vaszko, T.; Kasler, M.; Olah, E.; Arason, A.; Agnarsson, B. A.; Johannsson, O. Th.; Barkardottir, R. B.; Teixeira, M. R.; Pinto, P.; Lee, J. W.; Lee, M. H.; Lee, J.; Kim, S. -W.; Kang, E.; Park, S. K.; Kim, Z.; Tan, Y. Y.; Berger, A.; Singer, C. F.; Yoon, S. -Y.; Teo, S. -H.; Von Wachenfeldt, A.. - In: JOURNAL OF CLINICAL ONCOLOGY. - ISSN 0732-183X. - 35:20(2017), pp. 2240-2250.

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

Toss A.;Medici V.;
2017

Abstract

Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations.We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/2 mutations and implications for cancer risk prediction. Materials and Methods Wegenotyped 1,802male carriers ofBRCA1/2mutations fromthe Consortiumof Investigators ofModifiers 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 formale 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 variantswas associatedwith breast cancer risk (odds ratio per standard deviation of PRS, 1.36;95%CI, 1.19 to 1.56; P = 8.6 3 1026). 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=3.23 1029). 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.
27-apr-2017
35
20
2240
2250
Prediction of breast and prostate cancer risks in male BRCA1 and BRCA2 mutation carriers using polygenic risk scores / Lecarpentier, J.; Kuchenbaecker, K. B.; Barrowdale, D.; Dennis, J.; McGuffog, L.; Leslie, G.; Lee, A.; Al Olama, A. A.; Tyrer, J. P.; Frost, D.; Ellis, S.; Easton, D. F.; Antoniou, A. C.; Tischkowitz, M.; Evans, D. G.; Henderson, A.; Brewer, C.; Eccles, D.; Cook, J.; Ong, K. -R.; Walker, L.; Side, L. E.; Hodgson, S.; Izatt, L.; Eeles, R.; Orr, N.; Porteous, M. E.; Davidson, R.; Adlard, J.; Silvestri, V.; Rizzolo, P.; Navazio, A. S.; Valentini, V.; Zelli, V.; Ottini, L.; Toss, A.; Medici, V.; Cortesi, L.; Zanna, I.; Palli, D.; Radice, P.; Manoukian, S.; Peissel, B.; Azzollini, J.; Peterlongo, P.; Viel, A.; Cini, G.; Damante, G.; Tommasi, S.; Alducci, E.; Tognazzo, S.; Montagna, M.; Caligo, M. A.; Soucy, P.; Simard, J.; Mulligan, A. M.; Andrulis, I. L.; Glendon, G.; Southey, M.; Campbell, I.; James, P.; Mitchell, G.; Spurdle, A. B.; Holland, H.; Chenevix-Trench, G.; John, E. M.; Steele, L.; Ding, Y. C.; Neuhausen, S. L.; Weitzel, J. N.; Conner, T. A.; Buys, S. S.; Goldgar, D. E.; Godwin, A. K.; Sharma, P.; Rebbeck, T. R.; Vijai, J.; Robson, M.; Lincoln, A.; Musinsky, J.; Gaddam, P.; Offit, K.; Loud, J. T.; Greene, M. H.; Toland, A. E.; Senter, L.; Huo, D.; Nielsen, S. M.; Olopade, O. I.; Nathanson, K. L.; Domchek, S. M.; Lorenchick, C.; Jankowitz, R. C.; Couch, F. J.; Janavicius, R.; Hansen, T. V. O.; Bojesen, A.; Nielsen, H. R.; Skytte, A. -B.; Sunde, L.; Jensen, U. B.; Pedersen, I. S.; Krogh, L.; Kruse, T. A.; Thomassen, M.; Osorio, A.; De La Hoya, M.; Garcia-Barberan, V.; Caldes, T.; Segura, P. P.; Balmana, J.; Gutierrez-Enriquez, S.; Diez, O.; Teule, A.; Del Valle, J.; Feliubadalo, L.; Pujana, M. A.; Lazaro, C.; Izquierdo, A.; Darder, E.; Brunet, J.; Fostira, F.; Hamann, U.; Sutter, C.; Meindl, A.; Ditsch, N.; Gehrig, A.; Dworniczak, B.; Engel, C.; Wand, D.; Niederacher, D.; Steinemann, D.; Hahnen, E.; Hauke, J.; Rhiem, K.; Wappenschmidt, B.; Schmutzler, R. K.; Kast, K.; Arnold, N.; Wang-Gohrke, S.; Lasset, C.; Damiola, F.; Barjhoux, L.; Mazoyer, S.; Stoppa-Lyonnet, D.; Belotti, M.; Van