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Departments of Environmental Health (Occupational Health Program) [R. F., M-T. W., D. M., K. T. K., D. C. C.] and Cancer Cell Biology [K. T. K.], Harvard School of Public Health, Boston, Massachusetts 02115; Thoracic Surgery Unit, Department of Surgery [J. C. W.], and Pulmonary and Critical Care Unit, Department of Medicine [D. C. C.], Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02114; University of California at San Francisco, Department of Epidemiology and Biostatistics, San Francisco, California 94143 [J. K. W.]
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To date, several polymorphisms in the wild-type p53 gene locus have been described. The codon 72 polymorphism on the 4th exon of the p53 gene, which produces variant proteins with an arginine (CGC) or proline (CCC), has been reported to be associated with bladder and lung cancer (11, 12, 13) .
An association of the codon 72 p53 polymorphism with lung cancer susceptibility has been reported by several authors. In one study, Weston et al. (13) reported an increased frequency of the proline allele in adenocarcinomas, but a later study by this same group (14) did not confirm this finding in a different set of cancer cases and controls. The homozygous Pro/Pro genotype was found to be overrepresented in a study of Japanese lung cancer, especially in Kreyberg type I but not in adenocarcinoma (15) . More recently, an enhanced risk was reported for African Americans with both the Pro/Pro genotype and an early onset of lung cancer (16) . A Swedish study has also suggested that the codon 72 alleles may not be functionally involved in lung cancer but, rather, may be a marker in linkage dysequilibrium with other cancer susceptibility sites (17) . A Spanish study reported that there was no difference in the prevalence of the codon 72 p53 polymorphism between lung cancer cases and controls. However, in that study, the Pro allele of the p53 germ-line polymorphism increased slightly the lung cancer risk for the GSTM1-null genotype among smokers (18) . Murata et al. (19) reported that, among 191 lung cancer cases, 115 colorectal cancer patients, and 152 controls, there was a statistically significant difference in genotype frequency only in nonsmokers with lung cancer, with the homozygous Arg/Arg genotype overrepresented in that group.
Hence, the literature to date has not been consistent with respect to the association of codon 72 polymorphism with lung cancer susceptibility. In the present study, we conducted a large case-control study of lung cancer patients and controls and examined the genotype frequency of codon 72 of lung cancer patients and controls, using PCR-based genotyping methods to further evaluate the possible relevance of this polymorphism for lung cancer risk.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A detailed interviewer-administered questionnaire was completed for each case and control by a trained interviewer. A modified standardized American Thoracic Society respiratory questionnaire (20) with additions on a detailed occupational and environment exposure history was used. The questionnaire included information on average cigarettes smoked daily for current smokers, years smoked, and time since quitting smoking for ex-smokers. As an indication of cumulative smoking exposure, pack-years were defined as the average number of packs smoked per day multiplied by years smoked. We also obtained information on all of an individual’s job titles, job tasks, years and dates of exposure, and family history of cancer in first-degree relatives.
p53 BstUI Polymorphism.
PCR-RFLP analysis of the codon 72 of the p53 gene originally
described by Ara et al. (1)
was used to
identify p53 BstUI genotypes. The two primers
were 5'-TTGCCGTCCCAAGCAATGGATGA-3' and 5'-TCTGGGAAGGGACAGAAGATGAC-3'.
