CHAPTER 2 Lung Cancer Susceptibility Genes

Introduction
After heart disease, cancer is the most common
cause of death and lung cancer is the most common
cause of cancer death in the United States [1]. From
1950 to 1988, lung cancer experienced the largest
increase in mortality rate of all the cancers and lung
cancer caused an estimated 146,000 deaths in the
United States in 1992 [2]. Lung cancer became the
leading cause of cancer death in men in the early
1950s and in women in 1987.
Cancer of the lung has frequently been cited as an
example of a malignancy that is solely determined
by the environment [3,4] and the risks associated
with cigarette smoking [3–7] and certain occupa-
tions, such as mining [8], asbestos exposure, ship-
building, and petroleum refining [9–14], are well
established. Most lung cancers are attributable to
cigarette smoking (e.g. [15]). Dietary studies have
found reduction in risk associated with high com-
pared to low consumption of carotene-containing
fruits and vegetables (for reviews see [16–19]). At
least one recent, very large meta-analysis [20] has
found significant protective effects of increased lev-
els of dietary β-cryptoxanthin although recent trials
of beta-carotene and vitamin A supplements have
not shown any significant reduction in lung cancer
risk; instead they showed an increased risk of lung
cancer death in the treated group [21–24]. Environ-
mental tobacco smoke (ETS, passive smoking) has
also been shown to be associated with increased risk
of lung cancer (for review see [3,4,25–27]) with a
recent prospective European study estimating that
between 16 and 24%of lung cancers in nonsmokers
and long-term ex-smokers were attributable to ETS
[28]. A recent meta-analysis 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
[29]. These environmental risk factors cannot be
reviewed in detail here. There is little doubt that
the majority of lung cancer cases are attributable to
(i.e., would not occur in the absence of) cigarette
smoking and other behavioral and environmental
risk factors [2,7,25,30]. However, some investiga-
tors have long hypothesized that individuals differ
in their susceptibility to these environmental in-
sults (e.g. [31–34]). It is well known that muta-
tions and loss of heterozygosity at genetic loci such
as oncogenes and tumor suppressor genes are in-
volved in lung carcinogenesis (see [35,36] for re-
views) but most of these changes are thought to
be accumulated at the somatic cell level. However,
evidence has beenmounting that certain allelic vari-
ants at some genetic loci may affect susceptibil-
ity to lung cancer, although these effects may be
small. Furthermore, mounting epidemiologic evi-
dence has suggested lung cancer may show famil-
ial aggregation after adjusting for cigarette smok-
ing and other risk factors, and that differential sus-
ceptibility to lung cancer may be inherited in a
Mendelian fashion. There is evidence that both lung
cancer and smoking-associated cancer in general
have an inherited genetic component, but the exis-
tence of such a genetic component has not been def-
initely proven. This chapter will detail the evidence
suggesting the existence of inherited major sus-
ceptibility loci for lung cancer risk, and will relate
these risks to the well-known risks due to environ-
mental risk factors, particularly personal cigarette
smoking.