The Role of Human Papillomavirus in Adenocarcinoma of the Uterine Cervix

Detta är en avhandling från Stockholm : Karolinska Institutet, Karolinska Institutet at Danderyds Hospital

Sammanfattning: Background: Cervical carcinoma is the third most common malignant disease in women worldwide. The absolute frequency of adenocarcinoma of cervix uteri has increased during the last decade and accounts for about 15-20% of invasive cervical cancers. Human papillomavirus (HPV) is considered the most important factor in the development of cervical squamous cell carcinomas. HPV DNA has been identified in about 95% of cervical carcinomas. Adenocarcinomas of the cervix are also linked to HPV but the correlation is probably less pronounced. The aim of this study was to analyse cervical adenocarcinomas with regard to the presence of HPV, the frequency of a specific mutation of the E6 gene of HPV 16 and the presence of p53 polymorphism, all of which may influence the risk of acquiring this carcinoma. Moreover, we intended to describe the symptoms and methods of detection of this tumour Material and methods: For the identification and typing of HPV, 173 cervical adenocarcinomas were analysed with Polymerase Chain Reaction (PCR), Single-Strand Conformation Polymorphism (SSCP) and/or DNA sequencing. In HPV16 positive cervical adenocarcinomas (28 cases), the E6 gene was analysed using the PCR-SSCP method for identification of the specific mutation (L83V). The results were correlated to those of 103 HPV 16 positive precancerous cervical lesions and 31 HPV 16 positive invasive cervical squamous cell carcinomas. For the analysis of p53 polymorphism, a PCR and SSCP based technique was used on 111 specimens and 188 controls (cell samples from women with normal cytology). Results: HPV was present in 68% of 173 adenocarcinomas. There was a significant correlation between the presence of HPV and age, illustrated by the fact that adenocarcinomas in younger women were more often HPV-positive than those in older women (p<0,001). The most common types of HPV were 18, 16 and 45. The HPV16 E6 variant L83V was present in 54% of the invasive adenocarcinomas. However, the predominance of the HPV16 variant observed earlier in squamous cell carcinomas was not seen in adenocarcinomas. Homozygosity for arginine in codon 72 of the p53 gene was present in 71% of the adenocarcinomas but only in 47% of the samples from healthy female controls (p<0,001). These results support the hypothesis that women with homozygosity for arginine in the p53 gene codon 72 may have an increased risk of developing adenocarcinoma of the cervix. Our data demonstrate that 70% of the cervical adenocarcinomas were detected due to manifested symptoms (mainly vaginal bleeding) and 92% of the women tested with a Pap smear had normal results within three years before the cancer was detected. Conclusion: HPV was identified in 68% of the cervical adenocarcinomas, and was predominant in younger women. Hence, the prevalence of HPV in women with cervical adenocarcinomas is age-related. The most frequently occurring type of HPV was 18. Women with homozygosity for arginine of the p53 gene may have an increased risk of developing cervical adenocarcinoma. Since there has been an increase in the incidence of adenocarcinoma of cervix uteri among younger women, and Pap smear screening is inadequate for its detection, there is a need for other screening techniques. Repetitive HPV testing and analysis of p53 may help identify women at risk.

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