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  • 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, Juliën A M; Barnes, Daniel R; Adlard, Julian; Andrulis, Irene L; Arnold, Norbert; Arun, Banu K; Benitez, Javier; Borg, Ake; Caligo, Maria A; Chung, Wendy K; Claes, Kathleen B M; Couch, Fergus J; Daly, Mary B; Dennis, Joe; Dhawan, Mallika; Domchek, Susan M; Eeles, Ros; Engel, Christoph; Evans, D Gareth; Feliubadaló, Lidia; Friedman, Eitan; Frost, Debra; Ganz, Patricia A; Garber, Judy; Gayther, Simon A; Gerdes, Anne-Marie; Godwin, Andrew K; Goldgar, David E; Hake, Christopher R; Hamann, Ute; Hogervorst, Frans B L; Hooning, Maartje J; Hopper, John L; Hulick, Peter J; Isaacs, Claudine; Izatt, Louise; 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; Rennert, Gad; Risch, Harvey A; Schmutzler, Rita K; 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

    Genetics in medicine, 09/2021, Letnik: 23, Številka: 9
    Journal Article

    To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS ) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. 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 and CBC risk. For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS 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 , 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 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. The PRS can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.

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