Predictive and prognostic significance of aberrant methylation of ADAMTS9 in human hepatocellular carcinoma

Objective: To investigate the aberrant methylation of a disintegrin-like and metalloprotease with thromobospondin type 1 motif 9 (ADAMTS9) gene in human hepatocellular carcinoma tissues, and to explore the correlations of their methylation status with predictive and prognostic significance. Methods: The methylation status of ADAMTS9 gene in 132 cases of hepatocellular carcinoma tissues and their corresponding para-cancerous liver cirrhosis tissues, and 15 cases of normal tissues were detected by methylation specific polymerase chain reaction (MSP). To study the relationship between the gene and the clinical data, the pathological characteristics and survival data of patients were used. Results: Positive rate of ADAMTS9 gene DNA promotor methylation in tumor tissues, para-cancerous liver cirrhosis tissues and the normal tissues were 66.67%, 29.55% and 0.00%, respectively. Significant difference among the three groups was observed (χ2 = 49.918，P = 0.000). The positive rate of methylation in tumor tissues was significantly higher than those in para-cancerous liver cirrhosis tissues and the normal tissues. The patients with a portal vein tumor thrombus had a higher methylation-positive rate (78.72%) as compared with the patients without portal vein tumor thrombus (60.00%), and the difference was statistically significant (P = 0.029). The positive rate of ADAMTS9 DNA methylation in the patients with stage Ⅰ/Ⅱ was greater than that in the patients with stage Ⅲ/Ⅳ(P = 0.008). Survival analysis showed that patients with methylation of ADAMTS9 had a lower two-year survival rate (29.5%) than that of the patients with no methylation of ADAMTS9 (50.0%), and the difference was statistically significant (P = 0.002). COX analysis showed that methylation of ADAMTS9 was an independent prognostic factor of hepatocellular carcinoma  (P = 0.013). Conclusion: The aberrant methylation of tumor suppressor gene ADAMTS9  DNA promotor may be involved in the formation and progression of hepatocellular carcinoma. These results suggest that the methylation of ADAMTS9 is an independent prognostic factor of hepatocellular carcinoma. DOI:10.3781/j.issn.1000-7431.2014.03.007