Epigenetic Biomarkers of HIV-Associated Hepatocellular Carcinoma in Nigeria

项目摘要 肝细胞癌是全球第六大常见恶性肿瘤。在尼日利亚，大约 肝癌的发病率为15-20/100,000人，现在是男性癌症相关死亡的主要原因。 肝细胞癌正在成为艾滋病毒感染者发病和死亡的主要原因。艾滋病病毒感染者超过3.4人 尼日利亚有一百万人口。随着艾滋病毒携带者预期寿命的提高，肝癌的发病率和流行率将 继续增加，使其成为一种突出的非艾滋病定义癌症。HIV阳性的肝癌患者一般 出现在更年轻的年龄和更晚期的疾病中，并且病程高度 咄咄逼人。很少有患者能够从根治或延长生命的疗法中受益，即使它们是 可用，因此在资源有限的情况下，如此，需要可用于 及早发现肝细胞癌是当务之急。检测循环中无细胞DNA中的甲基组特征 从血清/血浆中提取的(CfDNA)已成为一种有前途的非侵入性诊断方法， 癌症的预后和监测。已有研究表明，肝细胞癌有明显的DNA甲基化 与肝细胞癌的发生、发展和转移相关的改变，从而提示cfDNA的可能性 甲基化可作为肝癌早期检测的有价值的工具。这项研究的主要目的是确定 通过比较HIV患者的血液DNA甲基化模式，获得基于血液的微创甲基化标记 尼日利亚感染和未感染的肝细胞癌患者以及艾滋病毒阳性但未感染肝细胞癌的患者。沉重的负担 尼日利亚的艾滋病毒和肝癌提供了一个难得的机会，可以在大量患有艾滋病的患者中研究表观遗传标记 并检查HIV和其他风险因素(如慢性乙肝病毒)对表达的影响 和丙型肝炎病毒，这也是这一地区的地方病。我们将研究这些标记物与临床的关系。 HIV阳性肝细胞癌患者的病理和预后结果，并探讨这些甲基化特征 患有晚期纤维化和肝硬变的HIV感染患者的预期队列(由FibroScan®确定) 探讨其在肝细胞癌早期发现中的预测价值。

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.