Human mutL homolog 1 (hMLH1) is the most important member of Mismatch repair (MMR) genes encoding a number of DNA repair enzymes and thus cooperating to recognize and repair DNA mismatches . DNA methylation of hMLH1 has been found in ovarian and colorectal cancer cell lines for resistance to cisplatin[2,3]. Our previous study also demonstrated that DNA methylation of hMLH1 is involved in determining sensitivity to cisplatin in NSCLC A549/DDP cell line, and cisplatin resistance could be reversed by the demethylating agent 5-zaz-2’-deoxycytidine (5-Aza-dc) in vitro .
To determine whether DNA methylation of hMLH1 affects the prognosis of non-small cell lung cancer patients who received cisplatin-based adjuvant chemotherapy.
Methylation status of hMLH1 was examined by using nested methylation-specific PCR (nested MSP) in 84 archived non-small cell lung cancer (NSCLC) surgically resected tissue specimens from patients receiving cisplatin-based adjuvant chemotherapy. Univariate and multivariate analysis were used to investigate the relationship between hMLH1 methylation status and the clinical prognosis of the patients mentioned above.
In the cohort of 84 NSCLC cases, 80 tissue samples were successfully amplified by nested MSP. Among them, 36 samples (45%) were identified to be methylated. Moreover, hMLH1 methylation was not associated with age, gender, smoking status, T stage, histology and differentiation, but correlated with lymphatic metastasis (p=0.021). Multivariate logistic regression analysis showed that hMLH1 methylation may function as a significant independent prognostic factor for tumor recurrence in NSCLC patients treated with adjuvant cisplatin (HR 3.114, 95% CI 1.032-9.399; p= 0.044). However, Kaplan-Meier method (p=0.093) and multivariate Cox regression analysis (p=0.598) revealed that hMLH1 methylation was not associated with the survival of these patients.
The cisplatin-based adjuvant chemotherapy is more beneficial for NSCLC patients without hMLH1 methylation. hMLH1 methylation may have a potential to become a biomarker of individualized therapy for NSCLC patients.