Although invasive uterine cervical cancer in developed countries has remained on the decline, in most developed countries, it remains the most common HIV-related malignancy in developing countries and more than 90% of women die from it. Although infection with one of 20 HPV subtypes considered oncogenic has been known to be the necessary etiologic agent for invasive cervical cancer, it is generally agreed cofactors are necessary for progression. The availability of antiretroviral therapy has increased life expectancy for HIV infected women, however this benefit may have been lost due to cervical cancer. Several lines of evidence suggest that this interaction is specific to some HPV subtypes and that it may involve epigenetic mechanisms, i.e. changes in gene expression with no change in the DNA sequence. We are currently training two physician scientists in molecular epidemiology using a pilot case-control study currently underway at the Kilimanjaro Christian Medical Center (KCMC) in Moshi, Tanzania. In this study, we will identify HPV subtypes most commonly found in HIV-related cervical cancer. We will also determining the extent to which methylation alterations at key epigenomic regions involved in growth regulation influence the development of invasive cancer in women with and without HIV infection. Findings from the pilot study will be used as preliminary data for a larger R01 to be submitted mid 2009. The trainees are supervised by Dr. Oneko, the Chief of Obstetrics and Gynecology who is also a collaborator on the study. Although one trainee has received didactic training in epidemiology and biostatistics at Duke, and both are overseeing collection of questionnaire data and collection and processing of specimens, it has become apparent that to contribute to scientific discourse to better control cervical cancer especially in HIV infected women will require extensive practical training. We propose a three-year training program for the two mid-level obstetrician/gynecologists For KCMC. The overall goal of the proposed training is to develop epidemiologic research skills of two physicians in HIV-related malignancies, using the cervical cancer project for training. Skills to be acquired in the three-year period will include (1) the conduct of (a) statistical analyses using SAS or equivalent software, (b) literature reviews, and (c) writing manuscripts; and (2) prepare and submit a grant application. At the end of the proposed training, the trainees will be capable of collaborations with US and other investigators and contribute meaningfully to scientific discourse of HIV-related malignancies.
Identification of HPV subtypes common in HIV positive and negative cases of squamous intraepithelial lesions (SIL) and invasive cervical cancer will facilitate HPV vaccine decision making. Identification of epigenetic changes common in SIL or invasive cervical cancer will help develop biomarkers for discriminating cases likely to progress from those likely to spontaneously regress. ? ? ?
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