Purpose: Definitive chemoradiotherapy (dCRT) is one of the standard treatments for esophageal squamous cell carcinoma. Patients with a response to dCRT have a better prognosis than those resistant to dCRT while survival benefits for patients with residual tumors are limited. Nevertheless, few molecular markers to predict the response to dCRT are currently available. Here, we aimed to establish a DNA methylation marker to predict the response to dCRT.
Methods: A total of 104 patients were divided into screening (n = 43) and validation (n = 61) sets. A genome-wide DNA methylation analysis was performed using an Infinium HumanMethylation450 BeadChip array. Methylation levels were measured by quantitative methylation-specific PCR and normalized by the fraction of cancer cells in a sample.
Results: The genome-wide methylation analysis of seven responders and eight non-responders identified 18 genomic regions specifically (un)methylated in the responders. Among these, methylation of the promoter CpG island of ZNF695 was significantly associated with the response to dCRT in the screening set (P = 0.004), and a cutoff value was determined. In the validation set, the association was successfully validated (P = 0.021), and a high specificity (90 %) for the prediction of responders was obtained using the prefixed cutoff value. In addition, a multivariate analysis showed that ZNF695 methylation was an independent predictive factor for the response to dCRT (OR 7.55, 95 % CI 2.12-26.9, P = 0.002).
Conclusion: ZNF695 methylation was significantly associated with the response to dCRT and is a promising predictive marker for the response to dCRT.