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Background: Reliable biomarkers to predict prognosis are lacking for patients with pancreatic ductal adenocarcinoma (PDAC) who are being considered for appropriate multimodality treatment. The aim of this study was to investigate aberrant hypermethylation of a candidate set of tumor suppressor genes as a potential cancer-specific molecular marker system related to outcomes for patients with resected PDAC.
Methods: Isolated DNA samples from primary PDAC and individually matched adjacent normal tissue from 37 patients who underwent operative resection were analyzed. The methylation status of 6 gene promoters (RASSF1A, MGMT, GSTP1, APC, P16/CDKN2A, and NEFL) was determined by quantitative methylation-specific PCR (QMSP). Promoter site methylation levels were calculated and correlated with clinical, pathologic, and outcome factors.
Results: Hypermethylation of the neurofilament light chain (NEFL) gene was significantly higher in PDAC compared to matched adjacent normal tissue (p<0.01). Promoter methylation levels of APC in PDAC correlated with overall survival, HR = 1.004 (95% CI, 1.001-1.007), and APC gene hypermethylation in matched normal tissue was associated with death within one year after resection (OR 0.073; 95% CI, 0.007-0.724). Promoter methylation of APC in host normal tissue along with APC methylation levels of primary tumors and surgical resection margin status can be used to evaluate the risk of death within one year after resection with a predictive accuracy of 87%.
Conclusion: Hypermethylation of the promoter region of candidate tumor suppressor genes in patients with pancreatic adenocarcinoma treated by operative resection is associated with early recurrence and death. Larger scale studies will be necessary to validate patterns of gene methylation as a potential cancer-specific molecular marker system related to outcomes for pancreatic cancer.