Hereditary Genetics of Hepatocellular Carcinoma

肝细胞癌的遗传遗传学

基本信息

批准号：
10627405
负责人：
Kirk J Wangensteen
金额：
$ 20万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10627405
关键词：
Admixture Africa South of the Sahara African African American population Age Argentina Asia Brazil Cancer Etiology Cessation of life Chile Colombia Country DNA DNA Repair Defect Development Diagnosis Early Diagnosis Ecuador Ethnic group Europe Family history of Funding Genetic Genetic Predisposition to Disease Genetic Risk Ghana Heritability Hispanic Hispanic Populations Incidence Inherited Investigation Malignant neoplasm of liver Minority Minority Groups National Cancer Institute Pathogenicity Patients Peru Population Predisposition Prevalence Primary carcinoma of the liver cells Role South America South American TimeLine Underserved Population United States Variant cohesion design ethnic minority population exome sequencing gene repair genetic variant geographic difference high risk homologous recombination improved inhibitor therapy insight interest multi-ethnic parent grant response risk stratification risk variant therapeutic target tumor

项目摘要

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.

抽象的这 CA-22-057。家长补助金 (1R01CA259201)，遗传性正在提交申请以响应特别兴趣通知肝细胞癌的遗传学 (NOSI) 被识别为 NOT- ，曾是由美国国家癌症研究所 (NCI)（PI，Kirk J. Wangensteen 博士）资助建立。家长资助的目的是发现罕见的遗传性致病性或可能致病性（P/LP）相关的遗传变异肝细胞癌 (HCC) 发展（目标 1），并研究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（目标 2）本补充材料的科学重点与家长的目标 1 一致。拨款并专注于对 HCC 遗传易感性的多种族研究。补充通过扩大目标 1 中研究的人群以包括全球范围来增加家长补助金的价值撒哈拉以南非洲和南美洲的少数民族人口同样注重遗传因素与这些服务不足人群的 HCC 发展相关。在全球范围内，肝癌是癌症相关死亡的第三大原因，并且其发病率正在迅速增加世界许多地区和国家的 HCC 发病率存在明显的地理差异。撒哈拉以南非洲地区，例如加纳，是全世界肝癌发病率最高的地区之一。美国的 HCC 发病率也很高，而且该地区的 HCC 常常在早期就被诊断出来。与亚洲、欧洲和美国不同，这些国家已经开展了多项关于 HCC 遗传遗传学的研究。撒哈拉以南非洲地区缺乏研究，南美洲西班牙裔人群的调查也不足。本补充材料重点调查与以下疾病相关的罕见种系 P/LP 变异的流行情况：加纳撒哈拉以南非洲 HCC 患者和来自西班牙的西班牙 HCC 患者对 HCC 的易感性六个南美国家（阿根廷、巴西、智利、哥伦比亚、厄瓜多尔和秘鲁）进行比较其他人群以及来自美国的人群（来自家长补助金）（目标 1）。研究肝癌一级家族史和 HCC 年龄在 P/LP 变异富集方面的差异它还检查了基因混合的影响，以深入了解相对祖先。加纳土著非洲人和南部西班牙裔人的 HCC 易感性的遗传因素美国并相互比较，以及来自父母补助金的美国非裔美国人和西班牙裔美国人（Subaim 1b）在此应用范围内，我们将完成全外显子组测序和分析。来自加纳的非洲原住民 (n=150) 和来自南美洲的西班牙裔 (n=150) 的种系 DNA – 两个没有出现在家长补助金或之前任何研究中的种族群体具有凝聚力的专家团队。为该项目汇集的资金将通过将全球高风险少数群体纳入其中，为家长补助金增加价值我们努力在不到一年的时间内识别与 HCC 发展相关的遗传风险变异。