Project Summary Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide. In Nigeria, the approximate incidence of HCC is 15-20/100,000 persons is now the leading cause of cancer-related mortality among men. HCC is emerging as a leading cause of morbidity and mortality in HIV-infected persons. HIV infects over 3.4 million people in Nigeria. As life expectancy with HIV improves, the incidence and prevalence of HCC will continue to increase making it a prominent non-AIDS defining cancer. HIV-positive HCC patients generally present at a much younger age and at a more advanced stage of disease and the course of disease is highly aggressive. Very few patients are able to benefit from curative or life prolonging therapies even when they are available and thus in a resource limited setting such as this, the need for novel biomarkers that can be used for early detection of HCC are an urgent priority. Detecting methylomic signatures in circulating cell-free DNA (cfDNA) extracted from serum/plasma has emerged as a promising non-invasive approach for the diagnosis, prognosis and monitoring of cancers. HCC tumors have been shown to exhibit distinct DNA methylation alterations associated with HCC initiation, progression and metastasis and thus indicate the potential for cfDNA methylation to serve as a valuable tool for early detection of HCC. The main objective of this study is to identify minimally invasive, blood-based methylomic markers by comparing blood DNA methylation patterns in HIV- infected and uninfected HCC patients and in HIV-positive but HCC-free patients in Nigeria. The high burden of HIV and HCC in Nigeria offers a rare opportunity to study epigenetic markers in a large number of patients with HCC and examine how expression may be influenced by HIV as well as other risk factors such as chronic HBV and HCV which are also endemic in this region. We will examine associations of these markers with clinico- pathologic and prognostic outcomes in HIV-positive HCC patients and explore these methylation signatures in a prospective cohort of HIV-infected patients with advanced fibrosis and cirrhosis (as determined by Fibroscan) to examine their predictive value in HCC early detection.