By Pooja Toshniwal PahariaReviewed by Lexie CornerJun 20 2025A recent study published in the British Journal of Cancer examined whether genetic variants that regulate DNA methylation—known as methylation quantitative trait loci (mQTLs)—are associated with colorectal cancer (CRC) risk, recurrence, and survival.
Researchers used data from the largest DNA methylation study to date, analyzing over 400,000 methylation sites in blood. They combined this with case-control data from CRC patients in Scotland, incorporating detailed clinical information and long-term follow-up.
The goal was to explore whether DNA methylation patterns could help identify genes linked to CRC, potentially serving as diagnostic or prognostic markers.
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Background
Colorectal cancer is the second leading cause of cancer-related deaths worldwide. Identifying genetic and molecular risk factors is key to developing targeted screening programs and more personalized approaches to prevention and treatment. Stratifying patients by risk could improve outcomes by tailoring care to those more likely to develop CRC or experience recurrence.
While lifestyle and environmental factors are known to influence CRC risk, epigenetic changes—such as DNA methylation—also play a role in tumor development. DNA methylation can affect gene expression in colorectal tumors and has been linked to overall mortality. Genetic variants that influence methylation levels, like mQTLs, may offer insight into the genetic basis of CRC risk.
About the Study
The study explored associations between mQTLs and CRC using individual-level genome-scale data from several large case-control cohorts in Scotland. This included 6,821 CRC cases and 14,692 controls from studies such as the COGS, SOCCS I and III, Lothian Birth Cohort (LBC), and Generation Scotland (GS). After quality control procedures, the final dataset included 6,379 CRC cases and 11,008 controls.
Researchers derived 118,982 locus-specific mQTLs from the Genetics of DNA Methylation Consortium (GoDMC), which includes data from 27,750 Europeans and spans 36 large-scale methylation and transcriptome studies.
Participants were followed until July 1, 2017, or until death. Recurrence data came from the South East Scotland Database (SESCD), while mortality data were sourced from the Scottish Cancer Registry. In total, 2,045 CRC patients had complete data on genetics, recurrence, survival, and covariates.
The team used logistic regression to assess the relationship between mQTL scores and CRC risk. Cox proportional hazards models were used to evaluate associations between mQTLs and overall survival (OS), CRC-specific survival (CSS), and recurrence-free survival (RFS).
They also compared their findings with a recent meta-genome-wide association study (GWAS) on CRC, which identified 205 SNPs linked to 155 effector genes. Colocalization analyses were performed to determine whether genetic variants affecting methylation also influenced CRC risk. Only individuals of European ancestry were included, and SNPs with low call rates or rare minor allele frequencies were excluded.
Key Findings
The analysis revealed 19 mQTLs across 10 genomic regions that were associated with CRC risk. Two of these regions—linked to the STARD3 and MDGA2 genes—had not been previously reported.
Other regions included genes previously associated with CRC, such as GREM1, CABLES2, POU5F1B, POU2AF2 (also known as c11orf53), and POU2AF3 (COLCA2). Additional mQTLs mapped to regions linked to PANDAR, LAP3P2, PPA2, CTIF, and POU6F1. Some of these overlapped with known CRC GWAS loci, but were newly annotated to different genes in this study.
Among deceased participants, CRC was the leading cause of death in 71 % (n=1,415) of cases. Recurrence was reported in 46 % (n=942). However, when analyzing only stage IV patients, no significant associations were found between mQTLs and advanced disease or metastasis, suggesting that methylation signals may not specifically drive progression.
Colocalization analysis identified shared causal variants for both methylation and CRC risk in three of ten regions. These included loci on chromosomes 6 (linked to PANDAR), 11 (COLCA1, POU2AF2, POU2AF3), and 20 (LAMA5, CABLES2). While this supports a potential role for DNA methylation in CRC susceptibility, the study found no strong evidence linking these mQTLs to recurrence or survival after adjusting for false discovery rates.
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Conclusions
The findings suggest that while DNA methylation-related genetic variants may influence CRC risk, they do not appear to affect disease recurrence or survival. Limitations such as unmeasured confounders, limited statistical power, and selection or lead-time bias could have influenced the results. For example, patients with more advanced but less clinically managed tumors might skew recurrence rates, and earlier detection could falsely appear to improve survival.
The authors recommend that future research incorporate environmental exposures and tissue-specific methylation data to better understand the role of epigenetic regulation in CRC risk and outcomes.
Journal Reference
Mesa-Eguiagaray, I., et al. (2025). Association between methylation quantitative trait loci and colorectal cancer risk, survival, and cancer recurrence. Br J Cancer, DOI: 10.1038/s41416-025-03064-8, https://www.nature.com/articles/s41416-025-03064-8
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