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

Martine Dumont, Nana Weber-Lassalle, GHS Study Group, Genome of the Netherlands Project, Charles Joly-Beauparlant, Corinna Ernst, Arnaud Droit, Bing Jian Feng, Stéphane Dubois, Annie Claude Collin-Deschesnes, Penny Soucy, Maxime Vallée, Frédéric Fournier, Audrey Lemaçon, Muriel A. Adank, Jamie Allen, Janine Altmüller, Norbert Arnold, Margreet G.E.M. Ausems, Riccardo BeruttiManjeet K. Bolla, Shelley Bull, Sara Carvalho, Sten Cornelissen, Michael R. Dufault, Alison M. Dunning, Christoph Engel, Andrea Gehrig, Willemina R.R. Geurts-Giele, Christian Gieger, Jessica Green, Karl Hackmann, Mohamed Helmy, Julia Hentschel, Frans B.L. Hogervorst, Antoinette Hollestelle, Maartje J. Hooning, Judit Horváth, M. Arfan Ikram, Silke Kaulfuß, Renske Keeman, Da Kuang, Craig Luccarini, Wolfgang Maier, John W.M. Martens, Dieter Niederacher, Peter Nürnberg, Claus Eric Ott, Annette Peters, Paul D.P. Pharoah, Alfredo Ramirez, Juliane Ramser

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Abstract

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.

Original languageEnglish
Article number3363
JournalCancers
Volume14
Issue number14
DOIs
Publication statusPublished - Jul 2022

Bibliographical note

Funding Information:
This work was part of: The PERSPECTIVE project, which was supported by the Government of Canada through Genome Canada (#13529) and the Canadian Institutes of Health Research (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; The PRE3VENTION project, which was supported by a grant from the Ministère de l’Économie, de la Science et de l’Innovation du Québec through the PSR-SIIRI-949 program; The PERSPECTIVE I&I project, funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l’Économie et de l’Innovation du Québec through Genome Québec, the Quebec Breast Cancer Foundation. Part of this work was also supported by NRNB (U.S. National Institutes of Health, National Center for Research Resources grant number P41 GM103504). Study specific funding information is provided in Supplementary Materials.

Publisher Copyright:
© 2022 by the authors.

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