RECQL – Breast Cancer

RECQL was first implicated as a breast cancer susceptibility gene through whole-exome sequencing of high-risk case cohorts from Quebec and Poland. In Quebec, the truncating variant c.643C>T (p.Arg215Ter) was found in 7 of 1,013 higher-risk cases versus 1 of 7,136 newborn controls (PMID:25915596). In an unselected Polish cohort, the founder splicing deletion c.1667_1667+3delAGTA appeared in 30 of 13,136 breast cancer cases and 2 of 4,702 controls (PMID:25915596), supporting initial enrichment.

Targeted RECQL screening in 448 unrelated BRCA1/2-negative familial breast cancer patients identified pathogenic truncating and splice variants in 9 probands versus one carrier in 1,588 controls (PMID:25945795). Functional assays demonstrated that missense variants such as p.Arg215Gln and p.Leu128Ter abrogate helicase activity in vitro, providing mechanistic support for loss-of-function pathogenicity.

A case–control meta-analysis of the Polish founder mutation c.1667_1667+3delAGTA in 2,596 cases and 2,132 controls found an adjusted odds ratio of 1.23 (95% CI 0.44–3.47; p = 0.69), indicating no high-risk effect (PMID:27832498). A Pakistani study of 302 early-onset and familial cases detected a single c.225G>A (p.Trp75Ter) carrier (0.3%) and concluded that RECQL plays a negligible role in that population (PMID:33342430).

Large cohort analyses in Hong Kong (1,110 cases; PMID:27125668) and African-American women (5,054 cases; PMID:32427313) reported very low RECQL LoF variant frequencies and inconsistent risk estimates, with some studies failing to demonstrate statistical association.

Experimental data robustly link RECQL deficiency to genomic instability. RECQL-null mouse embryonic fibroblasts display aneuploidy, chromosomal breakage and radiation hypersensitivity (PMID:17158923). Human cell knock-down models exhibit gamma-H2AX foci, sister chromatid exchanges and impaired fork recovery, underscoring a tumor-suppressive role for RECQL (PMID:18414032).

Despite biological plausibility and initial enrichment of rare LoF alleles, multiple large-scale case–control and replication studies have yielded conflicting or null associations. Current evidence is insufficient to support routine clinical testing of RECQL for breast cancer predisposition. Well-powered, ethnically diverse studies with segregation data are needed to clarify risk. Key take-home: RECQL loss-of-function variants remain of uncertain clinical utility for breast cancer risk assessment.

References

• Nature Genetics • 2015 • Germline RECQL mutations are associated with breast cancer susceptibility PMID:25915596
• PLoS Genetics • 2015 • Mutations in RECQL Gene Are Associated with Predisposition to Breast Cancer PMID:25945795
• Familial Cancer • 2017 • Analysis of a RECQL splicing mutation, c.1667_1667+3delAGTA, in breast cancer patients and controls from Central Europe PMID:27832498
• Hereditary Cancer in Clinical Practice • 2020 • Prevalence of RECQL germline variants in Pakistani early-onset and familial breast cancer patients PMID:33342430
• Molecular and Cellular Biology • 2007 • RECQL, a member of the RecQ family of DNA helicases, suppresses chromosomal instability PMID:17158923
• Cell Cycle • 2008 • Unique and important consequences of RECQ1 deficiency in mammalian cells PMID:18414032

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