INHALATION OF TOBACCO SMOKE

The association between cigarette smoking and lung cancer is
strong and well established. 3–5,43–47 The incidence of lung cancer
is correlated with the cumulative amount and duration of
cigarettes smoked in a dose–response relationship, 6,44,48 and
smoking cessation results in a leveling off of risk for lung cancer
at the time of smoking cessation. 6,49,50 Lung cancer rates and
smoking rates are also highly correlated in different geographic
regions. 51 In 1991, Shopland et al. 52 showed that the relative
risk (RR) of lung cancer for male smokers versus nonsmokers is
22.36 and that for female smokers versus female nonsmokers is
11.94. They also estimated that 90% of lung cancers in men and
78% in women were directly attributable to tobacco smoking.
Kondo et al. 53 showed a significant ( p 0.001) dose– response
relationship between number of cigarettes smoked and the frequency
of p53 mutations in tumors of lung cancer patients, suggesting
that somatic p53 mutations may be caused by exposure
to a carcinogen/mutagen in tobacco smoke or its metabolites.
BIOLOGIC RISK FACTORS
In general, all studies suggesting genetic susceptibility have also
shown strong risk resulting from cigarette smoking and often
have shown an interaction of high-risk genotype and smoking
on lung cancer risk. When trying to determine whether
a complex disease or trait such as lung cancer has a genetic
susceptibility, one asks three major questions:
1. Does the disease (lung cancer) cluster in families? If some
risk for lung cancer is inherited, then one would expect to
see clustering of that cancer in some families above what
would be expected by chance.
2. If the aggregation of lung cancer does occur in some families,
can the observation be explained by shared environmental/
cultural risk factors? In the study of lung cancer,
one needs to assess whether the familial clustering of lung
cancer is solely a result of clustering of smoking behaviors
or other environmental exposures within families.
3. If the excess clustering in families is not explained by measured
environmental risk factors, is the pattern of disease
consistent with Mendelian transmission of a major gene
(i.e., of transmission through some families of a moderately
high penetrance risk allele) and can this gene(s) be localized
and identified in the human genome?
In addition, inherited susceptibility factors for lung cancer
can also be identified by conducting large-scale case control
studies, just as these approaches have been successful for other
complex diseases that often result from a complex interplay of
genetic and environmental factors.