[Cancer Research 61, 612-615, January 15, 2001]
© 2001 American Association for Cancer Research
Tobacco Smoke-induced DNA Damage and an Early Age of Smoking Initiation Induce Chromosome Loss at 3p21 in Lung Cancer1
Tomoko Hirao,
Heather H. Nelson,
Tara Devi S. Ashok,
John C. Wain,
Eugene J. Mark,
David C. Christiani,
John K. Wiencke and
Karl T. Kelsey2
Department of Cancer Cell Biology [T. H., H. H. N., T. D. S. A., K. T. K.] and Occupational Health Program [D. C. C.], Harvard School of Public Health, Boston, Massachusetts 02115; Thoracic Surgery Unit, Department of Surgery [J. C. W.], Department of Pathology [E. J. M.], and Pulmonary and Critical Care Unit, Department of Medicine [D. C. C.], Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; and Laboratory for Molecular Epidemiology, Department of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, California 94143 [J. K. W.]
 |
ABSTRACT
|
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The short arm of chromosome 3 is thought to harbor a novel oncogenic
locus that is important in the genesis of lung cancer. The region at
3p21 is believed to contain a distinct locus that is sensitive to loss
from the action of tobacco smoke carcinogens and has been reported to
be specifically targeted for deletion in lung cancer. To investigate
whether 3p21 alteration in lung cancer is associated with carcinogen
exposure, PCR-based analysis was performed to detect loss of
heterozygosity (LOH) on chromosome 3 at 3p21 in non-small cell lung
carcinoma (NSCLC). We also measured instability at the
BAT-26 locus, because the mismatch DNA repair
gene, hMLH1, is found at 3p21. LOH at 3p21 was analyzed
for association with the clinical features of NSCLC, p53 mutation
status, polynuclear aromatic hydrocarbon-DNA adduct levels (measured
using 32P-postlabeling) and carcinogen exposure information
including cigarette smoking and asbestos exposure. Of 219 lung cancers,
150 cases (68.5%) were informative at the D3S1478
locus, and 44.2% of squamous cell carcinoma cases and 30.2% of
adenocarcinoma cases showed 3p21 LOH. None of the cancers showed
BAT-26 instability. The prevalence of 3p21 LOH was
higher in both current and former smokers compared with never smokers
and was higher in p53 mutated cases. Among squamous cell carcinoma
cases, there was a strong association of increased 3p21 LOH with
increasing polynuclear aromatic hydrocarbon-DNA adducts levels
(P = 0.03), as well as an increased
prevalence LOH with earlier age of smoking initiation
(P = 0.02). Our results confirm that 3p21
LOH is strongly associated with measures of biologically effective dose
of exposure to tobacco carcinogens. Our results also suggest that
alterations of hMLH1 are not related to any of the
reported associations, because there was no evidence of microsatellite
instability. Finally, LOH in 3p21 may be an early molecular event in
NSCLC, because it is significantly associated with a tendency to start
smoking at a young age.
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INTRODUCTION
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|---|
Lung cancer is the leading cause of cancer death in both women and
men in the United States (1)
and is increasing in
incidence worldwide. In the United States, 80% of lung cancer deaths
in men and 75% in women are estimated to be attributable to cigarette
smoking (1)
, and smoking is accepted as a major cause of
lung cancer (2, 3, 4)
. Recent studies have suggested that
specific genetic alterations in lung cancer occur in premalignant
clones long before the appearance of overt malignancies. Furthermore,
these changes may persist for many years after smoking cessation
(5)
. Wiencke et al. (6)
reported
recently that, in former smokers, age at smoking initiation was
inversely associated with increasing
PAH3
-DNA adduct levels in normal lung tissue. This suggests that smoking
during adolescence may produce physiological alterations that lead to
increased DNA adduct persistence (6)
. Little attention has
been paid to the relationship between early smoking initiation and
somatic mutation.
The loss of wild-type alleles at 3p, 9p, and 17p is widely described in
various human malignancies, and LOH at 3p has been reported to be a
relatively early event in lung carcinogenesis (7, 8, 9, 10, 11)
. 3p
deletion is a common finding in lung cancer that was first detected in
small cell lung carcinoma by cytogenetic analysis (12)
.
Recent studies have shown that 3p deletion can occur in preneoplastic
epithelial lesions as well as in invasive cancers (11
, 13)
. LOH at 3p occurs considerably more frequently in patients
who smoke than in those who have never smoked (14)
.
Many genetic alterations have been described in lung cancer, but their
association with individual patterns of exposure to tobacco and other
lung carcinogens has been less well studied. Because previous work has
suggested that loss of 3p21 is tobacco associated and possibly an early
event in lung carcinogenesis (15)
, we assessed LOH using a
well defined polymorphic marker in this region (D3S1478) and
examined whether this genetic alteration was associated with
self-reported patterns of tobacco use, asbestos exposure, and other
life-style factors in our prospective surgical case series of NSCLC. In
an effort to more specifically investigate whether detectable DNA
damage was also associated with LOH at 3p21, we further compared the
mean DNA adduct burden, derived from
32P-postlabeling of normal lung DNA, in patients
with and without LOH. Finally, because the hMLH1 DNA repair
gene, also located in the 3p21 region, has been hypothesized to be
targeted for deletion, we tested the association of LOH and
BAT-26 instability. BAT-26 is a reliable marker
of hMLH1 related microsatellite instability.
