Grant Number:	1R03CA282953-01A1 Interpret this number
Primary Investigator:	Liu, Yanhong
Organization:	Baylor College Of Medicine
Project Title:	Identifying Germline Pathogenic Variants in Familial Lung Cancer Among African-Americans
Fiscal Year:	2024

ABSTRACT Lung cancer (LC) is the third most common cancer in the U.S. with African Americans (AAs) having the highest incidence and mortality. While previous linkage, admixture, exome sequencing, and genome-wide association studies in European-Americans and Asian ancestry show statistically compelling effects, much of LC heritability in AAs is yet to be explained. Genetic Epidemiology of Lung Cancer Consortium (GELCC) is the only consortium in the U.S. that studies Familial Lung Cancer (FLC) families, but to date, the majority of data collection and analyses are of European-American (EA) ancestry. Our recent cross-ancestry genome-wide meta-analysis has shown that the genetic architecture of minority populations is distinct for LC risk in the general population. Previous studies have shown differences in allele frequencies due to differences in racial ancestry are more pronounced for rare variants. Our GELCC family- based studies have identified several very rare, high-risk pathogenic variants in EA families. However, no family- based LC study has been explored in the AAs because of the extremely low number of AA families and limited accessibility and availability of biospecimens. This application will capitalize on existing Whole Genome Sequencing (WGS) data from the valuable collection of GELCC AA families (120 FLC cases and 146 unaffected family members), 282 high-risk sporadic LCs with family history of LC or early-onset, and 154 unrelated controls. To increase power, especially in rare variant discovery where AA FLC families are limited, we will also utilize publicly available WGS data from the All of Us, one of the most racial/ethnically diverse biobanks in the U.S. (n ~ 50,080 ) as external population controls. We proposed in Aim 1, to identify rare and low-frequency, pathogenic variants in associated with LC risk in AAs; and Aim 2, to evaluate common, pathogenic variants associated with LC risk in AAs. Given the high genetic diversity in AAs, genetic analysis of this understudied population would facilitate new risk locus and pathogenic variants discovery that has not been previously found in EA studies, including those that are specific to African-ancestry populations or shared across divergent populations. Results from this family- based study will provide a database that can be mined for future studies of genetic differences in AAs. Identifying novel pathogenic variants in AAs will serve as a starting point to help future targeted LC screening and personalized risk assessment for AAs and will move us closer to the elimination of health disparities.





None