Cervical cancer in Zimbabwe : viral and host factors : studies on pathogenesis of cervical cancer in Zimbabwe with special reference to type-specific human paillomavirus (HPV) infection and human cytokine gene polymorphisms

Sammanfattning: Invasive cervical cancer (ICC) is the commonest cancer affecting Zimbabwean women. The recognition of the central role of the human papilloma virus (HPV) in the aetiopathogenesis of cervical cancer has led to application of HPV testing in the cervical screening and to the development of HPV vaccines for primary prevention of ICC. The applicability of both screening methods and vaccine strategies hinges on local knowledge of the types of HPVs that are involved in cervical oncogenesis. Technical constraints include the fact that the sampling of the cervix requires gynaecological examination by trained and skilled personnel working in adequately equipped facilities. There is therefore a glaring need for an alternate HPV source sample, which does not necessitate costly and specialized gynaecological examination. In order to address this concern we firstly set out to establish the prevalence and major types of HPV that are present in the Zimbabwean patients with ICC using cervical swabs. A parallel experiment was investigating the presence of HPV in urine and a type-specific concordance between cervical swab and urine as a potential alternate HPV source sample. We also hypothesized that cytokine gene polymorphisms could influence both the geographic distribution and possibly the familial clustering of cervical cancer. This hypothesis was tested in case-control studies. Methods: HPV-DNA was identified using the nested PCR methods. The types of HPVs were characterised using Restriction Fragment Length Polymorphism (RFLP). The presence of cytokine gene polymorphisms in women with cervical cancer and healthy controls was investigated by using the ARMS-PCR technique. Results: HPV was identified in 97% of ICCs. HPV types 16, 33, 18 and 31 were present in 61%, 39%, 18% and 4% of the cervical cancer samples respectively. HPV was identified and typed in 72% (31/43) of urine samples from cancer patients. There was an association between heterozygosity of the IL-10 (-1082 GA) but not in any polymorphisms of the TNF-alpha (-308'AG), the IFN-gamma (+874 'TA) or the polymorphisms at codons 10 and 25 of the TGF-beta1 and the occurrence of cervical cancer. Conclusion: We present the first prevalence data on HPV types in patients with ICC in Zimbabwe and show that, provided appropriate techniques are employed, HPV infection can be identified in a majority of the patients. Overall, our results suggest, that urine may be a practical sample in the investigation of HPV uro-genital infection. Future research should include urine testing in cervical screening programmes. The HPV types should be taken into consideration in tailoring locally relevant HPV vaccines. Our study of cytokine gene polymorphisms indicates that the differential geographic distribution of ICC may be determined, not by polymorphisms of single cytokine gene but by ethnically determined variations between the producer status and the Th-1 and Th-2 balance. We speculate that these variations and in our case, a possible shift towards Th-2 type responses, are influenced by natural selection in the face of geographically defined environmental pressures including infections.