Heetvelde, M.; Poppe, B.; De Leeneer, K.; Claes, K. B. M.; Kiiski, J. I.; Khan, S.; Nevanlinna, H.; Aittomaki, K.; Vvan Asperen, C. J.; Vaszko, T.; Kasler, M.; Olah, E.; Arason, A.; Agnarsson, B. A.; Johannsson, O. Th.; Barkardottir, R. B.; Teixeira, M. R.; Pinto, P.; Lee, J. W.; Lee, M. H.; Lee, J.; Kim, S. -W.; Kang, E.; Park, S. K.; Kim, Z.; Tan, Y. Y.; Berger, A.; Singer, C. F.; Yoon, S. -Y.; Teo, S. -H.; Von Wachenfeldt, A.. - In: JOURNAL OF CLINICAL ONCOLOGY. - ISSN 0732-183X. - 35:20(2017), pp. 2240-2250.
Lecarpentier, J.; Kuchenbaecker, K. B.; Barrowdale, D.; Dennis, J.; McGuffog, L.; Leslie, G.; Lee, A.; Al Olama, A. A.; Tyrer, J. P.; Frost, D.; Ellis, S.; Easton, D. F.; Antoniou, A. C.; Tischkowitz, M.; Evans, D. G.; Henderson, A.; Brewer, C.; Eccles, D.; Cook, J.; Ong, K. -R.; Walker, L.; Side, L. E.; Hodgson, S.; Izatt, L.; Eeles, R.; Orr, N.; Porteous, M. E.; Davidson, R.; Adlard, J.; Silvestri, V.; Rizzolo, P.; Navazio, A. S.; Valentini, V.; Zelli, V.; Ottini, L.; Toss, A.; Medici, V.; Cortesi, L.; Zanna, I.; Palli, D.; Radice, P.; Manoukian, S.; Peissel, B.; Azzollini, J.; Peterlongo, P.; Viel, A.; Cini, G.; Damante, G.; Tommasi, S.; Alducci, E.; Tognazzo, S.; Montagna, M.; Caligo, M. A.; Soucy, P.; Simard, J.; Mulligan, A. M.; Andrulis, I. L.; Glendon, G.; Southey, M.; Campbell, I.; James, P.; Mitchell, G.; Spurdle, A. B.; Holland, H.; Chenevix-Trench, G.; John, E. M.; Steele, L.; Ding, Y. C.; Neuhausen, S. L.; Weitzel, J. N.; Conner, T. A.; Buys, S. S.; Goldgar, D. E.; Godwin, A. K.; Sharma, P.; Rebbeck, T. R.; Vijai, J.; Robson, M.; Lincoln, A.; Musinsky, J.; Gaddam, P.; Offit, K.; Loud, J. T.; Greene, M. H.; Toland, A. E.; Senter, L.; Huo, D.; Nielsen, S. M.; Olopade, O. I.; Nathanson, K. L.; Domchek, S. M.; Lorenchick, C.; Jankowitz, R. C.; Couch, F. J.; Janavicius, R.; Hansen, T. V. O.; Bojesen, A.; Nielsen, H. R.; Skytte, A. -B.; Sunde, L.; Jensen, U. B.; Pedersen, I. S.; Krogh, L.; Kruse, T. A.; Thomassen, M.; Osorio, A.; De La Hoya, M.; Garcia-Barberan, V.; Caldes, T.; Segura, P. P.; Balmana, J.; Gutierrez-Enriquez, S.; Diez, O.; Teule, A.; Del Valle, J.; Feliubadalo, L.; Pujana, M. A.; Lazaro, C.; Izquierdo, A.; Darder, E.; Brunet, J.; Fostira, F.; Hamann, U.; Sutter, C.; Meindl, A.; Ditsch, N.; Gehrig, A.; Dworniczak, B.; Engel, C.; Wand, D.; Niederacher, D.; Steinemann, D.; Hahnen, E.; Hauke, J.; Rhiem, K.; Wappenschmidt, B.; Schmutzler, R. K.; Kast, K.; Arnold, N.; Wang-Gohrke, S.; Lasset, C.; Damiola, F.; Barjhoux, L.; Mazoyer, S.; Stoppa-Lyonnet, D.; Belotti, M.; Van Heetvelde, M.; Poppe, B.; De Leeneer, K.; Claes, K. B. M.; Kiiski, J. I.; Khan, S.; Nevanlinna, H.; Aittomaki, K.; Vvan Asperen, C. J.; Vaszko, T.; Kasler, M.; Olah, E.; Arason, A.; Agnarsson, B. A.; Johannsson, O. Th.; Barkardottir, R. B.; Teixeira, M. R.; Pinto, P.; Lee, J. W.; Lee, M. H.; Lee, J.; Kim, S. -W.; Kang, E.; Park, S. K.; Kim, Z.; Tan, Y. Y.; Berger, A.; Singer, C. F.; Yoon, S. -Y.; Teo, S. -H.; Von Wachenfeldt, A.
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