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

Abstract

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.

Germline RECQL gene mutations in Chinese patients with breast cancer

“…In this study, the RECQL mutation frequency was 2.719% (58/2133), occurring much less frequently than BRCA1/2 and PALB2 mutations (18,19). However, this value is higher than those reported in other countries, including Germany, the United States, and Canada, where the mutation frequency ranges from 0 to 2.6% (11,(20)(21)(22). In addition, we did not identify any single mutations in this study; all mutations were accompanied by BRCA1/2 double mutations or BRCA1/2 and PALB2 triple mutations, suggesting that BRCA1/2 or PALB2 may influence RECQL mutations, but this requires further verification.…”

Prevalence of RECQL germline variants in Pakistani early-onset and familial breast cancer patients

“…In other studies performed in China [ 7 , 11 ], higher pathogenic variant frequencies ranging from 0.54 to 1.6% were observed in BRCA1 and BRCA2 negative early-onset and/or familial breast cancer cases. In Caucasian studies conducted in the Australia [ 10 ], Canada [ 6 ], Poland [ 6 ], and USA [ 9 ], similar variant frequencies ranging from 0.1 to 0.4% have been reported in familial breast cancer patients, while no pathogenic variants were detected in studies performed in South-West Poland and West Ukraine [ 24 ]. In other Caucasian studies conducted in Belarus, Germany, and Australia, the frequency of pathogenic variants identified in controls were similar or higher than cases [ 8 , 10 ].…”

“…It encodes a DNA helicase, which is involved in the repair of DNA double-strand breaks and plays a crucial role in the maintenance of genomic stability. Several studies conducted among unselected breast cancer patients from Belarus and Germany [ 8 ], USA [ 9 ], and early-onset and familial breast cancer patients from Poland [ 6 ], Canada [ 6 ], and Australia [ 10 ] reported pathogenic RECQL variant frequencies ranging from 0 to 2.6%. Breast tumors associated with pathogenic RECQL variants were predominantly positive for the estrogen and progesterone receptors (ER and PR) [ 6 – 8 , 11 ].…”