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
Authors: Dumont Martine , Weber-Lassalle Nana , Joly-Beauparlant Charles , Ernst Corinna , Droit Arnaud , Feng Bing-Jian , Dubois Stéphane , Collin-Deschesnes Annie-Claude , Soucy Penny , Vallée Maxime , Fournier Frédéric , Lemaçon Audrey , Adank Muriel A. , Allen Jamie , Altmüller Janine , Arnold Norbert , Ausems Margreet G. E. M. , Berutti Riccardo , Bolla Manjeet K. , Bull Shelley , Carvalho Sara , Cornelissen Sten , Dufault Michael R. , Dunning Alison M. , Engel Christoph , Gehrig Andrea , Geurts-Giele Willemina R. R. , Gieger Christian , Green Jessica , Hackmann Karl , Helmy Mohamed , Hentschel Julia , Hogervorst Frans B. L. , Hollestelle Antoinette , Hooning Maartje J. , Horváth Judit , Ikram M. Arfan , Kaulfuß Silke , Keeman Renske , Kuang Da , Luccarini Craig , Maier Wolfgang , Martens John W. M. , Niederacher Dieter , Nürnberg Peter , Ott Claus-Eric , Peters Annette , Pharoah Paul D. P. , Ramirez Alfredo , Ramser Juliane , Riedel-Heller Steffi , Schmidt Gunnar , Shah Mitul , Scherer Martin , Stäbler Antje , Strom Tim M. , Sutter Christian , Thiele Holger , van Asperen Christi J. , van der Kolk Lizet , van der Luijt Rob B. , Volk Alexander E. , Wagner Michael , Waisfisz Quinten , Wang Qin , Wang-Gohrke Shan , Weber Bernhard H. F. ,   Genome of the Netherlands Project,   GHS Study Group, Devilee Peter , Tavtigian Sean , Bader Gary D. , Meindl Alfons , Goldgar David E. , Andrulis Irene L. , Schmutzler Rita K. , Easton Douglas F. , Schmidt Marjanka K. , Hahnen Eric , Simard Jacques 
Published: July 2022

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.