000164977 001__ 164977 000164977 005__ 20230915090603.0 000164977 0247_ $$2doi$$a10.3390/cancers14143363 000164977 0247_ $$2pmid$$apmid:35884425 000164977 0247_ $$2pmc$$apmc:PMC9317824 000164977 0247_ $$2altmetric$$aaltmetric:133300570 000164977 037__ $$aDZNE-2022-01381 000164977 041__ $$aEnglish 000164977 082__ $$a610 000164977 1001_ $$00000-0002-5488-4839$$aDumont, Martine$$b0 000164977 245__ $$aUncovering the Contribution of Moderate-Penetrance Susceptibility Genes to Breast Cancer by Whole-Exome Sequencing and Targeted Enrichment Sequencing of Candidate Genes in Women of European Ancestry. 000164977 260__ $$aBasel$$bMDPI$$c2022 000164977 3367_ $$2DRIVER$$aarticle 000164977 3367_ $$2DataCite$$aOutput Types/Journal article 000164977 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1659706040_13580 000164977 3367_ $$2BibTeX$$aARTICLE 000164977 3367_ $$2ORCID$$aJOURNAL_ARTICLE 000164977 3367_ $$00$$2EndNote$$aJournal Article 000164977 500__ $$aCC BY 000164977 520__ $$aRare variants in at least 10 genes, including BRCA1, BRCA2, PALB2, ATM, and CHEK2, are associated with increased risk of breast cancer; however, these variants, in combination with common variants identified through genome-wide association studies, explain only a fraction of the familial aggregation of the disease. To identify further susceptibility genes, we performed a two-stage whole-exome sequencing study. In the discovery stage, samples from 1528 breast cancer cases enriched for breast cancer susceptibility and 3733 geographically matched unaffected controls were sequenced. Using five different filtering and gene prioritization strategies, 198 genes were selected for further validation. These genes, and a panel of 32 known or suspected breast cancer susceptibility genes, were assessed in a validation set of 6211 cases and 6019 controls for their association with risk of breast cancer overall, and by estrogen receptor (ER) disease subtypes, using gene burden tests applied to loss-of-function and rare missense variants. Twenty genes showed nominal evidence of association (p-value < 0.05) with either overall or subtype-specific breast cancer. Our study had the statistical power to detect susceptibility genes with effect sizes similar to ATM, CHEK2, and PALB2, however, it was underpowered to identify genes in which susceptibility variants are rarer or confer smaller effect sizes. Larger sample sizes would be required in order to identify such genes. 000164977 536__ $$0G:(DE-HGF)POF4-353$$a353 - Clinical and Health Care Research (POF4-353)$$cPOF4-353$$fPOF IV$$x0 000164977 588__ $$aDataset connected to CrossRef, PubMed, , Journals: pub.dzne.de 000164977 650_7 $$2Other$$abreast cancer 000164977 650_7 $$2Other$$agenetic susceptibility 000164977 650_7 $$2Other$$amoderate-penetrance genes 000164977 650_7 $$2Other$$awhole-exome sequencing 000164977 7001_ $$aWeber-Lassalle, Nana$$b1 000164977 7001_ $$aJoly-Beauparlant, Charles$$b2 000164977 7001_ $$00000-0001-7756-8815$$aErnst, Corinna$$b3 000164977 7001_ $$aDroit, Arnaud$$b4 000164977 7001_ $$aFeng, Bing-Jian$$b5 000164977 7001_ $$aDubois, Stéphane$$b6 000164977 7001_ $$aCollin-Deschesnes, Annie-Claude$$b7 000164977 7001_ $$aSoucy, Penny$$b8 000164977 7001_ $$aVallée, Maxime$$b9 000164977 7001_ $$aFournier, Frédéric$$b10 000164977 7001_ $$00000-0002-1817-7029$$aLemaçon, Audrey$$b11 000164977 7001_ $$aAdank, Muriel 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