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

Abstract

Background 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. Methods Pancreatic, gallbladder and ampullary cancers, normal pancreas, chronic pancreatitis, and benign gall-bladder 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. Results 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. Conclusion 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.

Expression of Fragile Histidine Triad (FHIT) and WW-Domain Oxidoreductase Gene (WWOX) in Nasopharyngeal Carcinoma

“…Guler, et al demonstrated coordinate absence or reduction of FHIT and WWOX expression in 55 and 63% of invasive breast tumors was reported (Guler et al, 2004). Coordinate loss of FHIT and WWOX has also been reported in other tumors (Dumon et al, 2001;Guler et al, 2004;Bloomston et al, 2009). These investigators provided some evidence for our study to a certain extent.…”

“…Furthermore, several mechanisms such as deletions, point mutations, methylation, loss of a whole chromosome and genetic recombination contributed to loss of FHIT and WWOX expression, we did not explore deeply on the mechanisms. However, some evidence demonstrated that loss of FHIT and WWOX expression was proportionally more frequent than abnormalities in p53, p16, or SMAD4 expression (Bloomston et al, 2009). It is well-known that aberrant p53 expression which happens at early event in carcinogenesis.…”

Aberrant crypt focus and fragile histidine triad protein in sporadic colorectal carcinoma

“…Fhit staining intensity in our patients had a strong association with smoking and non-vegetarian dietary intakes, thereby re-confirming the previous hypothesis of epigenetic factors in deletions and dysregulation in Fhit gene, as in lung cancer development [16][17][18][19]21,22,24,48] . Many of our carcinoma cases were negative for Fhit protein although expression for the protein was retained by a couple of cases which could be the result of a dysregulated gene that have been observed in other tumors, including lungs and breast [20,21,24,33,43,48] . Our observation in the normal control was similar to Hao et al [30] where they documented cytoplasmic expression in normal colonic epithelial cells from basal onwards to luminal differentiated cells.…”

“…The affected crypt thereby undergoes fission to give rise to an early flat lesion like ACF [6,38] . Similarly to our observations, gradual reductions in the intensity of Fhit protein had been reported by other groups in colon cancer and its early precursor lesions, and also in other pre-neoplastic lesions in breast, pan- T1 T2 T3 T4 N0 N1 N2 M0 M1 Total Negative 9 3 12 12 12 Weak 3 14 1 10 8 18 18 Moderate 16 2 8 7 3 15 3 18 Strong 24 3 27 0 27 27 Total 3 63 9 57 15 3 72 3 75 creas, cervix, lung and esophagus [15][16][17][18]20,21,[25][26][27][28][29][30][31]33,43,44] . Functional loss of the tumor suppressor protein Fhit, like p53, is believed to result in loss of inhibitory function in cell proliferation due to release phenomena in many downstream proteins acting on cell proliferations [16][17][18][19]45] .…”

Upregulation of tumor suppressor WWOX promotes immune response in glioma

“…WWOX gene spans more than a million base pairs and is thus prone to many chromosomal rearrangements observed in different cancers [22][23][24]. The loss or reduced expression of WWOX was found in various cancer [25][26][27]. However, whether the alterative expression of WWOX has the effect to immune system has not been studied.…”