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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.
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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