AI Insight
This study identified genetic variants in non-coding regions that increase colorectal cancer risk specifically in Hispanic/Latino populations by disrupting microRNA binding sites. Using genomic data from 453 Hispanic/Latino individuals and computational analysis, researchers found 19 variants across nine genes that alter gene regulation, with three genes (DCBLD2, GREM1, and SMC1B) showing strong evidence that risk variants prevent normal gene silencing, leading to cancer-promoting overexpression. The findings suggest these variants increase cancer susceptibility by removing microRNA-mediated gene repression rather than through changes in DNA methylation or promoter activity.
Why it matters
Hispanic individuals experience disproportionately high colorectal cancer rates but remain underrepresented in genetic research, limiting personalized prevention and treatment strategies. This work identifies ancestry-specific genetic risk factors that could improve risk assessment, early detection, and targeted interventions for this underserved population.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Colorectal cancer (CRC) disproportionately affects Hispanic individuals, who remain underrepresented in genomic discovery and lack ancestry-matched functional resources. Many CRC risk variants are non-coding, and those in 3′ untranslated regions (3′ UTRs) can alter microRNA (miRNA) binding sites and reprogram post-transcriptional gene regulation. Here, we identify allele-specific miRNA-binding variants at CRC risk loci within the Hispanic population using a discovery pipeline anchored to Hispanic-relevant resources. CRC-associated 3′ UTR variants were compiled from the GWAS Catalog, further verified in Hispanic/Latino individuals using the All of Us Research Program cohort (n = 453), expanded into proxy sets using Admixed American-specific linkage disequilibrium, annotated against Ensembl transcripts, and evaluated with TargetScan and RNAhybrid. Screening of 38 CRC-associated 3′ UTR SNPs identified 19 variants that alter miRNA binding across nine genes, with each gene represented by a variant confirmed in the Hispanic cohort. Three oncogenic loci, DCBLD2 (lead SNP rs11552978), GREM1 (lead SNP rs10318), and SMC1B (rs3747239, prioritized as an AMR-specific proxy in near-complete LD with confirmed lead rs6007600), met all prioritization criteria. In each case, the risk allele disrupts a strong miRNA-binding site, while the gene shows increased tumor expression, weak correlation between expression and methylation, and an absence of local active transcriptional chromatin marks (cCREs/H3K27Ac). These results suggest that the variants promote gene overexpression through loss of miRNA-mediated repression rather than changes in promoter methylation. Overall, the study identifies non-coding CRC susceptibility variants in the Hispanic population and highlights DCBLD2, GREM1, and SMC1B as strong candidates for functional validation.