Coordinate Loss of Fragile Gene Expression in Pancreatobiliary Cancers: Correlations Among Markers and Clinical Features

Abstract

Loss of expression of fragile gene products, Fhit and Wwox, occurs in many cancer types, with loss exhibited early in the neoplastic process in some. Wwox has been understudied in pancreatobiliary cancers, especially in relation to other involved tumor suppressors. We have assessed the status of the Fhit and Wwox proteins encoded by DNA damage susceptible chromosome fragile sites encompassed by FHIT and WWOX tumor suppressor genes. Pancreatic, gallbladder and ampullary cancers, normal pancreas, chronic pancreatitis, and benign gallbladder specimens were stained for expression of Fhit, Fhit effector protein Fdxr, Wwox, and other tumor suppressors by immunohistochemistry, and comparisons were made between benign and malignant tissue. Correlations of expression among proteins and clinicopathologic features were sought using Spearman's rank order. Survival curves were created using the Kaplan-Meier method and compared by log-rank analysis. Predictors of survival were determined using multivariate Cox proportional hazards analysis. Fhit and Wwox were ubiquitously expressed in benign samples and significantly and coordinately reduced in pancreatic, gallbladder, and ampullary cancers. In pancreatic cancers, Fdxr expression was positively correlated with Fhit and Wwox expression. Neither Fhit nor Wwox expression correlated with expression of other tumor suppressors or with clinicopathologic characteristics measured. Loss of Fhit and Wwox expression does not predict tumor progression or patient survival, suggesting that loss of expression of genes at the exquisitely replication stress sensitive chromosome fragile regions is an early event in the pathogenesis of cancers of the gallbladder, pancreas, and ampulla.