Hereditary Genetics of Hepatocellular Carcinoma

肝细胞癌的遗传遗传学

• 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
• 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; 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

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。父母赠款（1R01CA259201），世袭 申请正在响应特殊利益通知 肝细胞癌的遗传学 （NOSI）被确定为未 ， 曾是 通过国家癌症研究所（NCI）（PI，Kirk J. Wangensteen博士）的资助建立。目的 父母的赠款是发现稀有的遗传病原或可能的致病性（P/LP）遗传变异 随着肝细胞癌（HCC）发育（AIM 1），并研究是否遗传 同源重组DNA损伤修复（HR-DDR）基因的缺陷使HCC肿瘤敏感 PARP抑制剂疗法（AIM 2）。该补充剂的科学重点与父母的目标1保持一致 格兰特（Grant）并专注于对HCC的遗传遗传倾向的多种族调查。具体来说，这是 补充通过在AIM 1中扩大研究的人群以包括全球，从而增加了父母赠款的价值 撒哈拉以南非洲和南美洲的少数民族人口同样关注神父因素 与这些服务不足的人群中的HCC发展相关。 在全球范围内，HCC是与癌症相关死亡的第三主要原因，其发病率正在迅速增加 世界上许多地区。 HCC事件和国家 /地区的地理差异明显 撒哈拉以南非洲（例如加纳）在全球HCC发病率最高。南部的一部分 美国也发生了很高的HCC事件，并且HCC经常在该地区早期被诊断出。重要的是， 与亚洲，欧洲和美国不同，有关HCC的遗传遗传学的几项研究已经存在 进行的研究缺乏撒哈拉以南非洲的研究，在南美西班牙裔中对西班牙裔的研究不足。 这种补充侧重于研究与 来自加纳的撒哈拉以南非洲HCC患者和西班牙裔HCC患者的易感性 六个南美国家（阿根廷，巴西，智利，哥伦比亚，厄瓜多尔和秘鲁）与每个国家进行比较 来自父母赠款的其他人和人口（AIM 1）。补充剂进一步 研究肝癌一级家族史和HCC年龄的p/LP变体富集差异 诊断（Subaim 1A）。它还研究了遗传混合对相对祖先的见解的影响 加纳原住民对HCC易感性的遗传贡献以及南方的西班牙裔 美国和彼此之间的比较，与父母赠款的非洲裔美国人和西班牙裔在美国 （Subaim 1b）。在此应用程序的范围内，我们将完成全面的测序和分析 来自加纳的非洲原住民的种系DNA（n = 150）和来自南美的西班牙裔（n = 150） - 两个 在父母赠款或任何先前研究中未代表的种族群体。专家的凝聚力团队 为该项目组装的将通过在 我们在不到一年的时间表中确定与HCC开发相关的遗传风险变异的努力。