Abstract
BACKGROUND: Smoking is a well-established risk factor for colorectal cancer (CRC) development. However, the reliability of DNA methylation-based smoking signatures in predicting smoking status and their prognostic value in CRC remain unclear, particularly across different biological sample types. RESULTS: Five previously validated methylation-based smoking signatures were analyzed in 2237 CRC patients with blood-derived DNA and 2273 patients with tumor tissue-derived DNA. Blood-derived signatures showed strong correlations with self-reported smoking status, effectively differentiating current smokers from never smokers (all p < 0.0001), with excellent discriminative ability (median area under the receiver operating characteristic curve: 0.94). In contrast, tumor tissue-derived signatures exhibited much weaker associations with smoking status. Among non-metastatic CRC patients, blood-derived methylation signatures were significantly associated with increased risks of all-cause and non-CRC-related mortality, but not with CRC-specific mortality. Conversely, two tumor tissue-derived signatures demonstrated stronger associations with CRC-specific mortality compared to blood-derived signatures. CONCLUSIONS: Blood-derived methylation-based smoking signatures are robust indicators for smoking exposure and are associated with increased mortality risk among non-metastatic CRC patients. When applied to tumor tissue, signatures showed stronger associations with CRC-specific mortality.