RecQ DNA helicases germline variants in Lynch-like syndrome

Area of Science:

• Genetics
• Molecular Biology
• Cancer Research

Background:

• Lynch-like syndrome (LLS) has an unclear molecular basis, with some cases linked to mismatch repair gene variants and others to germline DNA repair gene variants.
• LLS patients often develop colorectal cancer (CRC) earlier, have a stronger family history of CRC, and respond better to immunotherapy than sporadic CRC cases.
• Identifying cancer-susceptibility genes in LLS is crucial for improving diagnosis, treatment, and surveillance strategies.

Purpose of the Study:

• To identify cancer-susceptibility genes in patients with Lynch-like syndrome (LLS).
• To understand the molecular underpinnings of LLS and its association with colorectal cancer (CRC).
• To provide evidence for enhanced genetic testing and risk assessment in LLS.

Main Methods:

• Germline exome sequencing of 102 LLS participants.
• Creation of in vitro models to assess the impact of loss-of-function (LoF) variants in DNA repair genes.
• Evaluation of gene/protein expression and DNA repair capacity (H2AX phosphorylation) post-irradiation.

Main Results:

• Nine rare LoF variants in DNA repair genes were identified, including three in RecQ DNA helicases (WRN, RECQL5).
• LLS patients exhibited a higher mutational burden in DNA repair genes across different cancer types.
• In vitro models demonstrated impaired DNA repair in cells with LoF variants, evidenced by reduced gene-protein expression and increased H2AX phosphorylation.

Conclusions:

• Loss-of-function variants in RecQ DNA helicase genes contribute to DNA repair deficiency, genomic instability, and CRC development in LLS.
• Incorporating RECQL5 into genetic testing panels can enhance CRC risk assessment, diagnosis, and treatment outcomes for LLS patients.