Germline predisposition to oncogenic alkylating damage in colorectal cancer

Area of Science:

• Genetics and Cancer Biology
• Molecular Epidemiology
• Nutritional Oncology

Background:

• Red meat consumption is a known risk factor for colorectal cancer (CRC), associated with increased tumor alkylating DNA damage.
• The rs16906252-T variant acts as a cis-eQTL, downregulating MGMT, a key gene in repairing alkylating DNA damage.
• This suggests rs16906252-T carriers may have a heightened susceptibility to mutations caused by alkylating agents.

Purpose of the Study:

• To investigate the association between the rs16906252-T variant, alkylating DNA damage, and colorectal cancer.
• To examine the interaction between red meat consumption and rs16906252-T in CRC development.
• To identify specific mutations mediated by alkylating damage in CRC.

Main Methods:

• Mutational signature deconvolution of whole-exome sequencing data from large CRC cohorts (TCGA, NHS/HPFS, COCA-CN).
• Analysis of the relationship between rs16906252-T and alkylation-dependent tumor mutations.
• Investigation of lifestyle data, specifically red meat intake, in relation to rs16906252-T status.

Main Results:

• rs16906252-T carriers showed significantly higher tumor alkylating damage in CRC patients.
• The rs16906252-T variant is rare in East Asian ancestries, correlating with negligible alkylating damage in CRC patients from these populations.
• KRAS G12D and G13D mutations were identified as key drivers of carcinogenicity mediated by the alkylating mutational signature.
• A synergistic effect was observed between rs16906252-T and high red meat intake on tumor alkylating damage.

Conclusions:

• Individuals carrying the rs16906252-T variant are predisposed to oncogenic alkylating damage in colorectal cancer.
• Red meat consumption exacerbates this predisposition, potentiating the alkylating damage and CRC risk.
• These findings support a causal link between red meat and CRC, paving the way for personalized dietary and screening strategies.