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Definitive chemoradiotherapy (dCRT) is the major treatment for esophageal squamous cell carcinoma (ESCC), and prediction of the response to dCRT is important so as not to miss an opportunity to cure an ESCC. Nevertheless, few validated markers are available. Here, we aimed to identify a highly reproducible marker using multi-layer omics analysis. 117 ESCC samples from 67 responders and 50 non-responders were divided into screening, validation, and re-validation sets. In the screening cohort (n = 41), somatic mutations in 114 genes showed no association with dCRT response. Genome-wide DNA methylation analysis using Infinium HumanMethylation450 BeadChip array identified four genic regions significantly associated with dCRT response. Among them,  FGF5  methylation was validated to be associated with dCRT response (n = 34;  P  = 0.001), and further re-validated (n = 42;  P  = 0.020) by bisulfite-pyrosequencing. The sensitivity and specificity in the combined validation and re-validation sets (n = 76) were 45% and 90%, respectively, by using the cut-off value established in the screening set, and  FGF5  methylation had predictive power independent from clinicopathological parameters. In ESCC cell lines,  FGF5  promoter methylation repressed its expression.  FGF5  expression was induced by cisplatin (CDDP) treatment in three unmethylated cell lines, but not in two methylated cell lines. Exogenous  FGF5  overexpression in a cell line with its methylation conferred resistance to CDDP. In non-cancerous esophageal tissues,  FGF5  was not expressed, and its methylation was present in a small fraction of cells. These results showed that  FGF5  methylation is a validated marker for ESCC sensitivity to dCRT.

FGF5 methylation is a sensitivity marker of esophageal squamous cell carcinoma to definitive chemoradiotherapy