Cancer Control Research
3U01CA076293-05S1
Anderson, Marshall W.
GENETIC EPIDEMIOLOGY OF LUNG CANCER
AbstractLung cancer is the most common form of cancer mortality in men and women
in the United States, and represents a significant burden on health care
resources. Our long-term objective is to characterize lung cancer
susceptibility gene(s), as it will allow identification of individuals
at especially high risk (including former smokers) who can then be
targeted for intensive efforts at smoking prevention, environmental risk
reduction, and possibly chemoprevention. Accumulated evidence suggests
that there are genetic susceptibility components in lung cancer, and
that gene-environment interactions are important. Familial aggregation
of lung cancer has been observed and segregation analysis studies have
suggested that differential susceptibility to lung cancer may be
explained by Mendelian codominant inheritance of a major autosomal
gene(s) that acts in conjunction with cigarette smoking to produce
earlier age of onset of lung cancer. We hypothesize that there are
specific genotypes that greatly increase the risk of developing lung
cancer, through interaction with cigarette smoking and/or other
environmental agents. Our specific aims are 1. To utilize established
lung cancer family research resources to identify familial lung cancer
(FLC) pedigrees for genetic linkage analysis. Six established centers
will accrue blood samples, tumor tissue, and risk factor data from
available relevant family members in 85 pedigrees (containing 4 or more
affected cases and an expected lod score (ELOD) of 0.3 or higher).
Sampling has been completed for 7 extended pedigrees, and genotyping has
begun on these families. We will also accrue a minimum of 125 affected
sib/relative pairs, in addition to those in the 85 FLC kindreds; 2. To
genotype informative individuals in the FLC pedigrees with 400 evenly
spaced markers (approximately 10 centimorgans) throughout the genome.
DNA isolated from blood, archival paraffin blocks will be used for
genotyping both living and deceased affected and unaffected family
members. We have shown that archival DNA can be genotyped with our
global marker set; and 3. To map a lung cancer susceptibility gene(s)
by genetic linkage analysis of the FLC pedigrees. Both parametric (lod-
score) and non-parametric relative-pair methods will be utilized in the
genetic linkage analyses. This research proposes to identify a
subpopulation of persons who may be at a relatively high risk to develop
lung cancer from even low level exposure to cigarette smoke and other
environmental agents. The strategy to use linkage in high risk families
has proven successful for the identification of susceptibility genes in
breast, colon, and prostate cancers. While major breakthroughs have been
made in understanding the genetic susceptibility basis of these other
cancers, studies to identify specific major loci affecting lung cancer
risk are notably lacking. The high case-fatality rate and low resection
rate makes the study of lung cancer families particularly challenging
because it is difficult to collect adequate numbers of biospecimens for
DNA analysis. We believe only a multidisciplinary, collaborative effort
to identify, accrue, and genotype FLC families will be successful in
characterizing the genetic basis of FLC.
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