HIV Associated DNA Hypermethylation in Cervical Cancer

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Our goal is to understand the molecular pathogenesis of HIV-associated invasive cervical cancer (ICC) and its precursor, cervical intraepithelial neoplasia grade 3 (CIN-3), and to use this information to develop molecular assays for cervical cancer control in resource-poor settings with endemic HIV. Even prior to the HIV epidemic, ICC was a major public health problem in the developing world, and HIV increases the risk of CIN-3/ICC, making ICC of even greater concern. Available strategies for cervical cancer control (cytology or HPV based screening for CIN-3 and carcinoma in situ (CIS), visual screening with immediate ablation) are inappropriate for resource-poor settings with endemic HIV. Cytology is insensitive and costly; most HIV-positive women are infected with HPV; and visual screening and cryoablation without disease confirmation results in over-treatment, which is of concern in HIV+ women, since cryotherapy causes ulcers associated with increased risk of HIV transmission. Further, while we have reported that vaccines to prevent high risk types of HPV infection (which are known to be central to development of ICC) appear effective, current vaccines may be of limited interest in Africa, and do not prevent development of ICC in those already infected with HPV. It is known that the subset of women who develop persistent HPV infection are at increased risk of ICC, and the increased risk of CIN-3/ICC associated with HIV infection is thought the result of HIV-associated immune suppression and inability to resolve HPV infection. However, persistent HPV infection is alone not sufficient for progression to ICC and exposure to relevant co-factors is necessary, a fact underscored by our findings that only 25% of HIV-positive women with persistent HPV progressed to CIN-3. We hypothesize that the increased risk of progression associated with HIV infection is the result of both HIV-induced persistence of HPV infection and HIV induced DNA hypermethylation (silencing) of numerous genes, including many central to cervical cancer oncogenesis. Further, we hypothesize that these molecular changes are potential biomarkers for women with, and at risk of >CIN-3/ICC. These hypotheses are based on "in vitro" studies demonstrating HIV induction of widespread hypermethylation; studies showing that CpG island DNA hypermethylation plays a major role in the pathogenesis of cancers and occurs early in carcinogenesis; and our pilot studies of cervical biopsies demonstrating that HFV infection is associated with an increased risk of hypermethylation of many genes that appear to be important in oncogenesis of cervical neoplasia. To address these hypotheses, we will first identify a panel of hypermethylated genes that are predictive of CIN-3/ICC among both HIV and HIV+ women (Aim 1), and then perform a nested case control study (Aim 2) assessing the risk of developing CIN-3 in relationship to HPV persistence, HIV, and the presence or acquisition of the candidate hypermethylated genes. Lastly we will explore the HIV related factors (CD4 counts, viral load, HAART), which might be associated with the presence or acquisition of the hypermethylated genes of interest.