Each PCR reaction mixture (50 µl) contained 10 pmol of each primer,
2.0 mM MgCl2, 200
mM each dNTP, 1 unit of Taq polymerase
and 100–300 ng of genomic DNA. Reaction mixtures were preincubated for
5 min at 94°C. PCR conditions were 94C° for 30 s and 55°C
for 1 min, followed by 72°C for 1 min for 35 rounds. After
confirmation of an amplified fragment of the expected size (199 bp) on
an agarose gel, the PCR products were digested with 2 units of
restriction enzyme BstUI (New England Biolabs, Beverly,
MA) at 60°C for 16 h. DNA fragments were electrophoresed
through a 2% agarose gel and stained with ethidium bromide (Fig. 1)
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2 and t
tests) were used first to compare cases and controls for demographic
variables and genotype prevalence. Multivariate logistic regression
analysis was performed to assess the association between the
p53 polymorphism and lung cancer. Potential confounding
factors adjusted for included sex, age (years), race, education level,
smoking status (current, ex-smoker, nonsmoker) and pack-years. For the
purpose of modeling the association between the p53 variant
gene frequency and lung cancer, we compared the homozygous
(Pro/Pro) variant and the heterozygous genotype
(Arg/Pro) with the homozygous (Arg/Arg)
genotype, respectively. Because of low number of homozygous
Pro/Pro subjects in some subgroups based on pack-years, we
combined the homozygous Pro/Pro variant with heterozygous
Arg/Pro as a single group to compare with the homozygous
Arg/Arg genotype. In this model, we assumed that
risk associated with the Arg/Pro genotype would be
intermediate between that of the Arg/Arg and the
Pro/Pro genotypes. On the basis of this assumption, we coded
the data as follows (using logistic regression model):
Arg/Arg genotype = 0; Arg/Pro genotype = 0.5; Pro/Pro genotype = 1. The resulting coefficient
yields the risk associated with having the Pro/Pro +
Arg/Pro versus Arg/Arg genotype,
adjusting for covariates. |
Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Men are overrepresented in the cases (54.9 versus 45.1%),
with females overrepresented in the controls (54.9 versus
45.1%). The mean ages were 65.5 years for cases and 61.6 years for
controls. Predictably, cases were significantly more likely to be
current smokers (41.9 versus 17.9%), to have smoked more
cigarettes per day (28.6 versus 15.4), and to have
accumulated more pack-years (57.8 versus 22.6) than the
controls. There was no statistically significant difference between
cases and controls with regard to education and race.
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. The frequencies of the three genotypes, Arg/Arg,
Arg/Pro, and Pro/Pro, were 46.5, 41.6, and
12.0%, respectively, in controls. The crude genotypic frequencies in
the lung cancer patients were similar to those of the controls. When
lung cancer cases were stratified by histological subtype, the
distribution of the three genotypes in adenocarcinoma patients differed
from controls: Arg/Arg, Arg/Pro, and
Pro/Pro were 39.3, 44.3, and 16.4%, respectively. There was
no statistically significant difference in the prevalence of the
polymorphism among squamous cell, large cell, small cell, mixed cell,
and bronchoalveolar cell subtypes.
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. Within lung adenocarcinoma patients and controls, the variant
Pro/Pro genotype was strongly associated with cigarette
smoking, with a higher prevalence in current smokers. Among cases, but
not controls who smoked, the prevalence of the variant genotype
appeared to vary by cumulative cigarette consumption category, with a
lower prevalence of the Pro/Pro genotype in light smokers
but a higher prevalence in moderate and heavy smokers among
adenocarcinoma cases but not controls. In older cases (65–71 years),
the prevalence of the Pro/Pro genotype was higher than in
controls (not statistically significant). The other variables examined
were not statistically significant between cases and controls.
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. We first compared the Pro/Pro genotype with the
Arg/Arg genotype. The crude
OR3
for Pro/Pro versus Arg/Arg was 1.61
(P = 0.03; 95% CI, 1.04–2.49). After adjustment for
age, sex, race, education, pack-years, and smoking status, the same
covariates, the OR remained elevated 1.59 (P = 0.06;
95% CI, 0.97–2.61). For the purpose of this analysis, the
Pro/Pro genotype was combined with the Arg/Pro
genotype because of low prevalence of the Pro/Pro in
subgroups of subjects based on pack-years. The combined variant
genotype group had a 1.34-fold higher risk for adenocarcinoma than the
genotype Arg/Arg (P = 0.06; 95% CI,
0.98–1.83). After adjustment for the same covariates, the OR was 1.45
(P = 0.04; 95% CI, 1.02–2.06). Because we assumed the
genetic contribution to risk might be less at very high doses of
smoking (21)
, we excluded the group that included the top
15% of subjects based on pack-years (84 pack-years) and
repeated the same logistic regression model (data not shown). The OR
(both crude and adjusted) rose slightly, with an adjusted OR for the
combined variant genotype of 1.50 (95% CI = 1.03–2.18) and an
adjusted OR for the Pro/Pro genotype of 1.79 (95% CI =
1.06–3.02). To avoid the effect of ethnicity, we ran the logistic
model two ways (with all races or with only Caucasians), but the
results remained almost the same.
