Saturday, November 23, 2024
11/23/2024
Project Summary Cervicalcancer (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. Effective screening and early detection is the key to preventing CC. However, multiple Pap smear visits for screening test remains costly in LMICs and coverage of CC preventive strategy reach fewer women at risk of CC in LMICs, in particular HIV-infected women. An alternative easy, affordable, non-invasive CC front-line screening tool for HIV-associated CC is urgently needed in LMICs with high HIV prevalence. The molecular changes by which HIV infection promotes cervical carcinogenesis remain largely unknown. Epigenetic aberrations, especially global DNA methylation (DNAm) loss in repetitive element (RE) regions, have been recognized as a hallmark of human cancers. REs are DNA sequences that occur in multiple copies throughout the genome. If REs are activated (for example, by HIV infection) they can multiply and reinsert themselves into human DNA at new genomic locations, leading to genomic instability and somatic mutations that may cause cancer. DNAm in these REs is a protective mechanism to stabilize RE from translocation, and its loss has been observed seen in the early phase of tumorigenesis. Specifically, HIV infection has been shown to reduce global DNAm level and reactivate RE translocation activity. We thus hypothesize that HIV infection may promote CC development via causing global demethylation of RE and that such epigenetic changes in self-collected cervical intraepithelial neoplasia (CIN) samples may predict progression into invasive CC. We propose two study aims. In Aim 1, we will identify and validate HIV-associated CC global RE DNAm biomarkers. We will utilize the existing DNAm data from our ongoing U54 CC epigenomic project in Nigeria (U54CA221205, PI: Hou/Murphy) to generate global RE DNAm data for biomarker development using our novel bioinformatics methods. We will then validate the biomarkers by implementing an affordable, targeted, and quantitative PCR-based DNAm platform in a LMIC laboratory. In Aim 2, using the same PCR-based approach, we will test if the biomarkers validated in Aim 1 can predict risk of CC progression. We will leverage two groups of samples from longitudinal cohorts of HIV-positive women who had low-grade CIN: a) Nigeria Pap smear samples from our U54 cohort; and b) Tanzania cervicovaginal swab samples from an independent U54 cohort (U54CA190155, PI: Wood/Soliman). Testing our biomarkers in self-collectable cervicovaginal swabs in our Tanzania cohort allows us to test their feasibility and clinical relevance in LMIC settings. If successful, our study may help develop new possible future CC screening and early detection tools for women living with HIV in LMICs.
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