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 Journal Article

   

Authors:	Lakeman, I. M. M.; van den Broek, A. J.; Vos, J. A. M.; Barnes, D. R.; Adlard, J.; Andrulis, I. L.; Arason, A.; Arnold, N.; Arun, B. K.; Balmaña, J.; Barrowdale, D.; Benitez, J.; Borg, A.; Caldés, T.; Caligo, M. A.; Chung, W. K.; Claes, K. B. M.; GEMO Study Collaborators; EMBRACE Collaboratorst; Collée, J. M.; Couch, F. J.; Daly, M. B.; Dennis, J.; Dhawan, M.; Domchek, S. M.; Eeles, R.; Engel, C.; Evans, D. G.; Feliubadaló, L.; Foretova, L.; Friedman, E.; Frost, D.; Ganz, P. A.; Garber, J.; Gayther, S. A.; Gerdes, A. M.; Godwin, A. K.; Goldgar, D. E.; Hahnen, E.; Hake, C. R.; Hamann, U.; Hogervorst, F. B. L.; Hooning, M. J.; Hopper, J. L.; Hulick, P. J.; Imyanitov, E. N.; OCGN Investigators; HEBON Investigators; KconFab Investigators; Isaacs, C.; Izatt, L.; Jakubowska, A.; James, P. A.; Janavicius, R.; Jensen, U. B.; Jiao, Y.; John, E. M.; Joseph, V.; Karlan, B. Y.; Kets, C. M.; Konstantopoulou, I.; Kwong, A.; Legrand, C.; Leslie, G.; Lesueur, F.; Loud, J. T.; Lubiński, J.; Manoukian, S.; McGuffog, L.; Miller, A.; Molina Gomes, D.; Montagna, M.; Mouret-Fourme, E.; Nathanson, K. L.; Neuhausen, S. L.; Nevanlinna, H.; Ngeow Yuen Yie, J.; Olah, E.; Olopade, O. I.; Park, S. K.; Parsons, M. T.; Peterlongo, P.; Piedmonte, M.; Radice, P.; Rantala, J.; Rennert, G.; Risch, H. A.; Schmutzler, R. K.; Sharma, P.; Simard, J.; Singer, C. F.; Stadler, Z.; Stoppa-Lyonnet, D.; Sutter, C.; Tan, Y. Y.; Teixeira, M. R.; Teo, S. H.; Teulé, A.; Thomassen, M.; Thull, D. L.; Tischkowitz, M.; Toland, A. E.; Tung, N.; van Rensburg, E. J.; Vega, A.; Wappenschmidt, B.; Devilee, P.; van Asperen, C. J.; Bernstein, J. L.; Offit, K.; Easton, D. F.; Rookus, M. A.; Chenevix-Trench, G.; Antoniou, A. C.; Robson, M.; Schmidt, M. K.
Article Title:	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
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 decision-making. © 2021, The Author(s).
Keywords:	adult; major clinical study; clinical feature; cancer risk; breast cancer; prevalence; cohort analysis; genetic association; genetic variability; genotype; retrospective study; prediction; risk factor; age; tumor suppressor gene; heterozygosity; family history; european; estrogen receptor positive breast cancer; human; female; article; estrogen receptor negative breast cancer; genetic risk score
Journal Title:	Genetics in Medicine
Volume:	23
Issue:	9
ISSN:	1098-3600
Publisher:	Nature Publishing Group
Date Published:	2021-09-01
Start Page:	1726
End Page:	1737
Language:	English
DOI:	10.1038/s41436-021-01198-7
PUBMED:	34113011
PROVIDER:	scopus
PMCID:	PMC8460445
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85115935642&doi=10.1038%2fs41436-021-01198-7&partnerID=40&md5=b9654afe8706a410af0e2a6769d948a2
Notes:	Article -- Export Date: 2 November 2021 -- Source: Scopus

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