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Family Lung Cancer Newsletter - Summer 2006, 2010, 2011
News Flash

Major Lung Cancer Susceptibility Locus on Chromosome 6:
The Genetic Epidemiology of Lung Cancer Consortium (GELCC) is conducting a multi-investigator (seven-site), interdisciplinary study to identify a lung cancer susceptibility gene(s).  The University of Cincinnati is one of the eight centers, with investigators from the Departments of Environmental Health (Marshall Anderson, PhD and Susan Pinney, PhD, epidemiology).  Dr. Anderson also is the Principal Investigator for the entire multi-site project.  We hypothesize that there are specific genotypes that greatly increase the risk of developing lung cancer through interaction with cigarette smoking or other environmental exposures.   

The specific aims of this project are:  1) To create a registry of high risk families for genetic linkage studies of lung cancer;  2) To identify a lung cancer susceptibility locus (loci) through linkage analysis of familial lung cancer pedigrees; and (if found) to identify and characterize the susceptibility gene(s). 3) To use our established research resources to identify an additional 1600 familial lung cancer (FLC) cases for genome-wide association studies; 4) To perform conditional genomic and functional studies of genes within the linkage region(s) identified or within a haplotype region containing a SNP signal identified by association analyses. 

In collaboration with seven other U.S. sites, we have screen an estimated 70,000 lung cancer cases (identified retrospectively through oncology practices or prospectively through pathology laboratories) to find 800 high risk families with at least three first-degree relatives with lung cancer.  Of these, we have developed the most informative 115 for linkage analysis.  In the Cincinnati area, we have already identified 2700 new lung cancer cases.

Through a genome-wide linkage study conducted by our research team, we have mapped a major susceptibility locus to 6q23-25, and discovered a rare risk haplotype containing a putative susceptibility gene in the region known as RGS17 (You et al, 2009). We also have identified significant linkage signals on Chromosomes 6p and 8p in families with a strong family history of lung cancer.  We have developed new methods to incorporate environmental covariates into linkage models, especially models using propensity scores.  Smoking history is obviously a critical covariant for linkage analysis of high-risk lung cancer families. In these analyses, we identified significant linkage signal on Chromosomes 6p and 8p, and confirmed our previous findings on 6q.  Survival analyses using haplotype information indicates that for those who carry the risk haplotype on Chromosome 6, any amount of smoking history confers an equal and very substantial risk of developing lung cancer.



Text Box: Figure 1. Time to lung cancer diagnosis among carriers of a susceptibility locus on 6q (left panel), noncarriers (middle panel), and individuals with unknown carrier status (right panel). Smoking strata are shown with the black line reserved for nonsmokers, blue line for light smokers (1-19 pack years), green line for 20-39 pack years and the red line for heavier smokers (40+ pack years).
Characterization of lung cancer susceptibility genes will help elucidate mechanisms of carcinogenesis, facilitate targeted screening and early detection efforts leading to very early treatment, and iden­tify candidates for chemoprevention trials. Such genes also may be involved in the development of other smoking related neoplasms. Knowledge of gene products from susceptibility loci may allow for the development of new therapies for lung cancer.




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