Microsatellite Instability, Expression of hMSH2 and hMLH1 and HPV Infection in Cervical Cancer and Their Clinico-Pathological Association

Abstract

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.

Loss of MSH2 protein expression is a risk factor in early stage cervical cancer

“…Only two studies have previously assessed MSH2 and MLH1 status in cervical cancers of squamous origin, but no solid conclusions could be drawn as to its prognostic value, mainly because of an insufficient number of patients. 20 In our study, loss of MSH2 expression was related to lymph node metastasis and cancer invasion beyond 10 mm, but not to disease recurrence or disease specific death. Presence of lymph node metastasis is the most important prognostic factor for survival, shown also in our population.…”

“…In colon cancer, absence of one of the two most frequently involved MMR proteins, MLH1 and MSH2, is a good predictor of MSI, while colon cancers with MSI show fewer lymph node metastases and have a better prognosis. 18 19 Few data are available on the role of MSI in cervical carcinogenesis, [20][21][22][23][24][25] and even less on MMR protein expression in cervical cancer. 20 26 27 MSI has been observed in 6-25% of invasive cervical cancers.…”

“…18 19 Few data are available on the role of MSI in cervical carcinogenesis, [20][21][22][23][24][25] and even less on MMR protein expression in cervical cancer. 20 26 27 MSI has been observed in 6-25% of invasive cervical cancers. [20][21][22][23][24][25] Furthermore, Chung et al showed loss of MSH2 expression in 7 of 50 squamous cervical cancers and Giarnieri et al showed loss of MSH2 in 10 of 23 cervical cancers.…”

“…[20][21][22][23][24][25] Furthermore, Chung et al showed loss of MSH2 expression in 7 of 50 squamous cervical cancers and Giarnieri et al showed loss of MSH2 in 10 of 23 cervical cancers. 20 26 Ciavattini et al recently found MSH2 and Mlh1 expression to be lower in 28 invasive squamous cell cervical cancers compared to cervical intraepithelial lesions. 27 These studies were too small to correlate findings to clinicopathological characteristics.…”

Microsatellite Analysis of Early Stage (la-Ilb) Uterine Cervical Squamous Carcinoma

“…In cervical cancer, microbe studies highlighted recurrent LOH at certain loci hunting has proved successful with the dissection of ( possibly being a manifestation of HIV-related cervical cancers [9][10][11]. In colorectal cancer, an inverse relationship has been demonstrated between microsatellite instability and loss of heterozygosity at tumor suppressor gene loci such as p53.…”