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

Wilcox, N. ; Wahlström, C. LU ; Kvist, A. LU and Simard, J. (2023) In Nature Genetics 55(9). p.1435-1439
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... (More)
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. © 2023, The Author(s). (Less)
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keywords
Exome, Exome Sequencing, Female, Humans, Mutation, Missense, Neoplasms, ATM protein, ATR protein, BRCA1 associated ring domain protein 1, BRCA1 protein, BRCA2 protein, checkpoint kinase 2, partner and localizer of BRCA2, adult, Article, breast cancer, cancer risk, cancer susceptibility, controlled study, female, gene frequency, gene identification, genetic association, genetic linkage, genetic susceptibility, genetic variability, human, lztr1 gene, major clinical study, map3k1 gene, missense mutation, oncogene, whole exome sequencing, exome, genetics, meta analysis, neoplasm
in
Nature Genetics
volume
55
issue
9
pages
5 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85168388705
  • pmid:37592023
ISSN
1061-4036
DOI
10.1038/s41588-023-01466-z
language
English
LU publication?
yes
id
69c36c9b-10ee-4f40-8800-b6aec24ba791
date added to LUP
2024-01-24 11:22:18
date last changed
2024-01-25 03:00:26
@article{69c36c9b-10ee-4f40-8800-b6aec24ba791,
  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 &lt; 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 &lt; 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. © 2023, The Author(s).}},
  author       = {{Wilcox, N. and Wahlström, C. and Kvist, A. and Simard, J.}},
  issn         = {{1061-4036}},
  keywords     = {{Exome; Exome Sequencing; Female; Humans; Mutation, Missense; Neoplasms; ATM protein; ATR protein; BRCA1 associated ring domain protein 1; BRCA1 protein; BRCA2 protein; checkpoint kinase 2; partner and localizer of BRCA2; adult; Article; breast cancer; cancer risk; cancer susceptibility; controlled study; female; gene frequency; gene identification; genetic association; genetic linkage; genetic susceptibility; genetic variability; human; lztr1 gene; major clinical study; map3k1 gene; missense mutation; oncogene; whole exome sequencing; exome; genetics; meta analysis; neoplasm}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{1435--1439}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Genetics}},
  title        = {{Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk}},
  url          = {{http://dx.doi.org/10.1038/s41588-023-01466-z}},
  doi          = {{10.1038/s41588-023-01466-z}},
  volume       = {{55}},
  year         = {{2023}},
}