Correlation between patterns of DNA mismatch repair hmlh1 and hmsh2 protein expression and progression of dysplasia in intraductal papillary mucinous neoplasms of the pancreas

Abstract

Defective DNA mismatch repair results from genetic or epigenetic alterations that most frequently inactivate the genes hMLH1 and hMSH2. This is thought to promote tumourigenesis by accumulation of mutations in oncogenes and tumour suppressor genes. This pathway, first reported in colon cancer, has been recently demonstrated in a subgroup of sporadic pancreatic adenocarcinomas. Intraductal papillary-mucinous neoplasms of the pancreas are a special type of pancreatic tumours, characterised by a spectrum of morphological changes from mild to moderate and to non-invasive, and they may associate with adenocarcinoma. An immunohistochemical study of hmlh1 and hmsh2 protein expression was performed on 26 intraductal papillary-mucinous neoplasms. All tumours showed nuclear expression of hmlh1 and hmsh2 proteins. There were two distinctive patterns of protein expression on the basis of the location of cells expressing these markers: the "normal" pattern, observed mainly in adenoma and rarely in intraductal papillary-mucinous neoplasms with moderate dysplasia and the "dysplastic" pattern, frequently encountered in moderate dysplasia neoplasms, non-invasive and invasive carcinomas. These findings suggest that defective DNA mismatch repair, due to inactivation of hMLH1 and hMSH2, does not play a significant role in the pathogenesis of intraductal papillary-mucinous neoplasms of the pancreas. Two patterns of protein expression were observed and were correlated with the progression of dysplasia in intraductal papillary mucinous neoplasms.

Immunohistochemical analysis of p53, APE1, hMSH2 and ERCC1 proteins in actinic cheilitis and lip squamous cell carcinoma

“…For the APE1 protein, the percentages [mean ± standard deviation (SD)] of tissues that expressed the APE1 protein in normal mucosa, AC and LSCC samples were 17. 35 We observed low immunohistochemical expression of p53 and APE1 in the normal mucosa compared to the LSCC group (P = 0.000 and P = 0.001 for p53 and APE1, respectively). Immunoreactivity of p53 and APE1 was low in the AC samples compared to the LSCC samples (P = 0.004 and P = 0.017, respectively), and when compared with the LM group, AC samples showed high immunoreactivity for p53 protein (P = 0.000).…”

“…For hMSH2, ERCC1 and APE1 proteins, the percentage of immunoreactive cells in all fields counted (20 fields for each specimen) was calculated. The median values of the percentage of cells immunoreactive for hMSH2, ERCC1 and APE1 proteins were used as a threshold to define the low (% of positive cells < median value) and high (% of positive cells ≥ median value) values for all samples 35 . Positive p53 expression was defined when more than 10% of cells were positive 36 …”

Different expression patterns of mucin core proteins and cytokeratins during intrahepatic cholangiocarcinogenesis from biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct—an immunohistochemical study of 110 cases of hepatolithiasis

“…IPMN-P is classified histopathologically into three types [21][22][23][24][25][26]; MUC1K/MUC2C type characterized by dark columnar cells, MUC1K/MUC2K type characterized by clear cells containing abundant intracytoplasmic mucin, and MUC1C/MUC2G type characterized by papillary proliferation of compact or oncocytic tumor cells. Interestingly, the IPN-B cases in this study could be classified into similar groups based on the MUC1/MUC2 immunophenotypes.…”

Role of inflammation in pancreatic carcinogenesis and the implications for future therapy

“…Other DNA repair systems linked to the onset of pancreatic cancer include the mismatch repair proteins, hmlh1 and hmsh2 [182] ; initiators of DNA repair, such as Bcl-2 [183] , and Rad51 [184] and MED1 [185] .…”