Genetic and environmental risk factors of cervical carcinoma in Situ

Abstract: Invasive cervical cancer is the third most common cancer form among women. In 1990 there were approximately 370,000 new cases diagnosed in the world. The risk of morbidity and mortality of cervical cancer among women is a problem, particularly in the developing countries.For the purpose of investigating various aspects of the natural history of cervical carcinoma, we have evaluated a PCR based fluorescent 5´exonuclease assay for typing and quantitating of human papillomavirus (HPV). Using this new technique, we have succeeded in detecting and quantitating HPV DNA from archival cervical smears and tumour biopsy specimens.To study the relationship between HPV 16 infection and risk of cancer in situ, including the effect of recurrent and persistent infection, we examined archival cervical smears collected from women over a time period of 26 years, spanning the time from infection to development of cancer in situ. Archival smears from 484 women with carcinoma in situ and the corresponding 619 individually matched controls were studied for presence for HPV 16. Women with multiple infected smears had an increased risk of cervical cancer development. For instance, women with three HPV infected smears had a dramatically elevated risk (OR=47.3 (95% CI 14.3-156.7)) of developing cervical cancer in situ.Further, we examined the relationship between amount of HPV 16 DNA and risk of developing cervical carcinoma in situ. A positive correlation was found between amount of HPV 16 DNA and risk of cervical cancer. The OR showed an approximately 70-fold (OR=68.8 95% CI 15.8-299.6) higher risk for women in the quintile with the highest amount of HPV 16 DNA in relation to women testing negative. This relationship was seen also when including only the first, cytologically normal, smear from each woman, taken on average 7.8 years before diagnosis. For young women (20-24 years old) in the quintile with the highest amount of HPV DNA the positive predictive value (PPV) was found to be 48%. Thus, HPV DNA amount appears to be a strong predictor of cancer risk.Finally, we evaluated a hypothesis concerning the importance of homozygosity for arginine (p53Arg) at codon 72 in the p53 gene for the risk of developing cervical cancer. We were unable to find any association between the genotype at codon 72 and risk of cervical cancer in our patient cohort, despite the large sample size.

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