Germline RECQL mutations are associated with breast cancer susceptibility

Abstract

Several moderate- and high-risk breast cancer susceptibility genes have been discovered, but more are likely to exist. To discover new breast cancer susceptibility genes, we used 2 populations (from Poland and Quebec, Canada) and applied whole-exome sequencing in a discovery phase (n = 195), followed by validation. We identified rare recurrent RECQL mutations in each population. In Quebec, 7 of 1,013 higher-risk breast cancer cases and 1 of 7,136 newborns carried the c.634C>T (p.Arg215*) variant (P = 0.00004). In Poland, 30 of 13,136 unselected breast cancer cases and 2 of 4,702 controls carried the c.1667_1667+3delAGTA (p.K555delinsMYKLIHYSFR) variant (P = 0.008). RECQL is implicated in resolving stalled DNA replication forks to prevent double-stranded DNA (dsDNA) breaks. This function is related to that of other known breast cancer susceptibility genes, many of which are involved in repairing dsDNA breaks. We conclude that RECQL is a breast cancer susceptibility gene.

Identification of novel hereditary cancer genes by whole exome sequencing

“…However, most of the breast cancer exome studies reported so far failed to discover genes, whose significance is similar to BRCA1, BRCA2, CHEK2, PALB2, etc. [19][20][21][22]25,28,[132][133][134][135][136]. For example, Snape et al [133] subjected to WES 50 patients with familial breast cancer; they composed the list of promising candidates, but did not communicate yet the results of subsequent case-control study or segregation analysis.…”

“…The issue of false negatives may become particularly important upon the analysis of patient groups. For example, many WES studies focus on novel mutations which occur in more than one family within the analyzed group of patients [19,20,24] or are shared by all affected members within the kindred [30,32,73]. Given the rarity of considered variants, insufficient sensitivity of WES may substantially compromise study outcomes.…”

“…Many WES studies focus on protein-truncating mutations; this approach is justified by the fact that overtly deleterious alleles (stop-codons, frameshifts, splice site aberrations) represent the majority of known disease-causing germ-line mutations in cancer genes [19][20][21]25,29,32,33,82,95]. Current tools for characterization of missense variants remain limited.…”

RECQL: a new breast cancer susceptibility gene

“…Candidate genes, such as those that encode proteins involved in the DNA damage response or DNA repair, have been identified by high throughput next generation sequencing and are being evaluated to determine their importance in cancer risk. Within the last month, Cybulski et al 4 and Sun et al 5 independently performed whole exome sequencing in breast cancer patients from distinct population groups and provided convincing evidence that mutations in the gene encoding the RECQL DNA helicase, a member of the conserved RecQ family of DNA helicases implicated in the maintenance of genomic stability, are associated with breast cancer susceptibility. recurrent RECQL breast cancer associated mutation (c.1667_1667C3delAGTA) was screened in over 13,000 breast cancer patients and 4,702 cancer-free individuals of Polish descent.…”

“…24,25 Upon discovery that RECQL mutations predispose individuals to breast cancer, 4,5 it is an even greater priority to determine the precise molecular roles of RECQL. It is highly probable that RECQL functions with some of the proteins listed in Table 1 and other HR proteins to prevent the accumulation of DNA damage or repair DSBs that are incurred at stalled replication forks.…”