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display the association of the combined
contributions of genotype and smoking exposure to lung adenocarcinoma
risk, where the Arg/Arg genotype and no pack-years
(nonsmokers) was used as the referent group. Pack-years were divided
into quartiles, and the Pro/Pro and Arg/Pro
genotypes (examined) were one category. As expected, lung
adenocarcinoma risk increased with increasing cumulative cigarette
dose. In addition, at each level of smoking except the light smokers,
the risk associated with smoking was higher for persons with the
Pro/Pro + Arg/Pro combined genotype. The group
with both the heaviest tobacco smoke exposure and the p53
combined Pro/Pro + Arg/Pro genotype had the
highest risk of lung adenocarcinoma, roughly 39-fold higher (95% CI,
10.76–140.51) than the lowest risk group of nonsmokers who were
p53 Arg/Arg. The results revealed the same trend
when quintiles or sextiles of pack-years were used. Because the number
of cases who had never smoked was too low (n = 17), we
combined those who had never smoked with subjects who smoked 1–29
pack-years into a single group and reran the logistic regression model;
the results showed the same trend. As expected, the adjusted OR for
lung adenocarcinoma by p53 and pack-years decreased,
and the 95% CI became tighter (Table 5)
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In this study, we examined the prevalence of p53 codon 72 polymorphisms in a Caucasian group of lung cancer patients and controls. The prevalence of the Pro/Pro genotype in adenocarcinoma cases was statistically different from that of the controls (16.4 versus 12.0%). A Japanese study reported that the prevalence of the Pro/Pro variant in patients with adenocarcinoma was 1.2-fold higher, which was not statistically different from controls (15) . Weston et al. (13) reported a prevalence of 26% for their pooled control group and 21% in all types of lung cancer combined. Jin et al. (16) reported that the susceptible Pro/Pro genotype was associated with a 1.6-fold higher risk of all types of lung cancer combined in African Americans and 1.9-fold higher risk in Mexican Americans, with neither reaching statistical significance. Weston et al. (14) later reported no association between the allele frequencies of p53 and susceptibility for all lung cancers in a Caucasian and an African-American population. The discordance in these studies may be the result of choice of controls, the small sample sizes, and hence, the inability to stratify by histological type.
In our study, the frequency of the Pro/Pro genotype in adenocarcinoma was much lower than that of the Arg/Arg genotype in the low pack-years stratum. The prevalence of the Pro/Pro genotype rose linearly with pack-years. Our results show that the frequency of the Pro/Pro genotype was low at lower cumulative cigarette levels, in contrast to several other published reports (13, 14, 15) . However, the major reason for the low prevalence of the Pro/Pro genotype in our study was that, at light cumulative levels, the number of subjects was small. Because the homozygous Pro/Pro variant frequency is so low in some pack-years quintiles, we reanalyzed the data after combining the heterozygous and homozygous variants and found a statistically significant association with adenocarcinoma. Furthermore, we found that the most important confounding factor for the study appears to be pack-years, which must be adequately adjusted in the analysis of association between p53 genotype and lung adenocarcinoma. The association of the p53 codon 72 variant genotype with increased lung adenocarcinoma risk was modified by gender, race, age, education, smoking status, and pack-years and remained statistically significant after we adjusted for these factors.
As expected, the OR for lung adenocarcinoma increased with dose of cigarette tobacco smoke for both genotypes. In addition, at each level of smoking except for light smokers, subjects with the p53 combined variant genotype experienced higher risk of adenocarcinoma than subjects who had the p53 Arg/Arg genotype. Individuals with the heaviest tobacco smoke exposure and p53 combined genotype had the highest risk of lung cancer, roughly 38-fold higher than the lowest risk group of nonsmokers who were Arg/Arg. These data suggest that the presence of the p53 gene product exerts a protective effect for smoking-induced lung cancer and that the presence of one variant allele alters this product. Thus, the modifications by p53 and pack-years work independently and increase the risk of the susceptible genotypes for lung adenocarcinoma. Considering the biological role of p53 in carcinogenesis, one of the most plausible interpretations for the distribution of the Pro/Pro genotype is that this heritable polymorphism imparts high risk of developing adenocarcinoma.
Genetic differences in risk may be smaller at high loads of carcinogen exposure, when environmental influences may overcome the association with a genetic predisposition (21 , 24 , 25) . However, in our study, we found that there was little difference between the susceptible genotypes and pack-years at higher doses of smoking.
The reason for the observed tissue-specific difference in the risk conferred by the germ-line p53 polymorphism is unknown. There have been changing trends in the occurrence of adenocarcinoma of the lung over the past two decades. It has been hypothesized that changes in cigarette composition and smoking behavior have produced a histological shift over the past decades. The proportional decrease in lung small cell carcinomas may be related to a reduction in exposure of the central bronchi to polyaromatic hydrocarbons, and the dramatic rise in lung adenocarcinoma may be related to increased exposure of the peripheral lung to tobacco-specific nitrosamines. The hypothesis suggested by Kawajiri et al. (23) is that different carcinogenic processes are involved in the genesis of various tumor types because of the presence of functionally different p53 alleles (Pro- or Arg-type). The functional difference of the p53 polymorphism at codon 72 has been reported (26) . A p53 Arg/Arg genotype induces apoptosis with faster kinetics and suppresses transformation more efficiently than the p53 Pro/Pro genotype.
