Carino Gurjao, Jules Cazaubiel, Chichun Tan, Brendan Reardon, Matan Hofree, Tomotaka Ugai, Jeffrey A Meyerhardt, Jonathan A Nowak, Edward L Giovannucci, Jeffrey P Townsend, Shuji Ogino, Marios Giannakis
{"title":"Germline predisposition to oncogenic alkylating damage in colorectal cancer.","authors":"Carino Gurjao, Jules Cazaubiel, Chichun Tan, Brendan Reardon, Matan Hofree, Tomotaka Ugai, Jeffrey A Meyerhardt, Jonathan A Nowak, Edward L Giovannucci, Jeffrey P Townsend, Shuji Ogino, Marios Giannakis","doi":"10.1101/2025.06.30.25330572","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Red meat consumption is a risk factor for colorectal cancer (CRC) and has been linked to tumor alkylating DNA damage. <i>rs16906252</i> -T is a cis expression quantitative trait locus (eQTL) variant associated with silencing of <i>MGMT</i> , a central alkylating damage repair gene. We hypothesize that <i>rs16906252</i> -T carriers are predisposed to alkylating damage mutations.</p><p><strong>Methods: </strong>We conducted mutational signature deconvolution of CRC whole-exome sequencing data from The Cancer Genome Atlas (TCGA, n = 540), the Nurses' Health Studies/ Health Professional Follow-up Study (NHS/HPFS, n = 900) as well as non-western samples from the Pan-Cancer Analysis of Whole Genomes (COCA-CN, n = 295); and examined the relationship of <i>rs16906252</i> -T with putative alkylation-dependent tumor mutations. Leveraging lifestyle data from NHS/HPFS, we also investigated the interaction between red meat consumption and <i>rs16906252</i> -T.</p><p><strong>Results: </strong>Among CRC patients, <i>rs16906252</i> -T carriers exhibited higher tumor alkylating damage compared to non-carriers. In the general population <i>, rs16906252</i> -T is largely absent in individuals with East Asian ancestries, and we consistently find a negligible contribution of alkylating damage in CRC patients with East Asian ancestries. We show that the alkylating mutational signature's carcinogenicity is mainly mediated by <i>KRAS</i> G12D and G13D mutations. We also observe a synergistic effect of <i>rs16906252</i> -T with high pre-diagnosis red meat intake for tumor alkylating damage.</p><p><strong>Conclusions: </strong><i>MGMT rs16906252</i> -T carriers are predisposed to CRC oncogenic alkylating damage which is potentiated by red meat intake.</p><p><strong>Impact: </strong>Our results support a causal relationship between red meat and CRC and can lead to tailored dietary and screening guidelines for CRC prevention.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236874/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"medRxiv : the preprint server for health sciences","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2025.06.30.25330572","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Red meat consumption is a risk factor for colorectal cancer (CRC) and has been linked to tumor alkylating DNA damage. rs16906252 -T is a cis expression quantitative trait locus (eQTL) 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 CRC whole-exome sequencing data from The Cancer Genome Atlas (TCGA, n = 540), the Nurses' Health Studies/ Health Professional Follow-up Study (NHS/HPFS, n = 900) as well as non-western samples from the Pan-Cancer Analysis of Whole Genomes (COCA-CN, n = 295); and examined the relationship of rs16906252 -T with putative alkylation-dependent tumor mutations. Leveraging lifestyle data from NHS/HPFS, we also investigated the interaction between red meat consumption and rs16906252 -T.
Results: Among CRC patients, rs16906252 -T carriers exhibited higher tumor alkylating damage compared to non-carriers. 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 CRC patients 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 pre-diagnosis red meat intake for tumor alkylating damage.
Conclusions: MGMT rs16906252 -T carriers are predisposed to CRC oncogenic alkylating damage which is potentiated by red meat intake.
Impact: Our results support a causal relationship between red meat and CRC and can lead to tailored dietary and screening guidelines for CRC prevention.