Rare Genetic Variants and Cancer Susceptibility
type: CreativeWork
description: Genetic susceptibility to breast cancer is known to be conferred by common variants, identified through GWAS, together with some rarer variants conferring higher disease risks. The latter, identified through genetic linkage or targeted sequencing studies, includes protein-truncating variants and some rare missense variants in ATM, BARD1, BRCA1, BRCA2, CHEK2, RAD51C, RAD51D, PALB2 and TP53. However, these variants together explain less than half the familial relative risk of breast cancer. Similarly for other cancers, GWAS have identified many susceptibility loci and rare variants have been identified in a few genes, e.g. from familial studies. Across cancers, a large proportion of the heritability remains unexplained and the contribution of rare coding variants across the whole coding landscape is largely unknown. Rare variants may be one source of the missing heritability. GWAS are underpowered to detect rare variants but recent advances in NGS datasets, particularly the availability of WES and WGS data for large case-control and cohort studies, facilitate the investigation of rare variants across the whole-exome or whole-genome, with no prior hypothesis of association. In Chapter 3, we performed a meta-analysis across 3 large whole-exome sequencing datasets from the Breast Cancer Association Consortium and UK Biobank. Burden tests were performed for protein-truncating and rare missense variants in over 15,000 genes, and family history information was incorporated to increase the power to detect associations. Associations between protein-truncating variants and breast cancer risk were identified at exome-wide significance for ATM, BRCA1, BRCA2, CHEK2 and PALB2 together with MAP3K1. Associations at P<1x10-4 were additionally identified for LZTR1, ATRIP and BARD1. For deleterious rare missense variants or protein-truncating variants, we additionally identified an association for CDKN2A at exome-wide significance. The overall contribution to the heritability of breast…
abstract: Genetic susceptibility to breast cancer is known to be conferred by common variants, identified through GWAS, together with some rarer variants conferring higher disease risks. The latter, identified through genetic linkage or targeted sequencing studies, includes protein-truncating variants and some rare missense variants in ATM, BARD1, BRCA1, BRCA2, CHEK2, RAD51C, RAD51D, PALB2 and TP53. However, these variants together explain less than half the familial relative risk of breast cancer. Similarly for other cancers, GWAS have identified many susceptibility loci and rare variants have been identified in a few genes, e.g. from familial studies. Across cancers, a large proportion of the heritability remains unexplained and the contribution of rare coding variants across the whole coding landscape is largely unknown. Rare variants may be one source of the missing heritability. GWAS are underpowered to detect rare variants but recent advances in NGS datasets, particularly the availability of WES and WGS data for large case-control and cohort studies, facilitate the investigation of rare variants across the whole-exome or whole-genome, with no prior hypothesis of association. In Chapter 3, we performed a meta-analysis across 3 large whole-exome sequencing datasets from the Breast Cancer Association Consortium and UK Biobank. Burden tests were performed for protein-truncating and rare missense variants in over 15,000 genes, and family history information was incorporated to increase the power to detect associations. Associations between protein-truncating variants and breast cancer risk were identified at exome-wide significance for ATM, BRCA1, BRCA2, CHEK2 and PALB2 together with MAP3K1. Associations at P<1x10-4 were additionally identified for LZTR1, ATRIP and BARD1. For deleterious rare missense variants or protein-truncating variants, we additionally identified an association for CDKN2A at exome-wide significance. The overall contribution to the heritability of breast…
author: Senior, Naomi
language: eng
keywords: Cancer, Whole genome sequencing, whole exome sequencing, rare genetic variants, burden tests, heritability
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/f916b828-57c8-480e-bd3e-bc3172478b05/download
license: https://creativecommons.org/licenses/by/4.0/
date published: 2024-09-30
date modified: 2026-07-22T22:24:08Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.116911