Methylation signatures distinguish non small cell lung cancer subtypes and associated with survival in smokers with lung squamous cell carcinoma.
retrospective_cohort · Level III
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- Also identified by DOI 10.1093/jnci/djag067.
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Abstract
Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) are the two major histologic subtypes of non-small cell lung cancer and differ in prognosis, biological behavior, and molecular characteristics. Although aberrant DNA methylation has been implicated in lung cancer and patient survival, systematic investigations of subtype-specific methylation signatures distinguishing these subtypes remain limited. We identified DNA methylation signatures that distinguish LUSC from LUAD and evaluated their associations with survival among ever-smokers using data from The Cancer Genome Atlas, with independent validation in the CURELUNG cohort. Survival analyses assessed associations between a methylation-based score and patient survival. Integrative analyses incorporating mRNA expression, global proteomic profiles, and transcription factor (TF) motifs enrichment were performed to explore potential regulatory features associated with the identified methylation markers. Eleven differentially methylated CpG sites distinguished LUSC and LUAD and demonstrated high classification accuracy in an independent validation cohort. Among LUSC cases, lower methylation scores (below the median) were associated with a 2.7-fold increased risk of mortality during the first two years of follow-up based on piecewise Cox regression models. Integrative analyses revealed subtype-specific differences in CALML3 expression and enrichment of TF binding motifs near the identified signatures, particularly C2H2 zinc-finger motifs. This study identified a subtype-specific DNA methylation signature that robustly distinguishes LUAD and LUSC and is associated with early survival among ever-smokers with LUSC. These findings highlight biologically meaningful epigenetic patterns that may contribute to histology-specific tumor behavior and provide a foundation for future mechanistic and biomarker development studies.