Grant Number:	2R01CA243483-06A1 Interpret this number
Primary Investigator:	Amos, Christopher
Organization:	University Of New Mexico Health Scis Ctr
Project Title:	Sequencing Familial Lung Cancer
Fiscal Year:	2026

Abstract Lung cancer (LC) is the leading cause of cancer mortality in the U.S. Although tobacco smoking and other environmental exposures are the major contributors to LC risk, multiple family and genome-wide association studies have demonstrated that genetic factors significantly modulate risk. Through prior NIH funding the Genetic Epidemiology of LC Consortium (GELCC) has developed a large, unique database and biospecimen collection from individuals with a strong family history of LC • DIIHFWHG UHODWHG SHUVRQV , assembling a unique specimen and data resource. We hypothesize that LC risk is partially conferred by genetic factors that greatly increase the risk for cancer and modulate tumor growth. To test this hypothesis and accomplish our goals, we will pursue the following aims. Aim 1: Identify additional genetic factors conferring a high risk of LC development. We will evaluate and use new approaches for collecting samples and data from familial lung cancer cases. During the current cycle, we updated and extended information about the families we have collected, and developed a relational phenotype and DNA inventory database and reporting functions. This systematic approach has created a unique repository of findable and harmonized data. During the next study period we will characterize co-aggregations of LC with other cancers. We will leverage social media in addition to our existing approaches, to identify and recruit additional familial lung cancer (FLC) cases. Aim 2: Evaluate broader impact of candidate loci identified through genomic sequencing. Our current studies have identified 168 candidate variants with high penetrance and moderate-to-large effects on FLC risk. In this aim, through analysis of other existing independent LC WES and WGS data repositories we will identify the broader impact of these variants, individually or in combination, on LC risk. Aim 3: Perform functional studies on candidate variants associated with LC risk. We will assess the association of candidate loci on expression patterns of downstream genes in existing RNA-Seq datasets from normal lung tissue of LC subjects. We will experimentally assess whether these associations are causative through knock-down and overexpression assays in broncho-epithelial and LC cell lines. The goal of this research application is to identify additional germline genetic factors that confer a high risk for LC and to characterize the mechanisms by which these factors influence LC risk. Identifying genetic factors for LC will provide insight into the specific causes and pathways underlying its development. Further, high-risk individuals identified using WES could then reap the greatest benefit from screening modalities and prevention measures.




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