Abstract
Up to 30% of all breast cancer cases may be inherited and up to 85% of those may be due to segregation of susceptibility genes with low and moderate risk [odds ratios (OR) ≤ 3] for (mostly peri- and post-menopausal) breast cancer. The majority of low/moderate-risk genes, particularly those with minor allele frequencies (MAF) of < 30%, have not been identified and/or validated due to limitations of conventional association testing approaches, which include the agnostic nature of Genome Wide Association Studies (GWAS). To overcome these limitations, we used a hypothesis-driven integrative genomics approach to test the association of breast cancer with candidate genes by analyzing multi-omics data. Our candidate-gene association analyses of GWAS datasets suggested an increased risk of breast cancer with ERCC6 (main effect: 1.29 ≤ OR ≤ 2.91, 0.005 ≤ p ≤ 0.04, 11.8 ≤ MAF ≤ 40.9%), and implicated its interaction with ERCC8 (joint effect: 3.03 ≤ OR ≤ 5.31, 0.01 ≤ pinteraction ≤ 0.03). We found significant upregulation of ERCC6 (p = 7.95 × 10–6) and ERCC8 (p = 4.67 × 10–6) in breast cancer and similar frequencies of ERCC6 (1.8%) and ERCC8 (0.3%) mutations in breast tumors to known breast cancer susceptibility genes such as BLM (1.9%) and LSP1 (0.3%). Our integrative genomics approach suggests that ERCC6 may be a previously unreported low- to moderate-risk breast cancer susceptibility gene, which may also interact with ERCC8.
Highlights
Up to 30% of all breast cancer cases may be inherited and up to 85% of those may be due to segregation of susceptibility genes with low and moderate risk [odds ratios (OR) ≤ 3] for breast cancer
Results of our analysis of the cancer genome atlas (TCGA)21 breast tumor data revealed that 95% of genes mutated in breast tumors had mutation frequencies that were below 1% (Fig. 3a)
We found that the mutation frequency of ERCC6 (1.8%) in breast tumors was similar to those of known breast cancer susceptibility genes, such as BRCA1 (2.9%), BRCA2 (2.9%), BLM (1.9%), FGFR2 (1.5%), and CHEK2 (1.0%) (Fig. 3a)
Summary
Up to 30% of all breast cancer cases may be inherited and up to 85% of those may be due to segregation of susceptibility genes with low and moderate risk [odds ratios (OR) ≤ 3] for (mostly periand post-menopausal) breast cancer. The majority of low/moderate-risk genes, those with minor allele frequencies (MAF) of < 30%, have not been identified and/or validated due to limitations of conventional association testing approaches, which include the agnostic nature of Genome Wide Association Studies (GWAS). To overcome these limitations, we used a hypothesis-driven integrative genomics approach to test the association of breast cancer with candidate genes by analyzing multiomics data. We report on the analysis of raw multiomics data from several relevant GWAS, transcriptome, and somatic mutation datasets to test the association of breast cancer with two candidate genes, ERCC6 and ERCC8
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
