Germline Predisposition to Oncogenic Alkylating Damage in Colorectal Cancer.

Area of Science:

• Genetics and Cancer Research
• Molecular Epidemiology
• Cancer Prevention

Background:

• Red meat consumption is a known risk factor for colorectal cancer (CRC), associated with increased alkylating DNA damage.
• The rs16906252-T variant acts as a cis expression quantitative trait locus (eQTL) linked to the silencing of MGMT, a key gene in repairing alkylating DNA damage.
• This study hypothesizes that carriers of the rs16906252-T variant are more susceptible to mutations caused by alkylating damage.

Purpose of the Study:

• To investigate the association between the MGMT rs16906252-T variant and alkylating DNA damage in colorectal cancer (CRC).
• To examine the interaction between red meat consumption and the rs16906252-T variant in relation to CRC risk.
• To explore the role of alkylating damage in CRC pathogenesis, particularly in relation to specific mutations and ancestry.

Main Methods:

• Utilized mutational signature deconvolution on whole-exome sequencing data from large CRC cohorts (TCGA, NHS/HPFS, COCA-CN).
• Analyzed the relationship between the rs16906252-T variant and alkylation-dependent tumor mutations.
• Integrated lifestyle data, specifically red meat consumption, to assess gene-environment interactions.

Main Results:

• rs16906252-T carriers showed significantly higher tumor alkylating damage in CRC patients compared to non-carriers.
• The rs16906252-T variant was found to be rare in East Asian ancestries, correlating with negligible alkylating damage in CRC patients from these populations.
• Alkylation-induced carcinogenicity was primarily mediated by KRAS G12D and G13D mutations, with a synergistic effect observed between rs16906252-T and high red meat intake on tumor alkylating damage.

Conclusions:

• Carriers of the MGMT rs16906252-T variant are predisposed to oncogenic alkylating damage in CRC, a process exacerbated by red meat consumption.
• These findings provide evidence for a causal link between red meat and CRC.
• The results may guide the development of personalized dietary recommendations and screening protocols for CRC prevention.