PROJECT SUMMARY/ABSTRACT The long-term goals of this project are to a) understand the epidemiology of Human papillomavirus virus (HPV)- associated oral and oropharyngeal cancers (OOPC) among people living with HIV (PLWH) as well as the role of epigenetic biomarkers in OOPC, and b) to develop potential targeted interventions to improve prevention and early detection of OOPC. HPV causes ~5% of cancers worldwide, including an increasing proportion of OOPCs; our recent data showed that 17% of OOPC samples have HPV infections. This worsening public health problem is even more serious in countries with high HIV prevalence, such as Nigeria. The impact of HIV infection on immune dysfunction promotes transmission and reactivation of oncogenic HPV co-infections. HIV-HPV co- infection then synergistically increases the prevalence of oral potentially malignant disorders (OPMDs), and the hazards of progression to OOPC among PLWH. As HIV is controlled with antiretroviral therapy (ART), PLWH live longer with chronic inflammation and continued immunodeficiency, making them even more susceptible to HPV infection and its cancer-promoting consequences. Epigenetic biomarkers represent a field with untapped potential for identifying HPV-infected PLWH who are at risk of progression to invasive OOPC. DNA methylation (DNAm) modifications are a well-studied epigenetic mechanism in cancer including OOPC. DNAm modifications are inducible by exogenous factors, including HIV and HPV infection and their associated cancers. Countries like Nigeria provide unique resources and opportunities to study HPV-associated cancers in PLWH, particularly longitudinal studies of the progression of OPMDs into malignant OOPCs. We hypothesize that oral HPV infection may induce DNAm changes in PLWH, some of which are mechanisms in OOPC development. Such changes may differ by HPV subtype, and can be seen in OPMDs that predict the progression to invasive OOPC. We plan to examine tissue-specific epigenetic biomarkers in 4 groups of HIV(+) patients: 1) HPV(+) OOPC (n=150); 2) HPV(-) OOPC (n=150); 3) HPV(+) with benign warts (n=100), and 4) HPV(+) with OPMDs (n=400). Recruitment will be conducted at the College of Medicine, University of Ibadan/University College Hospital (COMUI/UCH) in Nigeria, West Africa as well as 10 other hospital satellite recruitment sites. COMUI/UCH is the largest radiation oncology referral site in Nigeria and one of the leading centers for oncological services in the region. We will also study HIV (-) OOPC patients derived from our existing cohort (SHINI) in the same area. Our primary Aims are to: 1) Understand the epidemiology of HPV-associated OOPCs in PLWH; 2) Identify DNAm biomarkers of HPV- associated OOPCs in PLWH; and 3) Examine DNAm biomarkers for OOPC aggressiveness and OPMD progression during follow up. Our research team has a long and successful collaboration record and the Northwestern University MPIs have extensive experience studying HPV-associated cervical c...