Grant Number:	3R37CA259201-02S2 Interpret this number
Primary Investigator:	Wangensteen, Kirk
Organization:	Mayo Clinic Rochester
Project Title:	Hereditary Genetics of Hepatocellular Carcinoma
Fiscal Year:	2022

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.





None. See parent grant details.