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Lakeman IMM , van den Broek AJ , Vos JAM , Barnes DR , Adlard J , Andrulis IL , Arason A , Arnold N , Arun BK , Balmaña J , Barrowdale D , Benitez J , Borg A , Caldés T , Caligo MA , Chung WK , Claes KBM , Collée JM , Couch FJ , Daly MB , Dennis J , Dhawan M , Domchek SM , Eeles R , Engel C , Evans DG , Feliubadaló L , Foretova L , Friedman E , Frost D , Ganz PA , Garber J , Gayther SA , Gerdes AM , Godwin AK , Goldgar DE , Hahnen E , Hake CR , Hamann U , Hogervorst FBL , Hooning MJ , Hopper JL , Hulick PJ , Imyanitov EN , Isaacs C , Izatt L , Jakubowska A , James PA , Janavicius R , Jensen UB , Jiao Y , John EM , Joseph V , Karlan BY , Kets CM , Konstantopoulou I , Kwong A , Legrand C , Leslie G , Lesueur F , Loud JT , Lubiński J , Manoukian S , McGuffog L , Miller A , Gomes DM , Montagna M , Mouret-Fourme E , Nathanson KL , Neuhausen SL , Nevanlinna H , Yie JNY , Olah E , Olopade OI , Park SK , Parsons MT , Peterlongo P , Piedmonte M , Radice P , Rantala J , Rennert G , Risch HA , Schmutzler RK , Sharma P , Simard J , Singer CF , Stadler Z , Stoppa-Lyonnet D , Sutter C , Tan YY , Teixeira MR , Teo SH , Teulé A , Thomassen M , Thull DL , Tischkowitz M , Toland AE , Tung N , van Rensburg EJ , Vega A , Wappenschmidt B , Devilee P , van Asperen CJ , Bernstein JL , Offit K , Easton DF , Rookus MA , Chenevix-Trench G , Antoniou AC , Robson M , Schmidt MK
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
Genet Med. 2021 Sep;23(9) :1726-1737
PMID: 34113011    PMCID: PMC8460445    URL: https://www.ncbi.nlm.nih.gov/pubmed/34113011
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Abstract
PURPOSE: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS(313)) 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 PRS(313) and CBC risk. RESULTS: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS(313) 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 PRS(313), 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 PRS(313) 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. CONCLUSION: The PRS(313) can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS(313) needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.
Notes
1530-0366 Lakeman, Inge M M van den Broek, Alexandra J Vos, Juliën A M Barnes, Daniel R Adlard, Julian Andrulis, Irene L Arason, Adalgeir Arnold, Norbert Arun, Banu K Balmaña, Judith Barrowdale, Daniel Benitez, Javier Borg, Ake Caldés, Trinidad Caligo, Maria A Chung, Wendy K Claes, Kathleen B M GEMO Study Collaborators EMBRACE Collaborators Collée, J Margriet Couch, Fergus J Daly, Mary B Dennis, Joe Dhawan, Mallika Domchek, Susan M Eeles, Ros Engel, Christoph Evans, D Gareth Feliubadaló, 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, Clémentine Leslie, Goska Lesueur, Fabienne Loud, Jennifer T Lubiński, Jan Manoukian, Siranoush McGuffog, Lesley Miller, Austin Gomes, Denise Molina Montagna, Marco Mouret-Fourme, Emmanuelle Nathanson, Katherine L Neuhausen, Susan L Nevanlinna, Heli Yie, Joanne Ngeow Yuen 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 Teulé, Alex Thomassen, Mads Thull, Darcy L Tischkowitz, Marc Toland, Amanda E Tung, Nadine van Rensburg, Elizabeth J Vega, Ana Wappenschmidt, Barbara Devilee, Peter van Asperen, Christi J Bernstein, Jonine L Offit, Kenneth Easton, Douglas F Rookus, Matti A Chenevix-Trench, Georgia Antoniou, Antonis C Robson, Mark Schmidt, Marjanka K Orcid: 0000-0002-2228-429x P30 CA008748/CA/NCI NIH HHS/United States UL2014-7473/KWF Kankerbestrijding/ Journal Article United States Genet Med. 2021 Jun 10. doi: 10.1038/s41436-021-01198-7.