Identification of Novel Breast Cancer Risk Loci

Abstract

It has been estimated that >1,000 genetic loci have yet to be identified for breast cancer risk. Here we report the first study utilizing targeted next-generation sequencing to identify single-nucleotide polymorphisms (SNP) associated with breast cancer risk. Targeted sequencing of 283 genes was performed in 240 women with early-onset breast cancer (≤40 years) or a family history of breast and/or ovarian cancer. Common coding variants with minor allele frequencies (MAF) >1% that were identified were presumed initially to be SNPs, but further database inspections revealed variants had MAF of ≤1% in the general population. Through prioritization and stringent selection criteria, we selected 24 SNPs for further genotyping in 1,516 breast cancer cases and 1,189 noncancer controls. Overall, we identified the SNP rs56118985 to be significantly associated with overall breast cancer risk. Subtype analysis performed for patient subgroups defined by ER, PR, and HER2 status suggested additional associations of the SNP rs200504060 and the SNP rs142179458 with breast cancer risk. analysis indicated that coding amino acids encoded at these three SNP sites were conserved evolutionarily and associated with decreased protein stability, suggesting a likely impact on protein function. Our results offer proof of concept for identifying novel cancer risk loci from next-generation sequencing data, with iterative data analysis from targeted, whole-exome, or whole-genome sequencing a wellspring to identify new SNPs associated with cancer risk. .

Evaluation of three polygenic risk score models for the prediction of breast cancer risk in Singapore Chinese

“…[ 32 ], were not found to be statistically significant with BC risk in our study, it is possible that some of these SNPs failed to reach statistical significance as our study could have had insufficient power to detect the associations and additional studies of Asian ancestry are thus warranted to confirm if these SNPs are significantly associated with BC risk. GWAS and other discovery methods could also be done on Asian populations to further identify novel ethnic-specific SNPs that could have more significant associations with BC risk in Asians [ 41 ].…”

Whole‐exome sequencing of ovarian cancer families uncovers putative predisposition genes

“…However, the sample size of such study is likely to be significantly less than ExAC. Despite these limitations, the ExAC data has been commonly used and validated as an effective control dataset for estimating cancer risk for both known and newly discovered cancer predisposition genes/loci …”

“…Despite these limitations, the ExAC data has been commonly used and validated as an effective control dataset for estimating cancer risk for both known 15,[46][47][48] and newly discovered cancer predisposition genes/loci. 49,50 In summary, we conducted the largest WES study of hereditary OC to date and followed with a validation study to identify ANKRD11 and POLE as two possible OC predisposition genes. Identification of additional OC predisposition genes can potentiate ascertainment power and preventive care of individuals with high OC risk.…”

Subtype-specific associations between breast cancer risk polymorphisms and the survival of early-stage breast cancer

“…It has been accepted worldwide that breast cancer is a complex disease and consists of several intrinsic subtypes, which have different etiologies and prognosis [ 14 ]. By altering the related genes’ expression and/or function in key signaling pathways, we gradually realize putative SNPs may take effect on the basis of molecular subtypes, whether in risk or in clinical outcome of EBC [ 15 – 17 ].…”