The predictive ability of the 313 variant–based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

Lakeman, Inge M.M.; Van den Broek, Alexandra J.; Vos, Julien A.M.; Barnes, Daniel R.; Adlard, Julian; Andrulis, Irene L.; Arason, Adalgeir; Arnold, Norbert; Arun, Banu K.; Balmana, Judith; Barrowdale, Daniel; Benitez, Javier; Borg, Ake; Caldes, Trinidad; Caligo, Maria A.; Chung, Wendy K.; Claes, Kathleen B.M.; GEMO Study Collaborators; EMBRACE Collaborators; Collee, J. Margriet; Couch, Fergus J.; Daly, Mary B.; Dennis, Joe; Dhawan, Mallika; Domchek, Susan M.; Eeles, Ros; Engel, Christoph; Evans, D. Gareth; Feliubadalo, Lidia; Foretova, Lenka; Friedman, Eitan; Frost, Debra; Ganz, Patricia A.; Garber, Judy; Gayther, Simon A.; Gerdes, Anne-Marie; Godwin, Andrew K.; Goldgar, David E.; Hahnen, Eric; Hake, Christopher R.; Hamann, Ute; Hogervorst, Frans B.L.; Hooning, Maartje J.; Hopper, John L.; Hulick, Peter J.; Imyanitov, Evgeny N.; OCGN Investigators; HEBON Investigators; KconFab Investigators; Isaacs, Claudine; Izatt, Louise; Jakubowska, Anna; James, Paul A.; Janavicius, Ramunas; Jensen, Uffe Birk; Jiao, Yue; John, Esther M.; Joseph, Vijai; Karlan, Beth Y.; Kets, Carolien M.; Konstantopoulou, Irene; Kwong, Ava; Legrand, Clementine; Leslie, Goska; Lesueur, Fabienne; Loud, Jennifer T.; Lubinski, Jan; Manoukian, Siranoush; McGuffog, Lesley; Miller, Austin; Gomes, Denise Molina; Montagna, Marco; Mouret-Fourme, Emmanuelle; Nathanson, Katherine L.; Neuhausen, Susan L.; Nevanlinna, Heli; Yuen Yie, Joanne Ngeow; Olah, Edith; Olopade, Olufunmilayo I.; Park, Sue K.; Parsons, Michael T.; Peterlongo, Paolo; Piedmonte, Marion; Radice, Paolo; Rantala, Johanna; Rennert, Gad; Risch, Harvey A.; Schmutzler, Rita K.; Sharma, Priyanka; Simard, Jacques; Singer, Christian F.; Stadler, Zsofia; Stoppa-Lyonnet, Dominique; Sutter, Christian; Tan, Yen Yen; Teixeira, Manuel R.; Teo, Soo Hwang; Teule, Alex; Thomassen, Mads; Thull, Darcy L.; Tischkowitz, Marc; Toland, Amanda E.; Tung, Nadine; Janse van Rensburg, Elizabeth

The predictive ability of the 313 variant–based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

Lakeman, Inge M.M.; Van den Broek, Alexandra J.; Vos, Julien A.M.; Barnes, Daniel R.; Adlard, Julian; Andrulis, Irene L.; Arason, Adalgeir; Arnold, Norbert; Arun, Banu K.; Balmana, Judith; Barrowdale, Daniel; Benitez, Javier; Borg, Ake; Caldes, Trinidad; Caligo, Maria A.; Chung, Wendy K.; Claes, Kathleen B.M.; GEMO Study Collaborators; EMBRACE Collaborators; Collee, J. Margriet; Couch, Fergus J.; Daly, Mary B.; Dennis, Joe; Dhawan, Mallika; Domchek, Susan M.; Eeles, Ros; Engel, Christoph; Evans, D. Gareth; Feliubadalo, Lidia; Foretova, Lenka; Friedman, Eitan; Frost, Debra; Ganz, Patricia A.; Garber, Judy; Gayther, Simon A.; Gerdes, Anne-Marie; Godwin, Andrew K.; Goldgar, David E.; Hahnen, Eric; Hake, Christopher R.; Hamann, Ute; Hogervorst, Frans B.L.; Hooning, Maartje J.; Hopper, John L.; Hulick, Peter J.; Imyanitov, Evgeny N.; OCGN Investigators; HEBON Investigators; KconFab Investigators; Isaacs, Claudine; Izatt, Louise; Jakubowska, Anna; James, Paul A.; Janavicius, Ramunas; Jensen, Uffe Birk; Jiao, Yue; John, Esther M.; Joseph, Vijai; Karlan, Beth Y.; Kets, Carolien M.; Konstantopoulou, Irene; Kwong, Ava; Legrand, Clementine; Leslie, Goska; Lesueur, Fabienne; Loud, Jennifer T.; Lubinski, Jan; Manoukian, Siranoush; McGuffog, Lesley; Miller, Austin; Gomes, Denise Molina; Montagna, Marco; Mouret-Fourme, Emmanuelle; Nathanson, Katherine L.; Neuhausen, Susan L.; Nevanlinna, Heli; Yuen Yie, Joanne Ngeow; Olah, Edith; Olopade, Olufunmilayo I.; Park, Sue K.; Parsons, Michael T.; Peterlongo, Paolo; Piedmonte, Marion; Radice, Paolo; Rantala, Johanna; Rennert, Gad; Risch, Harvey A.; Schmutzler, Rita K.; Sharma, Priyanka; Simard, Jacques; Singer, Christian F.; Stadler, Zsofia; Stoppa-Lyonnet, Dominique; Sutter, Christian; Tan, Yen Yen; Teixeira, Manuel R.; Teo, Soo Hwang; Teule, Alex; Thomassen, Mads; Thull, Darcy L.; Tischkowitz, Marc; Toland, Amanda E.; Tung, Nadine; Janse van Rensburg, Elizabeth

URI: https://repository.up.ac.za/handle/2263/89110

Date: 2021-06-10

Abstract:

PURPOSE : To evaluate the association between a previously published 313 variant–based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. METHODS : We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. RESULTS : For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06–1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR= 1.15, 95% CI (1.07–1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. CONCLUSION : The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decisionmaking.

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