Mutations in RECQL Gene Are Associated with Predisposition to Breast Cancer

Abstract

The genetic cause for approximately 80% of familial breast cancer patients is unknown. Here, by sequencing the entire exomes of nine early-onset familial breast cancer patients without BRCA1/2 mutations (diagnosed with breast cancer at or before the age of 35) we found that two index cases carried a potentially deleterious mutation in the RECQL gene (RecQ helicase-like; chr12p12). Recent studies suggested that RECQL is involved in DNA double-strand break repair and it plays an important role in the maintenance of genomic stability. Therefore, we further screened the RECQL gene in an additional 439 unrelated familial breast cancer patients. In total, we found three nonsense mutations leading to a truncated protein of RECQL (p.L128X, p.W172X, and p.Q266X), one mutation affecting mRNA splicing (c.395-2A>G), and five missense mutations disrupting the helicase activity of RECQL (p.A195S, p.R215Q, p.R455C, p.M458K, and p.T562I), as evaluated through an in vitro helicase assay. Taken together, 9 out of 448 BRCA-negative familial breast cancer patients carried a pathogenic mutation of the RECQL gene compared with one of the 1,588 controls (P = 9.14×10-6). Our findings suggest that RECQL is a potential breast cancer susceptibility gene and that mutations in this gene contribute to familial breast cancer development.

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.…”

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.…”

“…5 A sequencing analysis of an additional 439 breast cancer patients revealed 9 RECQL germline mutations predicted to be pathogenic which included 3 nonsense mutations, one helicase domain-disruptive splice-site mutation, and 5 missense mutations in which the corresponding purified recombinant RECQL proteins were defective in helicase activity. Altogether, the pathogenic RECQL mutation frequency in the 448 familial breast cancer patients was 2.0% compared to 0.06% in 1,588 controls.…”

“…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.…”

“…30 Five breast cancer associated missense mutations identified in RECQL from the ethnic Chinese Han were found to reside at highly conserved residues in the helicase core or RecQ C-terminal (RQC) domains of RECQ1 that are implicated in strand separation, ATP hydrolysis, dimer formation, or protein stability. 5 Of these, the researchers determined that 4 RECQL missense mutations completely abolished helicase activity and the other greatly reduced helicase activity on a 19-bp forked duplex DNA substrate when incubated with the corresponding purified recombinant RECQL proteins under multi-turnover conditions in vitro. Three RECQL missense mutations identified in the breast cancer patients did not apparently affect helicase activity; however, it is conceivable that under more stringent conditions there may be detectable effects on DNA unwinding, other RECQL catalytic functions (strand annealing, branch-migration), or RECQL protein interactions.…”