# Genetic variants reshape the m6A epitranscriptome and drive transcriptomic reprogramming in colorectal cancer

## TL;DR

This study shows how genetic variants affect RNA methylation and gene expression in colorectal cancer, revealing a new link between genetics and cancer progression.

## Contribution

The study identifies a novel connection between cancer-associated SNPs and m6A RNA methylation in driving transcriptomic changes in colorectal cancer.

## Key findings

- Cancer-associated SNPs are enriched in hypermethylated m6A regions in colon cancer.
- SNPs in m6A regions are linked to altered gene expression and RNA splicing.
- ALKBH5 knockdown experiments confirm RNA methylation's role in gene regulation.

## Abstract

Genome-wide association studies (GWAS) have identified numerous single-nucleotide polymorphisms (SNPs) associated with various diseases, including cancer. However, the mechanisms by which these SNPs contribute to disease susceptibility remain largely unclear. While recent studies have explored the transcriptional impact of disease-associated SNPs, their role in post-transcriptional regulation has been less extensively investigated. In this study, we investigated whether cancer-associated SNPs influence gene expression by altering N6-methyladenosine (m6A) RNA methylation. We collected GWAS-identified SNPs across nine cancer types and integrated these with matched tumor and normal m6A RNA immunoprecipitation sequencing (m6A-seq) and RNA sequencing (RNA-seq) datasets. We first identified differentially methylated m6A sites and assessed whether cancer-associated SNPs were enriched within these regions. These analyses revealed that cancer-associated SNPs were significantly enriched within hypermethylated m6A regions in colon cancer. Integrative analysis revealed that SNPs enriched in m6A-modified regions are associated with altered gene expression and RNA splicing, suggesting that m6A methylation mediates the post-transcriptional impact of genetic variants. Experimental validation further confirmed altered gene expression following ALKBH5 knockdown, consistent with patient-derived data. Collectively, our findings support a novel mechanistic connection between genetic variants and RNA methylation-driven transcriptomic regulation in colorectal cancer, underscoring the epitranscriptome as a potential axis of oncogenic control.

The online version contains supplementary material available at 10.1038/s41598-025-23397-x.