A Large Case-Control Study Performed in Spanish Population Suggests That RECQL5 Is the Only RECQ Helicase Involved in Breast Cancer Susceptibility.

Simple Summary: Around 50% of the familial breast cancer (BC) cases are estimated to be caused by variants in low-, moderate-, and high-risk susceptibility genes; however, the other half is of unknown origin. The finding of new susceptibility genes is key to improve diagnosis, take preventive measures, and identify new therapies. In this context, previous studies have discussed whether the genes encoding for the RECQ helicase family could play a role in BC susceptibility, without very conclusive results. To clarify this, in this study, we sequenced the whole coding sequence of the RECQL1, BLM, WRN, RECQL4, and RECQL5 genes in 1993 Spanish BC familial cases and compared it with controls from gnomAD. No association was found for RECQL1, BLM, WRN, and RECQL4; however, we did find an association between RECQL5 and breast cancer as a moderate-risk gene, making it a perfect candidate for further studies. Around 50% of the familial breast cancer (BC) cases are estimated to be caused by germline variants in known low-, moderate-, and high-risk susceptibility genes, while the other half is of unknown genetic origin. In the present study, we wanted to evaluate the role of the RECQ helicases, some of which have been studied in the past as candidates, with unclear results about their role in the disease. Using next-generation sequencing (NGS) technology, we analyzed the whole coding sequence of BLM, RECQL1, RECQL4, RECQL5, and WRN in almost 2000 index cases from BC Spanish families that had previously tested negative for the known BC susceptibility genes (BRCAX) and compared the results with the controls extracted from gnomAD. Our results suggest that BLM, RECQL1, RECQL4, and WRN do not play a major role in BC susceptibility. However, in the combined analysis, joining the present results with those previously reported in a series of 1334 BC Spanish patients and controls, we found a statistically significant association between Loss of Function (LoF) variants in RECQL5 and BC risk, with an OR of 2.56 (p = 0.009; 95% CI, 1.18–4.98). Our findings support our previous work and places the RECQL5 gene as a new moderate-risk BC gene. [ABSTRACT FROM AUTHOR]