Breast Cancer Risk Genes — Association Analysis in More than 113,000 Women

Abstract

BACKGROUNDGenetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking. METHODSWe used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity. RESULTSProtein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants. CONCLUSIONSThe results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.

Cohort profile: The Singapore Breast Cancer Cohort (SGBCC), a multi-center breast cancer cohort for evaluation of phenotypic risk factors and genetic markers

“…The OncoArray contains~500,000 SNPs with a genome-wide backbone of~275,000 tag SNPs and additional content comprising variants associated with five common cancers (breast, colorectal, lung, ovarian, and prostate), ancestry, quantitative traits, and pharmacogenetics [24,25]. As part of Breast Cancer Risk after Diagnostic Gene Sequencing (BRIDGES) initiative [26], next-generation targeted sequencing of 34 genes known or are suspected to be associated with breast cancer was performed for 4,464 patients (Fig 1) PLOS ONE…”

High likelihood of actionable pathogenic variant detection in breast cancer genes in women with very early onset breast cancer

“…In addition, 1567 population control samples without breast cancer at entry aged 47-73 years from the PROCAS study 18 were tested as part of the Breast Cancer Risk after Diagnostic Gene Sequencing (BRIDGES) programme. 19 PV frequencies in the Manchester early onset cohort were compared with PV frequencies observed in women aged ≤30 years who took part in the prospectively ascertained POSH study (01/2000-01/2008). 15 16 Tumour pathology information was obtained through hospital record and cancer registries.…”

Characterisation of protein-truncating and missense variants in PALB2 in 15 768 women from Malaysia and Singapore

“…7 8 20 Target enrichment were performed using the Fluidgm Access Array system (n=5090) or the Fluidgm Juno system (n=11 342) and sequenced on Illumina HiSeq 2500 or HiSeq 4000. Specifically, the 11 342 samples analysed on the Fluidgm Juno system were described in Dorling et al 8 As PALB2 is a relatively rare breast cancer gene, we have combined both analyses in this paper and further characterised the role of missense variants in this population, which has previously not been reported. Library preparations were performed according to manufacturer's protocols as described previously.…”

“…4 5 Protein-truncating variants (PTVs) in PALB2 have been shown to be associated with fivefold to sevenfold increase in risk to breast cancer in women of European and Asian descent. [5][6][7][8] However, less is known about missense variants, especially variants found in understudied populations. Notably, unlike BRCA1 and BRCA2 where there have been extensive efforts to characterise the functional impact of missense variants, including using saturation genome editing approaches, multiplex homology directed repair assays and validated transcriptional assays, [9][10][11][12] there have been fewer reports on the functional characterisation of missense variants in PALB2.…”