Abstract A29: Investigation of RECQL variants in European and African American breast cancer cohorts

Although an average woman in the United States can have a 12.5% lifetime risk of developing breast cancer (BC), inherited genetic risk variants can greatly influence a woman’s overall lifetime risk. Genes that harbor BC risk variants are referred to as BC susceptibility genes. Unfortunately, mutations in known BC susceptibility genes only explain approximately 35% of hereditary BC cases, leaving a large portion, approximately 65%, genetically unexplained. With the introduction of next-generation sequencing, several attempts have been carried out to identify additional hereditary BC susceptibility genes using whole-exome sequencing. The majority of these studies were relatively unsuccessful; however, Cybulski et al. (2015) successfully associated two rare truncation variants in RECQL , p.K555delinsMYKLIHYSFR and p.R215*, in a Polish and French-Canadian cohort, respectively. Subsequently, two additional studies were carried out in northern and southern regions of China, which also confirmed that overtly deleterious coding mutations in RECQL are associated with familial BC. Herein, we investigated RECQL variants in BC-affected African Americans (AAs) and European Americans (EAs). To our knowledge, this study represents the first attempt to identify an association between RECQL variants and BC cases in the United States. We initially screened all RECQL coding exons using polymerase chain reaction and Sanger sequencing in 49 BC cases (19 AAs and 30 EAs) from Alabama. Primarily synonymous variants were detected in both ethnicities; thus, in order to further investigate the role of RECQL synonymous variants in BC risk, we analyzed RECQL in blood-derived exomes of 168 and 580 BC-affected AAs and EAs, respectively, from The Cancer Genome Atlas (TCGA) project using an in-house bioinformatics pipeline. A case-control analysis revealed that all rare synonymous variants detected in EA BC cases were associated with BC, and p.S64= was significantly associated in both ethnicities. Interestingly, only one truncation variant was detected (p.Y492*) in all 748 BC cases analyzed. Unlike previous findings, this preliminary analysis suggests that rare RECQL synonymous variants may also increase an individual’s lifetime risk of developing BC; further investigation is warranted. Citation Format: Madison R. Chandler, Sydney Bergstresser, Anna LW Huskey, Elizabeth Stallworth, Amber Davis, Holly Dean, Brandon Johnson, Nancy D. Merner. Investigation of RECQL variants in European and African American breast cancer cohorts [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A29.