# Methylation‐based alcohol consumption scores as prognostic biomarkers in colorectal cancer: Insights from a population‐based cohort

## TL;DR

This study shows that DNA methylation-based alcohol scores can predict survival outcomes in colorectal cancer patients more objectively than self-reported alcohol use.

## Contribution

This is the first study to evaluate methylation-based alcohol scores as prognostic biomarkers in colorectal cancer.

## Key findings

- The 3-CpG methylation score was robustly associated with all-cause and cause-specific mortality in non-metastatic CRC patients.
- The 450-CpG score was linked to overall mortality, non-CRC-related mortality, and alcohol-related mortality.
- Methylation scores correlated with self-reported alcohol intake and may improve risk stratification in CRC care.

## Abstract

Colorectal cancer (CRC) remains a leading cause of cancer‐related mortality, with alcohol consumption implicated in its etiology. However, alcohol's prognostic impact on CRC survival is unclear, and self‐reported intake is limited by bias. This population‐based cohort study evaluated blood DNA methylation‐based alcohol scores as objective prognostic tools in 2,129 CRC patients from Germany's DACHS study (2003–2021; median follow‐up: 10 years). Participants were recruited from 22 hospitals in Southwest Germany, including non‐metastatic (n = 1757) and metastatic (n = 372) patients with complete methylation and alcohol data. All three assessed methylation scores (3‐CpG, 450‐CpG, 144‐CpG) correlated with self‐reported lifetime/recent alcohol intake (Spearman's r: 0.29–0.36; p < 0.0001), particularly recent consumption. In non‐metastatic patients, self‐reported alcohol consumption showed a J‐shaped mortality risk, with elevated risks in heavy drinkers and abstainers. A similar dose–response pattern was observed for the 3‐CpG methylation score, which showed consistent and robust associations with increased overall mortality (adjusted hazard ratio [aHR] per standard deviation increase: 1.18, 95% CI: 1.11–1.25), non‐CRC‐related mortality (1.22, 1.13–1.32), and CRC‐specific mortality (1.12, 1.00–1.25). The 450‐CpG score was associated with overall mortality (1.07, 1.00–1.15), non‐CRC‐related mortality (1.14, 1.05–1.23), and alcohol consumption‐related mortality (1.59, 1.17–2.16). These findings highlight the potential utility of DNA methylation‐based alcohol scores, especially the 3‐CpG and the 450‐CpG scores, as prognostic tools for CRC outcomes. Such biomarkers may provide a more objective measure of alcohol exposure and complement self‐reported data in risk stratification and clinical decision‐making, though further validation is warranted before clinical implementation.

Alcohol's prognostic role in colorectal cancer remains uncertain, partly due to biases in self‐reported intake. This is the first study to evaluate blood DNA methylation‐based alcohol consumption scores as prognostic biomarkers in colorectal cancer. All three evaluated methylation scores were significantly correlated with self‐reported alcohol intake. The 3‐CpG score demonstrated robust and consistent associations with all‐cause and cause‐specific mortality in non‐metastatic patients. The 450‐CpG score was particularly associated with overall mortality, non‐CRC‐related mortality, and alcohol consumption‐related mortality. These findings highlight the potential of epigenetic biomarkers to provide objective exposure assessment and improve risk stratification in colorectal cancer care.