Methylation Patterns and Chemosensitivity in NSCLC

Abstract

Survival in advanced non-small-cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy is rather variable. Methylation-dependent transcriptional silencing of 14-3-3sigma, a major G2/M checkpoint control gene, could be a predictor of longer survival. A sensitive methylation-specific polymerase chain reaction assay was used to evaluate 14-3-3sigma methylation status in pretreatment serum DNA obtained from 115 cisplatin-plus-gemcitabine-treated advanced NSCLC patients. 14-3-3sigma methylation was observed in all histologic types in 39 patients (34%). After a median follow-up of 9.8 months, median survival was significantly longer in the methylation-positive group (15.1 vs 9.8 months; P = 0.004). Median time to progression was 8 months in the methylation-positive group, and 6.3 months in the methylation-negative group (P = 0.027 by the log-rank test). A multivariate Cox regression model identified only 14-3-3sigma methylation status and ECOG performance status (PS) as independent prognostic factors for survival. In an exploratory analysis, median survival for 22 methylation-positive responders has not been reached, while it was 11.3 months for 29 methylation-negative responders (P = 0.001). Methylation of 14-3-3sigma is a new independent prognostic factor for survival in NSCLC patients receiving platinum-based chemotherapy. It can be reliably and conveniently detected in the serum, thus obviating the need for tumor tissue analysis.

The potential of circulating nucleic acids as components of companion diagnostics for predicting and monitoring chemotherapy response

“…Methylation of this major G2/M checkpoint control gene was observed in all histologic types of 39 NSCLC patients. Median survival was significantly longer in the methylation-positive patient group than its counterpart [28]. Using the methyLight analysis, DNA methylation of RASSF1A (ras association domain family 1A) was investigated in pretherapeutic serum samples collected 1 year after surgery from 148 patients with breast cancer who were receiving adjuvant tamoxifen.…”