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,
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 Berutti,
Manjeet 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,
Steffi Riedel-Heller,
Gunnar Schmidt,
Mitul Shah,
Martin Scherer,
Antje Stäbler,
Tim M Strom,
Christian Sutter,
Holger Thiele,
Christi J van Asperen,
Lizet van der Kolk,
Rob B van der Luijt,
Alexander E Volk,
Michael Wagner,
Quinten Waisfisz,
Qin Wang,
Shan Wang-Gohrke,
Bernhard H F Weber,
Genome Of The Netherlands Project,
Ghs Study Group,
Peter Devilee,
Sean Tavtigian,
Gary D Bader,
Alfons Meindl,
David E Goldgar,
Irene L Andrulis,
Rita K Schmutzler,
Douglas F Easton,
Marjanka K Schmidt,
Eric Hahnen,
Jacques Simard
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.