Association and performance of polygenic risk scores for breast cancer among French women presenting or not a familial predisposition to the disease

Yue Jiao , Thérèse Truong (1) , Séverine Eon-Marchais , Noura Mebirouk , S. M. Caputo , Marie Gabrielle Dondon , Mojgan Karimi (1) , Dorothée Le Gal , Juana Beauvallet , Édith Le Floch , Claire Dandine-Roulland , Delphine Bacq-Daian , Robert Olaso , Juliette Albuisson , Séverine Audebert-Bellanger , Pascaline Berthet , Valérie Bonadona , Bruno Buecher , Olivier Md Msc Caron , Mathias Cavaillé , Jean Chiesa , Chrystelle Colas , Marie Agnès Collonge-Rame , Isabelle Coupier , Capucine D. Delnatte , Antoine de Pauw , Hélène Dreyfus , Sandra Fert-Ferrer , Marion Gauthier-Villars , Paul H. Gesta , Sophie Giraud , Laurence Gladieff , Lisa Golmard , Christine Lasset , Sophie Lejeune-Dumoulin , Mélanie Léoné , Jean Marc Limacher , Alain H. Lortholary , Elisabethe Luporsi , Véronique Mari , Christine M. Maugard , Isabelle Mortemousque , Emmanuelle Mouret-Fourme , Sophie Nambot , Catherine Noguès , Cornel Popovici , Fabienne Prieur , Pascal Pujol , Nicolas Sevenet , Hagay H. Sobol , Christine Toulas , Nancy A. Uhrhammer , Dominique Vaur , Laurence Venat , Anne Boland-Augé , Pascal Guénel (1) , Jean François Deleuze , Dominique Stoppa-Lyonnet , Nadine Andrieu , Fabienne El Khoury Lesueur

1 CESP - Centre de recherche en épidémiologie et santé des populations

Background: Three partially overlapping breast cancer polygenic risk scores (PRS) comprising 77, 179 and 313 SNPs have been proposed for European-ancestry women by the Breast Cancer Association Consortium (BCAC) for improving risk prediction in the general population. However, the effect of these SNPs may vary from one country to another and within a country because of other factors. Objective: To assess their associated risk and predictive performance in French women from (1) the CECILE population-based case-control study, (2) BRCA1 or BRCA2 (BRCA1/2) pathogenic variant (PV) carriers from the GEMO study, and (3) familial breast cancer cases with no BRCA1/2 PV and unrelated controls from the GENESIS study. Results: All three PRS were associated with breast cancer in all studies, with odds ratios per standard deviation varying from 1.7 to 2.0 in CECILE and GENESIS, and hazard ratios varying from 1.1 to 1.4 in GEMO. The predictive performance of PRS313 in CECILE was similar to that reported in BCAC but lower than that in GENESIS (area under the receiver operating characteristic curve (AUC) = 0.67 and 0.75, respectively). PRS were less performant in BRCA2 and BRCA1 PV carriers (AUC = 0.58 and 0.54 respectively). Conclusion: Our results are in line with previous validation studies in the general population and in BRCA1/2 PV carriers. Additionally, we showed that PRS may be of clinical utility for women with a strong family history of breast cancer and no BRCA1/2 PV, and for those carrying a predicted PV in a moderate-risk gene like ATM, CHEK2 or PALB2.

Keywords: BRCA1; BRCA2; Breast cancer; Genetic susceptibility; Polygenic risk score; Risk prediction; SNP

Domains: Cancer

Yue Jiao, Thérèse Truong, Séverine Eon-Marchais, Noura Mebirouk, S. M. Caputo, et al.. Association and performance of polygenic risk scores for breast cancer among French women presenting or not a familial predisposition to the disease. European Journal of Cancer, 2023, 179, pp.76-86. ⟨10.1016/j.ejca.2022.11.007⟩. ⟨hal-03949597⟩