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Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk.

ABSTRACT: Linkage and candidate gene studies have identified several breast cancer susceptibility genes, but the overall contribution of coding variation to breast cancer is unclear. To evaluate the role of rare coding variants more comprehensively, we performed a meta-analysis across three large whole-exome sequencing datasets, containing 26,368 female cases and 217,673 female controls. Burden tests were performed for protein-truncating and rare missense variants in 15,616 and 18,601 genes, respectively. Associations between protein-truncating variants and breast cancer were identified for the following six genes at exome-wide significance (P < 2.5 × 10^-6): the five known susceptibility genes ATM, BRCA1, BRCA2, CHEK2 and PALB2, together with MAP3K1. Associations were also observed for LZTR1, ATR and BARD1 with P < 1 × 10^-4. Associations between predicted deleterious rare missense or protein-truncating variants and breast cancer were additionally identified for CDKN2A at exome-wide significance. The overall contribution of coding variants in genes beyond the previously known genes is estimated to be small.

SUBMITTER: Wilcox N

PROVIDER: S-EPMC10484782 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk.

Wilcox Naomi N Dumont Martine M González-Neira Anna A Carvalho Sara S Joly Beauparlant Charles C Crotti Marco M Luccarini Craig C Soucy Penny P Dubois Stéphane S Nuñez-Torres Rocio R Pita Guillermo G Gardner Eugene J EJ Dennis Joe J Alonso M Rosario MR Álvarez Nuria N Baynes Caroline C Collin-Deschesnes Annie Claude AC Desjardins Sylvie S Becher Heiko H Behrens Sabine S Bolla Manjeet K MK Castelao Jose E JE Chang-Claude Jenny J Cornelissen Sten S Dörk Thilo T Engel Christoph C Gago-Dominguez Manuela M Guénel Pascal P Hadjisavvas Andreas A Hahnen Eric E Hartman Mikael M Herráez Belén B Jung Audrey A Keeman Renske R Kiechle Marion M Li Jingmei J Loizidou Maria A MA Lush Michael M Michailidou Kyriaki K Panayiotidis Mihalis I MI Sim Xueling X Teo Soo Hwang SH Tyrer Jonathan P JP van der Kolk Lizet E LE Wahlström Cecilia C Wang Qin Q Perry John R B JRB Benitez Javier J Schmidt Marjanka K MK Schmutzler Rita K RK Pharoah Paul D P PDP Droit Arnaud A Dunning Alison M AM Kvist Anders A Devilee Peter P Easton Douglas F DF Simard Jacques J

Nature genetics 20230817 9

Linkage and candidate gene studies have identified several breast cancer susceptibility genes, but the overall contribution of coding variation to breast cancer is unclear. To evaluate the role of rare coding variants more comprehensively, we performed a meta-analysis across three large whole-exome sequencing datasets, containing 26,368 female cases and 217,673 female controls. Burden tests were performed for protein-truncating and rare missense variants in 15,616 and 18,601 genes, respectively. ...[more]

PMID: 37592023

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Project description:Copy number variants (CNVs) are a major source of genetic variation and can disrupt genes or affect gene dosage. They are known to be causal or underlie predisposition to various diseases. However, the role of CNVs in inherited breast cancer susceptibility has not been thoroughly investigated. To address this, we performed whole-exome sequencing based analysis of rare CNVs in 98 high-risk Northern Finnish breast cancer cases. After filtering, selected candidate alleles were validated and characterized with a combination of orthogonal methods, including PCR-based approaches, optical genome mapping and long-read sequencing. This revealed three recurrent alterations: a 31 kb deletion co-occurring with a retrotransposon insertion (delins) in RAD52, a 13.4 kb deletion in HSD17B14 and a 64 kb partial duplication of RAD51C. Notably, all these genes encode proteins involved in pathways previously identified as essential for breast cancer development. Variants were genotyped in geographically matched cases and controls (altogether 278 hereditary and 1983 unselected breast cancer cases, and 1229 controls). The RAD52 delins and HSD17B14 deletion both showed significant enrichment among cases with indications of hereditary disease susceptibility. RAD52 delins was identified in 7/278 cases (2.5%, P = 0.034, OR = 2.86, 95% CI = 1.10-7.45) and HSD17B14 deletion in 8/278 cases (2.9%, P = 0.014, OR = 3.28, 95% CI = 1.31-8.23), the frequency of both variants in the controls being 11/1229 (0.9%). This suggests a role for RAD52 and HSD17B14 in hereditary breast cancer susceptibility. The RAD51C duplication was very rare, identified only in 2/278 of hereditary cases and 2/1229 controls (P = 0.157, OR = 4.45, 95% CI = 0.62-31.70). The identification of recurrent CNVs in these genes, and especially the relatively high frequency of RAD52 and HSD17B14 alterations in the Finnish population, highlights the importance of studying CNVs alongside single nucleotide variants when searching for genetic factors underlying hereditary disease predisposition.

Dataset Information

Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk.

Publications

Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk.

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