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Involvement of DNA MMR in the Aetiology of Vulvar Cancer

By Dorte M Skytt

Abstract

Background: Vulvar cancer is a rare malignancy with two different aetiologies. The first type is the dysplastic precursor lesion vulvar intraepithelial neoplasm (VIN) which affects younger women and is related to oncogenic Human Papillomavirus (HPV) infection. The second type is Vulvar Squamous Cell Carcinoma, which primarily affects older women and is unrelated to HPV. The purpose of this retrospective study was to examine whether defects in the DNA Mismatch Repair (MMR) system are involved in the development of either types of vulvar cancer. Methods: Paraffin-embedded tissue samples from 25 women with diagnosed vulvar cancer were selected for analysis. The expression of the MMR proteins was examined by immunohistochemical (IHC) stainings. Furthermore it was investigated whether microsatellite instability (MSI) in the five loci characteristic for MMR deficient cancers was present. Also whether there was loss of heterozygosity (LOH) near the chromosomal locations of the major MMR genes was studied. Results: There was not observed loss of expression of any of the three MMR proteins examined by immunohistochemistry. In fact expression of both hMSH2 and hMSH6 was significantly enhanced in 40-80 % of the VIN and the concurrent VIN/carcinoma tissue samples compared to the normal references. All the concurrent VIN/carcinomas and the solitary VIN tissue samples were infected with oncogenic HPV, whereas all the solitary carcinomas and all the metastases were HPV negative. MSI was examined in the five loci, but neither of vulvar cancer showed MSI in any of the loci studied. In 56% and 62% of the samples a degree of LOH was observed near the chromosomal location of the genes for hMSH2/6 and hMLH1, respectively. Since this apparent loss seemed random and did not affect the protein expression, it was not considered to inhibit MMR activity. Conclusion: By investigating the MMR system both by IHC, MSI and LOH analyses it can be concluded that defects in the MMR system do not seem to play any essential role in the primary aetiology of either types of vulvar cancer

Topics: Mismatch Repair (MMR), Microsatellite Instability (MSI), Vulvar cancer, Aetiology, LOH (loss of heterozygosity), Immunohistochemistry, DNA purification from paraffin, Human Papillomavirus (HPV), VIN
Year: 2006
OAI identifier: oai:rudar.ruc.dk:1800/2029
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