Hereditary Genetics of Hepatocellular Carcinoma

摘要 这 CA-22-057父母补助金（1 R 01 CA 259201），遗传 申请是为了回应特别关注通知而提交的 肝癌的遗传学 （NOSI）确定为非- ， 通过国家癌症研究所（NCI）（PI，Kirk J. Wangensteen博士）的资助建立。的目的 父母补助金是为了发现罕见遗传性致病性或可能致病性（P/LP）遗传变异， 与肝细胞癌（HCC）的发展（目的1），并调查是否携带遗传性 同源重组DNA损伤修复（HR-DDR）基因的缺陷使HCC肿瘤对 PARP抑制剂治疗（目的2）。本补编的科学重点与母版的目标1一致 该项目的重点是对肝癌遗传易感性的多种族调查。具体来说， 补助金增加了父母补助金的价值，扩大了目标1所研究的人口，包括全球 撒哈拉以南非洲和南美洲的少数民族人口，同样关注遗传因素 与这些服务不足的人群中HCC的发展相关。 在全球范围内，HCC是癌症相关死亡的第三大原因，其发病率在2010年迅速增加。 世界上许多地区。HCC的发病率存在明显的地理差异， 撒哈拉以南非洲，如加纳，有一些世界上最高的HCC发病率。南部部分地区 美国也有肝癌的高发病率，并且在该地区肝癌通常在早期被诊断。重要的是， 不像亚洲，欧洲和美国，那里已经有几项关于HCC遗传遗传学的研究， 尽管进行了大量的研究，但撒哈拉以南非洲缺乏研究，南美洲的西班牙裔也调查不足。 这份补充报告的重点是调查与以下疾病相关的罕见生殖系P/LP变异的患病率 来自加纳的撒哈拉以南非洲HCC患者和来自 六个南美国家（阿根廷、巴西、智利、哥伦比亚、厄瓜多尔和秘鲁），分别与 其他人和来自美国的人口从母赠款（目标1）。述补充剂还 研究肝癌一级家族史和HCC患者年龄对P/LP变异富集的影响 诊断（Subaim 1a）。它还研究了遗传混合物的影响，以深入了解相对祖先 来自加纳的非洲土著人和来自南非的西班牙裔人对HCC易感性的遗传贡献 美国和相互比较，并从父母补助金中获得非洲裔美国人和西班牙裔美国人的补助金 （Subaim 1b）。在本申请的范围内，我们将完成全外显子组测序和分析， 来自加纳的非洲土著人（n=150）和来自南美洲的西班牙裔人（n=150）的生殖系DNA-两个 在父母补助金或以前的任何研究中没有代表的族裔群体。有凝聚力的专家团队 为这个项目聚集的将增加价值的父母赠款，包括高风险的全球少数民族人口， 我们在不到一年的时间轴内鉴定与HCC发展相关的遗传风险变异的努力。

Abstract This CA-22-057. The parent grant (1R01CA259201), Hereditary application is being submitted in response to the Notice of Special Interest Genetics of Hepatocellular Carcinoma (NOSI) identified as NOT- , was established through funding from the National Cancer Institute (NCI) (PI, Dr. Kirk J. Wangensteen). The aims of the parent grant are to discover rare inherited pathogenic or likely pathogenic (P/LP) genetic variants associated with hepatocellular carcinoma (HCC) development (Aim 1), and to investigate whether carriage of inherited defects in homologous recombination DNA damage repair (HR-DDR) genes render HCC tumors sensitive to PARP inhibitor therapy (Aim 2). The scientific focus of this Supplement aligns with Aim 1 of the parent grant and is focused on multiethnic investigations into heritable genetic predisposition to HCC. Specifically, this Supplement adds value to the parent grant by expanding the population under study in Aim 1 to include global ethnic minority populations in sub-Saharan Africa and South America with the same focus on hereditary factors associated with HCC development in these underserved populations. Globally, HCC is the 3rd leading cause of cancer-related deaths, and its incidence is rapidly increasing in many regions of the world. There are marked geographic differences in the incidence of HCC and countries in Sub-Saharan Africa, such as Ghana, have some of the highest HCC incidence rates worldwide. Parts of South America also have high incidence of HCC, and HCC is often diagnosed at early ages in the region. Importantly, unlike Asia, Europe, and the US where several studies on the hereditary genetics of HCC have already been conducted, studies are lacking in sub-Saharan Africa and are under-investigated in Hispanics in South America. This supplement focuses on investigating the prevalence of rare germline P/LP variants associated with susceptibility to HCC among sub-Saharan African HCC patients from Ghana and Hispanic HCC patients from six South American countries (Argentina, Brazil, Chile, Colombia, Ecuador, and Peru) for comparison to each other and to populations from the United States from the parent grant (Aim 1). The Supplement further investigates differences in P/LP variant enrichment by first-degree family history of liver cancer and age at HCC diagnosis (Subaim 1a). It also examines the impact of genetic admixture for insights into the relative ancestral genetic contributions to HCC susceptibility among native Africans from Ghana and Hispanics from South America and compares with each other, and to African Americans and Hispanics in the US from the parent grant (Subaim 1b). Within the scope of this application, we will complete whole-exome sequencing and analysis of germline DNA among native Africans from Ghana (n=150) and Hispanics from South America (n=150) – two ethnic groups that are not represented in the parent grant or in any previous study. The cohesive team of experts assembled for this project will add value to the parent grant by including high-risk global minority populations in our effort to identify genetic risk variants associated with HCC development, in a timeline of less than one year.