Cervical cancer (CC) is one of the most common cancers in low and middle-income countries (LMICs). This situation is worsened by a high prevalence of human immunodeficiency virus (HIV) infection in certain African countries, such as Nigeria and Tanzania. The immune dysfunction caused by HIV infection promotes transmission and reactivation of persistent oncogenic viral co-infections of human papillomaviruses (HPV), the major risk factor of CC. Effective screening and early detection is the key to preventing cervical cancer. Affordable and minimally invasive tools are urgently needed in LMICs to enhance CC screening and risk stratification among HIV-infected women. The underlying molecular changes of HIV infection in promoting cervical carcinogenesis remain largely unknown. Epigenetic aberrations, especially loss of DNA methylation (DNAm) in DNA repetitive element (RE) regions has been recognized as a hallmark of human cancer. REs comprises at least 55% of the human genome, which can multiply and re-insert themselves into human DNA at new genomic locations, leading to genomic instability and somatic mutations that may cause cancer. DNAm, however, serves as a guard to suppress RE activities to maintain genomic stability. HIV infection reduces global DNAm level and reactivates the RE translocation activity. Hence, we hypothesize that HIV infection may promote CC development via global demethylation of RE in cervical tissue, which may inform the development of HIV-associated CC. Global demethylation of RE has been observed in various precancerous tissues is predictive of cancer development. However, such DNAm data on CC is very limited, especially for HIV-infected women in LMICs. We propose two study aims. In Aim 1, we will identify HIV- and CC-specific global RE DNAm biomarkers based on our ongoing U54 cervical cancer epigenomic project in Nigeria (U54CA221205, PI: Hou/Murphy), which have genome-wide DNAm data generated in cervical tissue samples from three groups of women (N=100 per group): a) HIV positive with CC; b) HIV positive and all cancer-free; and c) HIV negative with CC. We will then validate the biomarkers by implementing an easier and more affordable PCR-based methylation platform. In Aim 2, using the same PCR-based methylation platform, we will examine global RE DNAm biomarkers in cervical intraepithelial neoplasia grade 1 (CIN 1) samples and test whether these biomarkers predict the risk of progression to invasive CC or high grade of CIN. We will leverage two groups of samples from HIV-positive women who had CIN 1 at baseline: a) our U54 Nigeria cytology samples; and b) Tanzania cervicovaginal swab samples from an independent U54 project (U54CA190155, PI: Wood/Soliman). We will also investigate how HPV infection interplay with the global RE methylation biomarkers. If successful, our study may promote new affordable CC screening and early detection tools for HIV-infected women in LMICs.
|Effective start/end date||8/16/21 → 7/31/23|
- John E. Fogarty International Center for Advanced Study in the Health Sciences (5R21TW012092-02)
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