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Published on: July 28, 2010
Germline Predisposition to Oncogenic Alkylating Damage in Colorectal Cancer
Carino Gurjao1,2,3,4, Jules Cazaubiel1,2, Chichun Tan5
1Department of Medical Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts.
Background:
Red meat consumption is a risk factor for colorectal cancer and has been linked to tumor alkylating DNA damage. rs16906252-T is a cis expression quantitative trait locus variant associated with silencing of MGMT, a central alkylating damage repair gene. We hypothesize that rs16906252-T carriers are predisposed to alkylating damage mutations.
Methods:
We conducted mutational signature deconvolution of colorectal cancer whole-exome sequencing data from The Cancer Genome Atlas (n = 540), the Nurses' Health Study / Health Professionals Follow-Up Study (NHS/HPFS, n = 900), as well as non-Western samples from the Pan-Cancer Analysis of Whole Genomes (Colorectal Adenocarcinoma in China cohort, n = 295) and examined the relationship of rs16906252-T with putative alkylation-dependent tumor mutations. Leveraging lifestyle data from the NHS/HPFS, we also investigated the interaction between red meat consumption and rs16906252-T.
Results:
Among patients with colorectal cancer, rs16906252-T carriers exhibited higher tumor alkylating damage compared with noncarriers. In the general population, rs16906252-T is largely absent in individuals with East Asian ancestries, and we consistently find a negligible contribution of alkylating damage in patients with colorectal cancer with East Asian ancestries. We show that the alkylating mutational signature's carcinogenicity is mainly mediated by KRAS G12D and G13D mutations. We also observe a synergistic effect of rs16906252-T with high prediagnosis red meat intake for tumor alkylating damage.
Conclusions:
MGMT rs16906252-T carriers are predisposed to colorectal cancer oncogenic alkylating damage which is potentiated by red meat intake.
Impact:
Our results support a causal relationship between red meat and colorectal cancer and may inform tailored dietary and screening guidelines for colorectal cancer prevention.
Insights
Individuals with the MGMT rs16906252-T variant have increased colorectal cancer (CRC) risk due to alkylating DNA damage. Red meat consumption synergistically amplifies this risk, suggesting targeted prevention strategies.
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.
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