RecQ DNA helicases germline variants in Lynch-like syndrome

Lynch-like syndrome (LLS) is associated with an incomplete understanding of its molecular basis. Some LLS tumors harbor somatic variants in mismatch repair genes, whereas germline variants in other DNA repair genes point to a hereditary predisposition in certain cases. Clinically, LLS patients tend to develop colorectal cancer (CRC) earlier, have a stronger family history of CRC, and respond better to immunotherapy compared with sporadic CRC cases. This study seeks to identify cancer-susceptibility genes in LLS patients, which could affect diagnosis, treatment, and surveillance.

Germline exome sequencing was performed on 102 participants, including 14 previously reported cases. In vitro models were created to study the effect of loss-of-function (LoF) variants in DNA repair genes. Gene/protein expression was evaluated using quantitative real-time PCR and Western blotting, and DNA repair capacity was assessed via H2AX phosphorylation after ionizing radiation exposure.

Nine rare LoF variants were identified in DNA repair genes, including 3 in RecQ DNA helicases (WRN HGNC:12791, RECQL5 HGNC:9950). LLS patients had a higher mutational burden in DNA repair genes across various cancer phenotypes. In vitro, cells with these LoF variants showed reduced gene-protein expression and increased H2AX phosphorylation after irradiation, indicating impaired DNA repair.

A single LoF variant in RecQ DNA helicase genes can result in significant DNA repair deficiency, leading to genomic instability and contributing to CRC development in LLS. Therefore, we present evidence for incorporating RECQL5 into genetic testing panels for CRC risk assessment, which would enhance both diagnosis and treatment outcomes.