Our observations provide evidence that cigarette smoking should be appropriately controlled in the analysis of p53 codon 72 polymorphisms and lung cancer and that when adjusted for smoking, the presence of the codon 72 variant allele is associated with increased lung adenocarcinoma risk. The previously reported inconsistent findings for an association of the codon 72 variant in the p53 gene with lung cancer between light and heavy smokers could be attributable to confounding factors, to sample size limitations, and to various choices of controls.
Our study has several potential limitations that might have influenced
our results. First, our controls come from friends or spouses referred
by lung cancer cases or by cardiothoracic patients. A necessary
condition for the validity of our OR estimates of the genotype
association is that, conditional on the variables controlled in the
analysis, (a) the genotype distribution of the two kinds of
controls is the same and (b) represents the distribution in
the source population. To evaluate whether the first statement is
satisfied, we tested for differences in the genotype frequencies of the
two control groups, finding no significant differences
(2 = 0.4; P = 0.5). Given that
we found no significant differences in genotype frequencies and that
the frequency in the collapsed control group was similar to the
estimates observed in past studies of Caucasian populations, it seems
reasonable to assume that the two control groups represent a common
population. Selecting controls among friends or spouses of lung cancer
patients or other surgical patients might have introduced bias by two
different mechanisms (27)
. First, the distribution of
exposures among gregarious subjects, i.e., subjects who tend
to be named by more than one other person as controls, might be
different from the distribution among non-gregarious subjects and,
therefore, it might not represent the distribution in the source
population that includes both types of subjects. Second, exposure among
friends and spouses of patients might be similar to the exposure among
the patients themselves, and thus controls may not represent the
distribution in the source population. These two factors are likely to
be relevant for variables such as age, gender, smoking, or
dietary habit. However, within categories of these variables and among
the same racial or ethnic group, the genetic polymorphisms in
p53 are unlikely to be associated with being gregarious or
with having a friend or spouse with lung cancer. Therefore, the
genotype-disease association is unlikely to be affected substantially
by this type of bias.
On the other hand, the reported estimates for the effect of pack-years on lung cancer are likely to be underestimated. Moreover, our case population includes only surgically treated lung cancer patients (stages I and II), and those with more advanced tumors not eligible for surgery were not included. Thus, differential selection of cases with respect to the genotype could occur if the genotype is related to the stage at which the lung cancer is detected. To our knowledge, one Chinese study reported that patients with the Pro/Pro genotype were more than five times more likely to die at early postoperative stages than those with the Arg/Pro genotype (28) . This may introduce overestimation of the genotype OR because poorly differentiated tumors and tumor with metastasis are more likely to become inoperable. Finally, ethnicity could be a confounder of the OR for the genotype-disease association. However, in the context of our study, this type of confounding is unlikely to be important because we got almost the same results when we included all races or just Caucasian subjects in the logistic regression model. Therefore, ethnicity is unlikely to be strongly associated either with the genotype, as indicated above, or with lung adenocarcinoma risk.
Our analysis of the possible association between the p53 genotype and pack-years revealed that the susceptible genotype is more clearly associated with an increased risk of adenocarcinoma among smokers. This finding is in agreement with some reports (29 , 30) and is discordant with others (15) , and suggests that genetic susceptibility may play a role in certain medium exposure conditions but may be overpowered by heavy exposure to the carcinogens in high doses of tobacco smoke. Seemingly moderate genetic risk, combined with environmental exposures, can determine an important proportion of lung cancers. However, further study in defined light smoking subgroups is required to substantiate the findings that the Pro/Pro genotype predisposes individuals to adenocarcinoma of the lung.
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Acknowledgments |
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Footnotes |
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1 Supported by NIH Grants CA74386, ES/CA06409,
ES8357, and ES00002. 
2 To whom requests for reprints should be
addressed, at Harvard School of Public Health, 665 Huntington Avenue,
Boston, MA 02115. E-mail: dchris{at}hohp.harvard.edu
3 The abbreviations used are: OR, odds ratio; CI,
confidence interval.
Received 1/11/00; revised 6/14/00; accepted 8/ 7/00.
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