Association of common alleles of small effect (polymorphisms) with lung cancer risk

Results of hundreds of studies using association
analysis to evaluate the effects of various polymor-
phisms, in metabolic genes, growth factors, growth
factor receptors, markers of DNA damage and re-
pair and genomic instability, and in oncogenes and
tumor suppressor loci have been published. Many
of these studies have yielded inconsistent results.
The effects of risk alleles at these loci are expected
to be individually small, and they may interact with
smoking and/or other loci to increase lung cancer
risk. These association studies are beyond the scope
of this chapter. Two recent reviews [100,101] can
help the reader obtain an overview of these studies.
Discussion
All these lines of evidence suggest that there may
be one or several genes causing inherited increased
risk to lung cancer in the general population.While
association studies have given evidence that alle-
les at various genetic loci may influence lung can-
cer risk, there has frequently been disagreement be-
tween studies. The first linkage study of lung cancer
has given significant evidence of linkage to a region
on chromosome 6q. If a susceptibility locus is iden-
tified in this region, it will be of major public health
importance as it will allow identification of individ-
uals at especially high risk who can then be targeted
for intensive efforts at environmental risk reduc-
tion. In addition, identification of such a gene will
lead to better understanding of the mechanism of
carcinogenesis in general, perhaps eventually lead-
ing to better methods of prevention and treatment.
Confirmation of a genetic predisposition for lung
cancer can be obtained by finding evidence for link-
age of the putative susceptibility gene(s) to genetic
marker loci in a specific chromosomal region(s).
One potential problem in the search for such a link-
age is heterogeneity. There are different types of
heterogeneity of this disease and of its etiological
factors: (1) there is heterogeneity at the level of
histological types of lung cancer, (2) there is het-
erogeneity at the level of exposure to a variety of
environmental risk factors, and (3) there could be
heterogeneity at the level of inherited susceptibil-
ity loci, i.e., there could be one locus involved in
susceptibility for one family and a different locus
involved in susceptibility for another family. All of
these types of heterogeneity could possibly con-
found the identification of a susceptibility locus (or
loci) for lung cancer. The suggestive evidence in the
published linkage study [99] for susceptibility loci
at several other regions of the genome supports the
possibility of locus heterogeneity in lung cancer.
If, through linkage and positional cloning tech-
niques, a genetic locus or loci that contributes to
inheritable risk for lung cancer can be identified, or
one of the candidate loci suggested to modify risk
by association studies can be confirmed as a sus-
ceptibility locus, then the effects of the alleles at
this locus and its interaction with cigarette smok-
ing and the other well-known environmental risk
factors for lung cancer can be elucidated with much
more accuracy than presently possible and our un-
derstanding of lung carcinogenesis in general may
be increased.