Microsatellite instability, expression of hMSH2 and hMLH1 and HPV infection in cervical cancer and their clinico-pathological association.
Infection with specific genotypes of human papillomavirus (HPV) has been strongly implicated in cervical carcinogenesis. However, HPV infection alone is insufficient for malignant transformation of the cervical epithelium. An alteration of microsatellite repeats is the result of slippage owing to strand misalignment during DNA replication and is referred to as microsatellite instability (MSI). These defects in DNA repair pathways have been related to human carcinogenesis; however, the role of MSI in the tumorigenesis of cervical cancer remains unclear. The clinical and pathological features of cervical cancers which are MSI-positive have also not been fully characterized. This study investigated the prevalence of MSI in cervical cancer and its relationship to clinico-pathological characteristics and HPV infection. Polymerase chain reaction-based microsatellite assay combined with tissue microdissection was used to examine for MSI in 50 cervical squamous cell carcinomas in Hong Kong women. In addition, the immunohistochemical staining was performed to determine the expression of major DNA mismatch repair genes, hMSH2 and hMLH1. Six cases (12%) displayed a low frequency of MSI (MSL-L) showing MSI at one locus only in 5 loci examined. Seven cases (14%) showed a high frequency of MSI (MSI-H) having MSI at 2 or more loci. Grouping MSI-L and MSI-H cases together as MSI-positive, statistical analysis of HPV infection, tumor grade, clinical stage and clinical status failed to disclose differences between MSI-positive and MSI-negative cases (p > 0.05). However, MSI-H correlated with advanced stage of disease (p < 0.05). Individuals with MSI-H tumors appeared to have reduced overall survival compared to individuals with MSI-L and MSI-negative tumors, but the difference was not statistically significant (p = 0.059). An absence of either MSH2 or MLH1 expression was observed in 2 MSI-L and 4 MSI-H cases, respectively. The results suggest that MSI is present in a subgroup of cervical squamous cell carcinomas, and defects resulting in MSI may be related to tumor progression and possibly poor prognosis in cervical cancer.
Chung
T K
TK
Department of Obstetrics and Gynaecology, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.
Cheung
T H
TH
Wang
V W
VW
Yu
M Y
MY
Wong
Y F
YF
D048868:Adaptor Proteins, Signal Transducing; D020137:Base Pair Mismatch / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D018895:Microsatellite Repeats / Q000235:genetics*; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000235:genetics*; D009367:Neoplasm Staging; D009687:Nuclear Proteins; D027383:Papillomaviridae / Q000235:genetics*; D030361:Papillomavirus Infections / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D016612:Paraffin Embedding; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016019:Survival Analysis; D014412:Tumor Virus Infections / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D002583:Uterine Cervical Neoplasms / Q000150:complications* / Q000235:genetics* / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein