Download Lung Cancer Detection and Prevention

[CANCER RESEARCH (SUPPL.) 52. 2694s-2697s, May I, 1992|
Lung Cancer Detection and Prevention: Evidence for an Interaction between
Smoking and Genetic Predisposition1
Thomas A. Sellers,2 John D. Potter, Joan E. Bailey-Wilson, Stephen S. Rich, Henry Rothschild, and Robert C. Elston
Division of Epidemiology, School of Public Health [T. A. S., J. D, P.], Laboratory Medicine and Pathology [S. S. R.J, and Institute of Human Genetics [T. A. S.,
S. S. R.j, University of Minnesota, Minneapolis, Minnesota 55455, and Departments of Biometry and Genetics fJ. E. B.-W., R. C. E.] and Medicine [H. R.], Louisiana
State University Medical Center, New Orleans, Louisiana 70112
Abstract
The initiation and promotion of cancer is thought to result from a
series of genetic mutations, some of which may be inherited. Our analysis
of 337 lung cancer families suggested that, after allowing for an individ
ual's pack-years of tobacco use, the pattern of disease was best explained
by Mendelian codominant inheritance of an alÃ-elethat produced earlier
age of onset. Since lung cancer rarely occurs in the absence of exposure
to tobacco, differences in the prevalence of smoking across generations
could have a profound influence on the fit of genetic models. In the
present study, families were partitioned into two groups, based on the
birth cohort of the proband, i.e., born before World War I (age at death,
•¿611
years) or born after World War I (age at death, <60 years). This
partition was chosen because the year 1915 signaled the start of the
dramatic rise in tobacco use in the United States. In younger proband
families, in which parents were more likely to smoke, Mendelian codom
inant inheritance provided the best fit to the data. In older proband
families, for whom smoking among parents was less prevalent, the "no
major gene" and "environmental" hypotheses were rejected; however, no
Mendelian models could be distinguished. If the results on the families
with the most homogeneous exposure to tobacco across generations (born
after World War I) reflect the true underlying biology, then the influence
of genetic factors in the pathogenesis of lung has been underestimated;
the cumulative probability of lung cancer at age 80 for a noncarrier of
the gene, at the average level of tobacco consumption, is close to zero,
implying that virtually all lung cancer occurs among gene carriers.
Identification of this putative genetic factor has profound implications
for the detection and prevention of lung cancer.
Introduction
The initiation and promotion of lung cancer are considered
to be a series of genetic events, including point mutations,
chromosomal abnormalities, gene amplification, and altered
gene expression ( 1). The products of these altered genes may
prove to have utility in the development of new therapeutic
strategies and, if one or more of the mutations were shown to
be inherited, prevention activities could become more focused.
One approach to the identification of the relevant genes is to
study families in which at least one relative has lung cancer.
Epidemiological studies consistently demonstrate an excess
of lung cancer in some families that cannot be accounted for
by chance or common environmental exposure (2-5). Results
of segregation analyses are consistent with the Mendelian
inheritance of a gene that influences the age of onset of lung
cancer (6).
Confirmation of a genetic predisposition for lung cancer
necessitates linkage studies to identify the genetic location of
the putative major gene. Selection of informative families for
such analyses is usually determined by the family size and the
number of living family members affected with the disease.
Complicating the study of lung cancer susceptibility is the fact
that the disease rarely occurs in the absence of exposure to
environmental agents, such as tobacco smoke, radioactive ores,
heavy metals, and petrochemicals. This implies that lung cancer
is the result of a gene-environment interaction. Identification
of "high risk" families is complicated by the variation in prev
alence of the environmental exposure of family members that
would be requisite to "unmask" susceptibility and by the occur
rence of "sporadic" and "familial" cases in families.
This paper examines the influence of intergenerational dif
ferences in exposure to environmental causes of lung cancer on
models of inherited predisposition. The implications of the
results in terms of future research and intervention strategies
are discussed.
Materials
and Methods
Study Families. Subjects were chosen as probanas if they were
Caucasians who had died of a primary malignancy of the lung in one
of 10 southern Louisiana parishes (counties) within a 4-year period
(1976-1979). Of 440 probands identified, complete three-generation
pedigrees were obtained for 337 families (76%), comprising 4357
persons. Details of the ascertainment, participation rates, and methods
of data collection on these families have been previously reported (3,
7). Briefly, a complete listing of all deaths satisfying the aforementioned
eligibility criteria were obtained from the Office of Public Health
Statistics. Death certificates of the probands were searched to identify
next of kin, who were contacted to provide the pedigree structures,
including names, addresses, and phone numbers of all first-degree
relatives. Trained interviewers using standard protocols obtained infor
mation on each family member by telephone, mailed questionnaire, or
ill-person interview. Specific data items included cancer history (includ
ing age of onset, if affected) and use of tobacco products.
Statistical Methods. Segregation analyses were performed on the
lung cancer trait expressed as a dichotomy, affected or unaffected with
lung cancer, using the method of maximum likelihood. Depiction of
the pattern of phenotypes was achieved through the use of two sets of
parameters, type frequencies and transmission probabilities. Go et al.
(8) introduced the concept of "type" to describe an underlying discrete
characteristic that affects a person's phenotype. Genotypes are a special
case of types, in which transmission follows Mendelian laws of
inheritance.
Mendelian inheritance, if present, was assumed to be through a
single autosomal locus with two alÃ-eles,A and B, where A is associated
with the affected state. Additionally, random mating and Hardy-Wein
berg equilibrium for population frequencies of the types were assumed.
The likelihood of each pedigree was conditioned on each person's
smoking history and on the ages at which the probands became affected,
the latter being a correction factor appropriate for single ascertainment
of the pedigrees when age of onset is highly correlated with age at
examination (9, 10).
The general transmission probability model (11), allowing for vari
able age of onset (12) but using the logistic distribution (13, 14), was
employed. The logistic age of onset distribution, characterized by age
coefficient a and base line parameter ß
(where the mean of the distri
bution is -ß/aand the variance is 7r2/3a2),is only relevant to susceptible
persons, with susceptibility (7) defined by Go et al. (15) as the cumu
lative probability of being affected if one lives to age infinity.
Two biologically plausible models of how a putative alÃ-elemight
operate were evaluated. Model 1 states that a fixed proportion of the
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1Presented at the NCI Workshop "Investigational Strategies for Detection
and Intervention in Early Lung Cancer," April 21-24, 1991, Annapolis, MD.
2To whom requests for reprints should be addressed, at Division of Epide
miology, 1-210 Moos Tower. 515 Delaware St. S.E., Minneapolis, MN 55455.
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1992 American Association for Cancer Research.
SMOKING DIFFERENCES
AND LUNG CANCER SUSCEPTIBILITY
population would develop the disease if they lived long enough (i.e..
they form a susceptible subpopulation, in this case because of the
environment in which they live). The effect of the gene would be
manifested as an earlier age of onset. Model 2 states that all persons
develop lung cancer according to the same distribution of age of onset
but that the level of susceptibility is genotype dependent.
Segregation analyses were performed, under both biological models,
by fitting five hypothetical modes of transmission to the data, (a) No
major gene effect can be discerned. This implies that there is only one
age of onset distribution and only one level of susceptibility, (b) Envi
ronmental transmission of lung cancer is not dependent on genetic
factors but, rather, is due to known environmental influences (e.g.,
cigarette smoking) together with unmeasured environmental factors.
(c) Mendelian dominant implies that a single copy of the A alÃ-eleis
sufficient for an earlier age of onset (biological model 1) or greater
susceptibility (model 2). (¡i)Mendelian recessive states that inheritance
of two copies of the A alÃ-eleare necessary for an earlier age of onset
(biological model 1) or greater susceptibility (model 2). (e) Mendelian
codominant, a more general model that includes the preceding two
hypotheses as special cases, allows for the presence of three genotypes,
each with different (not necessarily additive) mean age of onset (model
1) or susceptibility (model 2). These hypotheses were tested against the
likelihood of an unrestricted (general) model in which all parameters
are adjusted to the empirical data, without restrictions, thereby provid
ing the best fit to the data. Twice the difference in the In/,3 for the data
under the hypothesis of interest (dominant, environmental, etc.) and
that under the unrestricted model was compared to the x2 distribution,
to assess departure from the hypothesis. The degrees of freedom for
the x2 statistic are given by the difference in the number of parameters
estimated under the two models being compared. A significant x2
indicates that the genetic or environmental hypothesis considered can
be rejected. Another method used to compare the hypotheses was AIC
(16), defined as
AIC = -2InL + 2 (no. of parameters estimated).
The hypothesis with the minimum AIC fits the data best. Mean differ
ences in tobacco use and age of onset of lung cancer were compared
between relatives of probands diagnosed early and late using SAS
(Statistical Analysis System).
Results
Of the 337 families studied, 106 were ascertained through a
proband whose age at death was <60 years (i.e., born after
World War I), and 231 through a proband whose age at death
was >60 years (i.e., born before World War I). The number
of affected relatives in each of these subsets is presented in
Table 1.
When segregation analyses were applied to all 337 families
combined under biological model 1 (type-dependent age of
onset), the hypotheses of no major gene, environmental, and
Mendelian recessive transmission were rejected, as previously
reported (6). While Mendelian dominant and codominant hy
potheses both explained the data well, the latter fitted signifi
cantly better. The likelihoods of the data under biological model
2 (type-dependent susceptibility) were smaller and not as ap
propriate for these data (6). This observation also held true
after the families were partitioned into the two age-of-onset
groups and, therefore, results obtained under this biological
model will not be presented here.
Results of the segregation analyses on the subset of families
ascertained through a proband born after World War I (families
with higher smoking prevalence) are presented in Table 2. The
pattern of disease in these families was explained only by
3The abbreviations used are: In/., log, likelihood; AIC, Akaike's information
criterion.
Table I Distribution of lung cancer in 337 families ascertained via lung cancer
probands, by age of onset category of the proband
Onset before age 60
106)RelativeProband (n=
affected106
Father
Mother
Brothers
Sisters
Sons
DaughtersNo.
15
312
2
0
0%100.0
age 60 or later
231)No.(n =
affected231
14.2
2.8
4.2
0.8
0.0
0.0Onset
15
4
32
18
2
0%100.0
6.5
1.7
4.92.8
0.6
0.0
Mendelian codominant inheritance; all other hypotheses could
be rejected. For the families ascertained through a proband
born prior to World War I, the hypotheses of no major type
and random environment could still be rejected. The models of
Mendelian transmission considered could not be rejected; how
ever, the three models could not be distinguished (Table 3).
Compared to the results obtained for all families, the estimated
gene frequency under the codominant hypothesis (q„
= 0.052)
was little changed in the families where the proband was born
after World War I (qa = 0.062 ±0.027) but was considerably
higher in the group where the proband was born before World
War I (qa = 0.169 ±0.085). Nonetheless, these estimates of
gene frequencies are not significantly different (P > 0.1). In
addition, the proportion of the population susceptible to the
affected state doubled in the group of families ascertained by
probands born after World War I (22% to 60%).
To determine if the differences in the segregation analysis
results on the two subsets of families were statistically signifi
cant, a test for heterogeneity was performed. The likelihood of
the data under Mendelian codominant transmission for all 337
families was 366.42 (6). The sum of the likelihoods for the early
onset (53.77) and late onset families (276.00) was significantly
smaller (P < 0.001 level), implying significant heterogeneity
between the two subsets.
One possible explanation for the observed heterogeneity is
that we have isolated a high risk, early onset subset of families.
However, the mean age of onset for the affected relatives with
known smoking status was the same for early versus late onset
families (Table 4). Conversely, if the stratification of families
according to birth cohort of the proband did isolate a subset
with more homogeneous distribution of environmental expo
sures across generations, one would expect to see differences in
the use of tobacco products in the two subsets of families. This
is confirmed in Table 4; parents of the probands born after
World War I were indeed more likely to use tobacco products
than the parents of probands born before World War I.
Discussion
The present study provides evidence that cohort differences,
presumably in the exposure to environmental factors, can influ
ence results of segregation analyses. Families were partitioned
a priori into two birth cohorts, to reflect the dramatic increase
in cigarette smoking that followed World War I. For both
subsets of families, no major effect and random environmental
transmission were rejected. For the late onset proband (born
before World War I) families the Mendelian hypotheses could
not be distinguished, while for the early onset proband (born
after World War I) families only codominant inheritance fitted
the data.
Because lung cancer rarely occurs in the absence of tobacco
exposure, the results observed for the early onset (probands
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SMOKING DIFFERENCES
AND LUNG CANCER SUSCEPTIBILITY
Table 2 Results of segregation analysis of lung cancer in 106 families ascertained through a lung cancer proband born after World War I
Hypothesis
Mendelian
Parameter
Dominant
Type frequency (qA)
0.090
Susceptibility (%)
Mean age
(years)
AA
AB
BBGoodness
(df)°P
of
85.6
Recessive
No major
type
Codominant
0.16
0.062
41.5
Environmental
General
model
0.035
59.6
42.9
39.9
77.6
77.614.3
57.9
78.69.9
(5)<0.0574.55273.0
(2)<0.02576.1258.3
0.12
90.2
onset
78.6
79.0
295.411.3(3)<0.02575.4962.4
79.010.0
of fit, x2
79.0
279.43.6
(3)<0.0574.2161.1
(2)>0.2569.7777.6
79.3
225.570.22
valueAIC*78.6
" X2= (—21nLof the data under the hypothesis) —¿
(—21nLof the data under the general model), df, degrees of freedom.
* AIC = —¿2lnL
+ 2 (no. of parameters estimated).
Table 3 Results of segregation analysis of lung cancer in 231 families ascertained through a lung cancer proband born before World War I
Hypothesis
major
type25.081.6
ParameterType
model0.1722.046.6
(q¿)Susceptibility
frequency
(%)Mean
age
(years)
AA
AB
BBGoodness
(df)°P
of
onset
49.6
80.70.34
of fit, x2
72.9
78.3
81.6
72.8
83.70.04
78.33.17(4)>0.50Codominant0.1721.846.5
81.617.07(5)<0.001Environmental0.2519.448.077.2
77.28.91
83.4
(4)>0.95MendelianRecessive0.2319.848.6 (3)>0.95No
(3)<0.05General
valueDominant0.02521.649.6
AIC"
295.77
298.60
297.47
308.50
306.34
303.43
°See footnotes to Table 2.
Table 4 Comparison of tobacco consumption and age of onset in relatives of 337
lung cancer patients, by age category of the proband
; smokers"
Age at onset
Relative
After World
War I
Before World
War I
After World
War I
Before World
War 1
FatherMotherBrothersSistersSonsDaughters73.6C19.
S1*78.038.9'42.042.658.46.971.628.965.
6"*42.666.468.058.254.564.074.763.860.6
" Excludes those with unknown smoking status: fathers, 34.4%; mothers,
22.3%; brothers, 21.1%; sisters, 18.4%; sons, 17.7%; daughters, 19.0%.
'' Excludes affected persons with unknown smoking status.
c P < 0.05.
aP<0.01.
born after World War I) families (where exposures were more
uniform across generations) are more likely to reflect the true
underlying biology. If so, these results suggest that the influence
of genetic factors in lung cancer pathogenesis is much greater
than our previous estimate; the probability of lung cancer at
age 80 for a noncarrier of the gene, at the average level of
tobacco consumption, is estimated by the model to be 2.8 x
10~27,implying that virtually all lung cancer occurs among gene
carriers. Conversely, the data also highlight the importance of
tobacco consumption; as the prevalence of smokers increased
over time, the subpopulation that was unmasked as susceptible
increased from 22% to 60% of the population.
It should be noted that these data do not support the inter
pretation that lung cancer is principally a genetic disease. The
risk of lung cancer for nonsmoking, gene carriers is low; the
cumulative probability by age 80 is only 52/100,000 (compared
with 2,175/100,000 smokers). Thus, these data are more con
sistent with the hypothesis that a genetic predisposition to lung
(and perhaps other) cancers is inherited and that the trait is
expressed only in the presence of an environmental insult; this
is tobacco smoke or its passively inhaled products in the vast
majority of cases.
The current results are consistent with the multistage theory
of carcinogenesis. The inherited predisposition may reflect a
tumor suppressor gene, both copies of which must be lost or
mutated for malignancy to progress. Homozygous gene carriers
could be considered to have inherited two "hits" (i.e., a mutant
tumor suppressor gene from each parent), with malignancy
manifest some time after a period of environmental exposure.
Hétérozygotes
inherit a single hit (i.e., only one mutant tumor
suppressor gene); thus, these individuals would be expected to
have a later age of onset than homozygotes. An alternative
explanation of these findings is that of a major gene influencing
enzymatic metabolism of the procarcinogens in tobacco smoke
to reactive carcinogenic intermediates. High inducibility of the
cytochrome P450 CYP1A1 gene has been correlated with bron-
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SMOKING DIFFERENCES
AND LUNG CANCER SUSCEPTIBILITY
chogenic carcinoma (17, 18). It should also be acknowledged
that there may not be simply one major gene segregating in
these families. There may be several different genes that are
transmitted in the same manner and occur in about the same
frequency in the population. The existence of such genetic
heterogeneity can be tested by linkage analyses in these families.
The implication that virtually all cases of lung cancer occur
among genetically predisposed individuals has tremendous pub
lic health implications; for the lung cancer susceptible, smoking
appears to be universally lethal. Given the observational nature
of the study design and analysis, it is premature to suggest
screening, counseling, or education for individuals with a posi
tive family history of lung (or perhaps other tobacco-associated)
cancer. However, this study does suggest that individuals with
out a family history of lung cancer should not be lulled into a
false sense of security; if parents and siblings have not been
challenged by environmental (tobacco) exposure, susceptibility
may not have been unmasked. It should also be stressed that,
for the lung cancer nonsusceptible, risk for a variety of other
disorders is certainly increased by smoking, especially for car
diovascular disease, which accounts for by far the greatest
smoking-related morbidity and mortality (19).
What is imperative is that these results be replicated in other
populations, allowing for potentially important covariates that
were not measured in this study (e.g., carotenoid intake, alcohol
use, physical activity, and passive smoking). Identification of
the susceptibility gene would enable the identification of high
risk individuals prior to onset of disease, enhance the benefit of
primary prevention efforts and elucidation of the gene function,
and increase our understanding of the pathogenesis of lung
cancer.
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2697s
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Lung Cancer Detection and Prevention: Evidence for an
Interaction between Smoking and Genetic Predisposition
Thomas A. Sellers, John D. Potter, Joan E. Bailey-Wilson, et al.
Cancer Res 1992;52:2694s-2697s.
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