Germline allelic expression of genes at 17q22 locus associates with risk of breast cancer. (September 2022)

• Record Type: Journal Article
• Authors: Esteves, Filipa; Xavier, Joana M.; Ford, Anthony M.; Rocha, Cátia; Pharoah, Paul D.P.; Caldas, Carlos; Chin, Suet-Feung; Maia, Ana-Teresa
• Is Part Of: European journal of cancer. Volume 172(2022)
• Page Start: 146
• Page End: 157
• Publication Date: 2022-09
• Subjects: Allelic expression -- Breast cancer -- Genetic risk -- Cis-acting variants -- Expression regulation -- Functional genomics; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2022.05.034
• Languages: English
• ISSNs: 0959-8049

Abstract

Abstract: Introduction: Translation of genome-wide association study (GWAS) findings into preventive approaches is challenged by the identification of the causal risk variants and the understanding of the biological mechanisms by which they act. We present using allelic expression (AE) ratios to perform quantitative case–control analysis as a novel approach to identify risk associations, causal regulatory variants, and target genes. Methods: Using the breast cancer (BC) risk locus 17q22 to validate this approach, we measured AE ratios in normal breast tissue samples from controls and cases, as well as from unmatched blood samples. Then we used in-silico and in-vitro analysis to map and functionally characterised candidate causal variants. Results: We found a significant shift in the AE patterns of STXBP4 (rs2628315) and COX11 (rs17817901) in the normal breast tissue of cases and healthy controls. Preferential expression of the G-rs2628315 and A-rs17817901 alleles, more often observed in cases, was associated with an increased risk for BC. Analysis of blood samples from cases and controls found a similar association. Furthermore, we identified two putative cis -regulatory variants – rs17817901 and rs8066588 – that affect a miRNA and a transcription factor binding site, respectively. Conclusion: We propose causal variants and target genes for the 17q22 BC risk locus and show that using AE ratios in case–control association studies is helpful in identifying risk and mapping causal variants. Highlights: Case-control analysis using AE as a phenotype detects risk associations. AE of STXBP4 and COX11 in breast tissue and blood associates with BC risk. rs17817901 and rs8066588 are putative cis-regulatory risk-causing variants. Biological risk mechanisms likely involve altered miRNA and protein binding.