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Dumont, M.* ; Weber-Lassalle, N.* ; Joly-Beauparlant, C.* ; Ernst, C.* ; Droit, A.* ; Feng, B.* ; Dubois, S.* ; Collin-Deschesnes, A.* ; Soucy, P.* ; Vallee, M.* ; Fournier, F.* ; Lemacon, A.* ; Adank, M.A.* ; Allen, J.* ; Altmueller, J.* ; Arnold, N.* ; Ausems, M.G.E.M.* ; Berutti, R.* ; Bolla, M.K.* ; Bull, S.* ; Carvalho, S.* ; Cornelissen, S.* ; Dufault, M.R.* ; Dunning, A.M.* ; Engel, C.* ; Gehrig, A.* ; Geurts-Giele, W.R.R.* ; Gieger, C. ; Green, J.* ; Hackmann, K.* ; Helmy, M.* ; Hentschel, J.* ; Hogervorst, F.B.L.* ; Hollestelle, A.* ; Hooning, M.J.* ; Horvath, J.* ; Ikram, M.A.A.* ; Kaulfuss, S.* ; Keeman, R.* ; Kuang, D.* ; Luccarini, C.* ; Maier, W.* ; Martens, J.W.M.* ; Niederacher, D.* ; Nürnberg, P.* ; Ott, C.* ; Peters, A. ; Pharoah, P.D.P.* ; Ramirez, A.* ; Ramser, J.* ; Riedel-Heller, S.* ; Schmidt, G.* ; Shah, M.* ; Scherer, M.* ; Stäbler, A.* ; Strom, T.M.* ; Sutter, C.* ; Thiele, H.* ; van Asperen, C.J.* ; van der Kolk, L.* ; van der Luijt, R.B.* ; Volk, A.E.* ; Wagner, M.* ; Waisfisz, Q.* ; Wang, Q.* ; Wang-Gohrke, S.* ; Weber, B.H.F.* ; Devilee, P.* ; Tavtigian, S.* ; Bader, G.D.* ; Meindl, A.* ; Goldgar, D.E.* ; Andrulis, I.L.* ; Schmutzler, R.K.* ; Easton, D.F.* ; Schmidt, M.K.* ; Hahnen, E.* ; Simard, J.*

Uncovering the contribution of moderate-penetrance susceptibility genes to breast cancer by whole-exome sequencing and targeted enrichment sequencing of candidate genes in women of European ancestry.

Cancers 14:3363 (2022)
Postprint Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Rare variants in at least 10 genes, including BRCA1, BRCA2, PALB2, ATM, and CHEK2, are associated with increased risk of breast cancer; however, these variants, in combination with common variants identified through genome-wide association studies, explain only a fraction of the familial aggregation of the disease. To identify further susceptibility genes, we performed a two-stage whole-exome sequencing study. In the discovery stage, samples from 1528 breast cancer cases enriched for breast cancer susceptibility and 3733 geographically matched unaffected controls were sequenced. Using five different filtering and gene prioritization strategies, 198 genes were selected for further validation. These genes, and a panel of 32 known or suspected breast cancer susceptibility genes, were assessed in a validation set of 6211 cases and 6019 controls for their association with risk of breast cancer overall, and by estrogen receptor (ER) disease subtypes, using gene burden tests applied to loss-of-function and rare missense variants. Twenty genes showed nominal evidence of association (p-value < 0.05) with either overall or subtype-specific breast cancer. Our study had the statistical power to detect susceptibility genes with effect sizes similar to ATM, CHEK2, and PALB2, however, it was underpowered to identify genes in which susceptibility variants are rarer or confer smaller effect sizes. Larger sample sizes would be required in order to identify such genes.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Breast Cancer ; Genetic Susceptibility ; Whole-exome Sequencing ; Moderate-penetrance Genes
ISSN (print) / ISBN 2072-6694
Journal Cancers
Quellenangaben Volume: 14, Issue: 14, Pages: , Article Number: 3363 Supplement: ,
Publisher MDPI
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology II (EPI2)
Grants U.S. National Institutes of Health, National Center for Research Resources

Ministère de l'Économie, de la Science et de l'Innovation du Québec
the Government of Canada through Genome Canada and the Canadian Institutes of Health Re-search (GPH-129344), the Ministère de l'Économie, de la Science et de l'Innovation du Québec through Genome Quebec, and the Quebec Breast Cancer Foundation