Genetic Markers of Malignant Transformation in IPMN of the Pancreas: A Meta-Analysis

Abstract

Background: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas has been recognized as an important precursor to pancreatic cancer. Since the WHO established a consensus in 1996 for grading IPMNs, numerous studies have characterized genetic mutations associated with these various histologic grades. However, the molecular basis for progression into cancer remains poorly understood. We hypothesize that malignant transformation of IPMN reflects a progression in molecular changes. To determine the risk of malignant transformation associated with specific genetic abnormalities, we performed themost comprehensive meta-analysis to date of genetic associations with IPMN grade. Methods: We conducted a meta-analysis reviewing Pubmed, Cochrane Library, and Embase databases from January 1996 thru October 2010. We included only studies that adhered to 1996 WHO guidelines for distinguishing adenoma and borderline IPMNs (IPM-A, IPM-B) vs. carcinoma in situ and invasive carcinoma (IPM-C) based on surgically resected specimens. Quantitative meta-analysis was performed of gene candidates using both fixedand random-effects models. The I2 test was used to evaluate study heterogeneity. Results: We identified 178 studies that satisfied the inclusion criteria (1,343 IPMN samples). In pooled analysis there was an overall positive association for IPM-C with MUC-1 expression (OR 5.90; 95% C.I. 2.5413.70), k-Ras mutations (OR 1.90; 95% C.I. 1.04-3.47), and p53 mutations (OR 2.00; 95% C.I. 0.80-4.98). The strongest positive association for IPM-C vs. IPM-A/B was with telomerase mutations (OR 15.95; 95% C.I. 6.32-40.25), consistent with this genetic abnormality occurring relatively later in the histologic progression of IPMN into cancer. Expression of MUC5AC was not associated with IPM-C vs. IPM-A/B (OR 0.71; 95% C.I. 0.23-2.23). We further summarize associations with 91 additional genes including Shh, Cox2, Smad4, APC, and S100A4 as well as findings from cyst and pancreatic fluid assays. Conclusion: This metaanalysis identifies MUC-1 expression and mutations in telomerase, p53 and k-Ras genes as molecular changes associated with IPMN progression to cancer. These associations provide a basis for the use of molecular markers in diagnostic grading of IPMNs as well as a basis for therapeutic targets.