SEGREGATION ANALYSES OF LUNG AND SMOKING-ASSOCIATED CANCERS

Given the evidence for familial aggregation of lung and other
smoking-associated cancers, after accounting for personal tobacco
use and occupational/industrial risk factors, segregation
analyses have been performed to determine whether patterns
of transmission consistent with at least one major, highpenetrance
genetic locus may be involved in lung cancer risk.
Sellers et al. 96 performed genetic segregation analyses on
the lung cancer proband families of Ooi et al. 59 described previously.
The trait was expressed as a dichotomy, affected or
unaffected with lung cancer. The analyses used the general
transmission probability model, 97 which allows for variable
age of onset of the lung cancer. 98–100 The likelihood of the
models was calculated using a correction factor appropriate
for single ascertainment, 101,102 that is, conditioning the likelihood
of each pedigree on the probands being affected by their
ages at examination or death.
Age of onset of lung cancer was assumed to follow a logistic
distribution that depended on pack-years of cigarette consumption
and its square, an age coefficient and a baseline parameter.
Results indicated compatibility of the data with Mendelian
codominant inheritance of a rare major autosomal gene that
produces earlier age of onset of the cancer. Segregation at this
putative locus could account for 69% and 47% of the cumulative
incidence of lung cancer in individuals up to ages 50 and
60, respectively. The gene was predicted to be involved in only
22% of all lung cancers in persons up to age 70, a reflection
of an increasing proportion of noncarriers succumbing to the
effects of long-term exposure to tobacco. 97,103
Gaudermann et al. 104 reanalyzed these same data using a
Gibbs sampler method to examine gene by environment interactions
and found evidence for a major dominant susceptibility
locus that acts in conjunction with cigarette smoking to increase
risk; this model was very similar to the previous results,
because the codominant Mendelian models predicted very
small numbers of homozygous susceptibility allele carriers.
Yang and coworkers105 performed complex segregation
analysis on the families of nonsmoking lung cancer probands
in metropolitan Detroit. Evidence was found for Mendelian
codominant inheritance with modifying effects of smoking and
chronic bronchitis in families of nonsmoking cases diagnosed
at ages. 40–59 The estimated risk allele frequency was 0.004.
Although homozygous individuals with the risk allele are rare in
the study population, penetrance was very high for early onset
lung cancer (85% in men and 74% in women by age 60). The
probability of developing lung cancer by age 60 in individuals
heterozygous for the rare allele was low in the absence of smoking
and chronic bronchitis (7% in men and 4% in women), but
in the presence of these risk factors it increased to 85% in men
and 74% in women, which was the same level predicted for homozygotes.
The attributable risk associated with the high-risk
allele declines with age, when the role of tobacco smoking and
chronic bronchitis become more important.
Wu et al. 106 performed segregation analysis of families of
125 women, nonsmoking lung cancer probands in Taiwan.
These lung cancer probands were diagnosed with lung cancer
between 1992 and 2002 at two hospitals in Taiwan. Complete
data on patients, spouses, and first-degree relatives were collected
for 108 families. Data collected on the patients and their relatives
included demographic, lifestyle, and medical history variables.
Complex segregation analysis using logistic models for age
at onset, including pack-years of cigarette smoking in the model
was performed on 58 of these families. An ascertainment correction
was made using the phenotype of the probands, but this
may have been inadequate because the 58 families were a subset
of the 108 families where there was at least one additional affected
relative in the family. The Mendelian codominant model
that included risk caused by personal smoking fit the data best,
significantly better than the sporadic or purely environmental
models. This model was not rejected against the general model
in an early onset (less than 60 years) subset of the families but
was rejected in the later-onset families and the total dataset.
Taken together, the Taiwan, Detroit, and Louisiana studies
share remarkably similar results and demonstrate statistical
evidence for at least one major gene that acts in conjunction
with personal smoking and possibly chronic bronchitis to increase
risk of lung cancer.
Although most of these studies included measures of
personal smoking on the cases (or probands) and controls in
the models, some of the aggregation studies did not include
measures of amount of cigarette smoking in the relatives, and
only one included measures of passive smoking. The segregation
analyses did not include passive smoking or occupational
risk factors in the models, and only one of these three studies
collected data on history of chronic bronchitis. Furthermore,
segregation analyses are not sufficient to prove the existence
of a major locus because only a subset of all possible models
can be tested. However, tracking the inheritance of lung
cancer with genetic markers in a family (linkage analysis) can
provide definitive evidence for genetic susceptibility to disease.
Segregation analyses are useful because they provide a model
that can be used for these subsequent analyses, and they provide
insights into the best designs for identifying genes that
have a high risk for disease.