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.

doi:10.1200/JCO.2016.69.4935

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. [10.1200/JCO.2016.69.4935]

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.

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.

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	Anno di pubblicazione
	
				2017
			
	Data di prima pubblicazione
	
				27-apr-2017
			
	Rivista
	
				JOURNAL OF CLINICAL ONCOLOGY
			
	N° del Volume
	
				35
			
	Fascicolo
	
				20
			
	Pagina iniziale
	
				2240
			
	Pagina finale
	
				2250
			
	Codice DOI
	
				https://dx.doi.org/10.1200/JCO.2016.69.4935
			
	Codice WoS
	
				WOS:000404985200006
			
	Codice Scopus
	
				2-s2.0-85024491245
			
	Codice PubMed
	
				28448241
			
	Citazione
	
				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. [10.1200/JCO.2016.69.4935]
			
	Tutti gli autori
	
						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...espandi
						
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