SULF2 Methylation Is Associated with In Vitro Cisplatin Sensitivity and Clinical Efficacy for Gastric Cancer Patients Treated with a Modified FOLFOX Regimen

OBJECTIVE: Biomarkers capable of discriminating the patients who are likely to respond to certain chemotherapeutic agents could improve the clinical efficiency. The sulfatases(SULFs) play a critical role in the pathogenesis of a variety of human cancers. Here, we focused our investigation on the prognostic and predictive impact of SULF2 methylation in gastric cancer. METHODS: Promoter CpG island methylation of SULF2 was analyzed in 100 gastric cancer samples. The in vitro sensitivity to cisplatin, docetaxel, gemcitabine, irinotecan and pemetrexed were determined by histoculture drug response assay(HDRA). Additionally, 56 gastric cancer patients treated with a modified FOLFOX regimen(biweekly oxaliplatin plus 5-FU and folinic acid) were retrospectively analyzed to further evaluate the prognostic and predictive impact of SULF2 methylation in gastric cancer. RESULTS: Methylated SULF2(SULF2M) was detected in 28 patients, while the remaining 72 patients showed unmethylated SULF2(SULF2U, methylation rate: 28%). Samples with SULF2U were more sensitive to cisplatin than those with SULF2M(inhibition rate: 48.80% vs. 38.15%, P = 0.02), while samples with SULF2M were more sensitive to irinotecan than SULF2U(inhibition rate: 53.61% vs. 40.92%, P = 0.01). There were no association between SULF2 methylation and in vitro sensitivity to docetaxel, gemcitabine and pemetrexed. SULF2 methylation was found to have a significant association with cisplatin efficacy(SULF2M: 57.14%, SULF2U: 80.56%, P = 0.02) and irinotecan efficacy(SULF2M: 89.29%, SULF2U: 62.50%, P = 0.01). Among the 56 patients receiving the modified FOLFOX regimen, a significant association was observed between survival and SULF2 methylation status(SULF2M: 309 days, 95% CI = 236 to 382 days; SULF2U: 481 days, 95% CI = 418 to 490 days; P = 0.02). Multivariate analysis revealed that SULF2 methylation was an independent prognostic factor of overall survival in gastric cancer patients treated with platinum-based chemotherapy. CONCLUSION: SULF2 methylation is negatively associated with cisplatin sensitivity in vitro. SULF2 methylation may be a novel prognostic biomarker for gastric cancer patients treated with platinum-based chemotherapy.