Preliminary study of p53 and c-erbB-2 expression in gallbladder cancer in Indian patients manuscript id: 8962091628764582

BACKGROUND: The inactivation of the tumour suppressor gene and activation of the proto-oncogene are the key steps in the development of the human cancer. The p53 and c-erbB-2 are the best examples of it. In the present study, our aim was to determine the role of these genes in the carcinogenesis of gallbladder by immunohistochemistry. METHODS: In all 78 consecutive patients of gall bladder diseases were studied for p53 and c-erbB-2 expression immunohistochemically and their expression was correlated with the age, grades and stages of the disease and presence of stone. An informed consent was obtained in each case. Chi square and z test were applied to see the association of p53 and c-erbB-2 over expression with other clinicopathological factors. RESULTS: Eight (20%) patients of gall bladder cancer were positive for p53 expression and 10 (25%) patients for c-erbB-2. The p53 positivity increased with increasing grade while cerbB-2 positivity decreased with increasing grade of gall bladder cancer. Mean age in cerbB-2 positive cases were lesser as compared to negative cases while p53 did not show such association with age. CONCLUSION: Only one case of gall bladder cancer co-expressed the p53 and c-erbB-2, thereby suggesting that p53 and c-erbB-2 may have independent role in carcinogenesis of gall bladder cancer. c-erbB-2 over expression in adenoma and younger age group indicates its role as an early event in carcinogenesis of gallbladder. However study of larger sample is required to further validate the results

High-level microsatellite instability is not involved in gallbladder carcinogenesis

The molecular alterations involved in the pathogenesis of gallbladder cancer are not yet well defined. Our aim was to determine the microsatellite status of gallbladder carcinomas and its possible correlation with alterations in K-ras and p53 genes as well as the clinicopathological characteristics of these tumors. A group of 37 gallbladder carcinomas was analyzed for alterations in a proposed panel of mononucleotide and dinucleotide markers of microsatellite instability. Somatic frameshift mutations at repeated sequences in the coding regions of TGF-βRII, Bax, hMSH3, hMSH6 were also examined. The findings were correlated with the presence of K-ras and p53 alterations, and tumors' clinicopathological features. Microsatellite instability and/or LOH was observed in 9 gallbladder carcinomas. Cases showing microsatellite instability displayed alterations only in dinucleotide markers and were classified as MSI-L carcinomas. A subset of gallbladder carcinomas is characterized by low-level instability, based on the analysis of the above mentioned panel of markers. The pathway of microsatellite instability seems to play a minor role in the pathogenesis of gallbladder cancer. © 2005 Elsevier Inc. All rights reserved

HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target?

Background: HER2 overexpression and/or amplification have been reported as predictive markers for HER2-targeted therapy in breast and gastric cancer, whereas HER3 is emerging as a potential resistance factor. The aim of this study was to perform a systematic review and meta-analysis of the HER2 and HER3 over-expression and amplification in biliary tract cancers (BTCs).Methods: An electronic search of MEDLINE, ASCO, ESMO and AACR was performed to identify studies reporting HER2 and/or HER3 membrane protein expression by immunohistochemistry (IHC) and/or gene amplification by in situ hybridization (ISH) in BTCs. Studies were classified as “high-quality” (HQ) if IHC overexpression was defined as presence of moderate/strong staining; or “low-quality” (LQ) where “any” expression was considered positive.Results: Of 440 studies screened, 40 met the inclusion criteria. Globally, HER2 expression rate was 26.5% (95%-CI 18.9-34.1%). When HQ studies were analyzed (n=27 studies), extra-hepatic BTCs showed a higher HER2 overexpression rate compared to intrahepatic cholangiocarcinoma: 19.9% (95%-CI 12.8-27.1%) vs. 4.8% (95%-CI 0-14.5%), respectively; p-value 0.0049. HER2 amplification rate was higher in patients selected by HER2 overexpression compared to “unselected” patients: 57.6% (95%-CI 16.2-99%) vs. 17.9% (95%-CI 0.1- 35.4%), respectively; p-value 0.0072. HER3 overexpression (4/4 HQ studies) and amplification rates were 27.9% (95%-CI 9.7-46.1%) and 26.5% (one study), respectively.Conclusions: Up to 20% of extrahepatic BTCs appear to be HER2 overexpressed; of these close to 60% appear to be HER2-amplified; while HER3 is overexpressed or amplified in about 25% of patients. Clinical relevance for targeted therapy should be tested in prospective clinical trials.<br/