Genetic Susceptibility to Lung Cancer

United States 1 with 162,000 deaths estimated for 2008 among
215,000 incident cases. Lung cancer became the leading cause
of cancer death in men in the early 1950s and in women in
1987. From 1950 to 1988, lung cancer experienced the largest
increase in mortality rate of all the cancers ,2 reflecting increases
in smoking behavior. Lung cancer prognosis often remains poor
because it is usually detected as a stage III or IV malignancy.
Identifying genetic factors that influence lung cancer risk could
help in identifying subsets of individuals at particularly high
risk, in whom early detection strategies could be adopted. In
addition, a better understanding of the genetic influences that
increase lung cancer risk may lead to the development of novel
approaches for chemoprevention and therapy.
Cancer of the lung has frequently been cited as an example
of a malignancy that is solely determined by the environment
3 and the risks associated with cigarette smoking 3–6
and certain occupations, such as mining, 7 asbestos exposure,
shipbuilding, and petroleum refining, 8–12 are well established.
About 85% to 90% of lung cancer risk can be associated with
cigarette smoking. 13–15 Environmental tobacco smoke (ETS,
passive smoking) has also been shown to be associated with
a mild increase in risk for lung cancer in North America and
Europe. 6,16–18 A recent prospective European study estimating
that between 16% to 24% of lung cancers in nonsmokers
and long-term ex-smokers were attributable to ETS. 19 A metaanalysis
of 22 studies showed that exposure to workplace ETS
increased risk of lung cancer in workers by 24%, and that this
risk was highly correlated with duration of exposure. 20
Dietary studies have found reduction in risk associated with
high compared with low consumption of carotene-containing
fruits and vegetables. 21–27 Subsequent chemoprevention trials
among high-risk subjects with a history of smoking and/or occupation
exposure showed a surprising increase in lung cancer risk
in these populations associated with beta-carotene supplementation.
28–30 At least one very large metaanalysis 31 found significant
protective effects of increased levels of dietary -cryptoxanthin,
another carotenoid.
There is little doubt that most lung cancer cases are attributable
to (i.e., would not occur in the absence of ) cigarette
smoking and other behavioral and environmental risk
factors, 2,6,16,32,33 and most studies indicate that duration of
cigarette smoke is a more important risk factor than intensity
or number of cigarettes smoked per day. 34–36 However,
it was conjectured long ago that individuals differ in their
susceptibility to these environmental insults. 37–39 Mutations
and loss of heterozygosity at genetic loci such as oncogenes
and tumor suppressor genes (TSGs) are involved in lung carcinogenesis,
40–42 but most of these changes are thought to accumulate
in individual somatic cells over time, as opposed to
the inherited risk to all cells that will result from mutations or
risk-increasing polymorphisms occurring in transmission from
germ cells. However, numerous studies show that certain allelic
variants at some genetic loci affect inherited susceptibility to
lung cancer. Furthermore, mounting epidemiologic evidence
has suggested that lung cancer shows familial aggregation after
adjusting for cigarette smoking and other risk factors, and that
differential susceptibility to lung cancer is inherited in some
families. This chapter describes inherited major susceptibility
loci and findings from well-replicated studies of loci for lung
cancer risk that have less pronounced effects. We also relate
these risks to the well-known risks as a result of environmental
risk factors, particularly personal cigarette smoking.