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MATERIALS AND METHODS
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Study Population.
Eligible cases consisted of all newly diagnosed patients with
resectable lung cancer who received treatment at the Massachusetts
General Hospital Thoracic Surgery, Oncology, and Pulmonary Services
from November 1992 through December 1996 (16)
. Patients
with recurrent disease or with nonoperable tumors were excluded. Of the
461 case patients enrolled consecutively in the parent study, a random
subset of 219 was analyzed for somatic loss at 3p21. Tumor-derived DNA
was obtained from archived pathology specimens as described previously
(17)
, and comparative constitutive DNA was derived from
circulating blood lymphocytes (QIAamp DNA Blood Mini kit; Qiagen).
Demographic and epidemiological data, including all of the data on
tobacco use, were gathered by interviewer review of a self-administered
questionnaire completed by patients and reviewed by a single reviewer
during the hospitalization for thoracic surgery.
LOH Analysis.
To evaluate LOH at chromosome 3p21, the microsatellite marker
D3S1478 was amplified by PCR containing
[
-32P]dCTP (DuPont NEN Life Science
Products). Primer sequences can be obtained from the Genome Database.
PCR was performed for 30 cycles with the annealing temperature of
62°C. Two µl of PCR product were mixed with 4 µl of loading
buffer, denatured, and separated by electrophoresis on a 6%
polyacrylamide-7 M urea gel at 60W at room
temperature. PCR products were detected by autoradiography (Biomax
film; Eastman Kodak). LOH was visually scored by >50% reduction in
allele intensity.
BAT-26 Instability.
For BAT-26 instability detection, PCR containing
[-32P]dCTP (DuPont NEN Life Science
Products) was performed for 30 cycles with the annealing temperature of
58°C. Primer sequences can be obtained from the Genome Database. Four
µl of PCR product were mixed with 4 µl of loading buffer,
denatured, and separated by electrophoresis on a 6% polyacrylamide-7
M urea gel. The temperature of the gel was
maintained at 55°C. The gel was then dried, and autoradiography was
performed.
p53 Analysis.
p53 mutations were detected using PCR-SSCP of exons 5–10 as described
previously by Nelson et al. (17)
. Briefly, the
primer sequences of Toguchida et al. (18)
were
used for amplification of DNA derived from adjacent 10-µm paraffin
sections that were used to generate DNA using standard protocols
(19)
. PCR amplification of primary tumor DNA was used for
p53 mutation sequencing to avoid polymerase artifact.
DNA Adducts.
PAH-DNA adduct levels were assessed in normal, nontumorous lung tissue
that was obtained as part of the surgical protocol. Adducts were
measured as described by Wiencke et al. (6)
.
Statistical Analysis.
Statistical analyses of 3p21 LOH, patient demographics, and tumor
traits included 
2, Wilcoxon rank-sum of means,
trend test, and unconditional logistic regression. All Ps
represent two-sided statistical tests and are considered statistically
significant for P < 0.05.
|
Results
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Of the 219 cases studied, 150 (68.5%) were informative at the
D3S1478 locus. The prevalence of 3p21 LOH was 34% (51 of
150). It was 33.6% when we restricted the data to the NSCLC cases (48
of 143). All further analyses of 3p21 LOH and patient traits were
restricted to the NSCLC cases (n = 143).
Table 1
summarizes the relationship between 3p21 LOH, clinical features, and
characteristics of the tumors. Nineteen of 43 squamous cell carcinomas
(44.2%) exhibited LOH at 3p21, as did 26 of 86 adenocarcinomas
(30.2%; P = 0.12 for squamous cell carcinoma
versus adenocarcinoma). There was no significant association
of 3p LOH with age, gender, or stage (Table 1)
.
We next examined 3p LOH status and carcinogen exposures. LOH was more
frequent in current smokers (32.3%) and ex-smokers (37.3%), than in
never-smokers (18.2%), but this difference was not statistically
significant. Evaluating all cases, as shown in Table 1
, the mean value
for pack-years and number of years smoked tended to be higher in
LOH-positive cases. However, this did not reach statistical
significance. There was a borderline significant association in the
unadjusted data of a history of asbestos exposure with LOH at 3p
(P = 0.1).
We also examined the association between 3p21 LOH and smoking as a
categorical variable, defined by tertiles (Fig. 1)
. LOH prevalence appeared to increase with increasing pack-years in all
cases; however, this trend was not statistically significant. A younger
age of smoking initiation was associated with a significantly higher
LOH prevalence among the squamous cell carcinoma cases
(P < 0.02; Fig. 1
). Interestingly, neither
pack-years (P = 0.83) nor years of smoking
(P = 0.34) were significantly associated with
LOH at 3p21 in patients with squamous cell carcinomas. When all cases
were examined using a logistic model, the association of LOH and
youngest age of onset of smoking was borderline significant
(P = 0.10), controlling for the effect of
histology (P = 0.07).
To further study the relationship between 3p21 loss and smoking
carcinogen dose, we investigated the relationship between prevalence of
LOH and PAH-DNA adduct levels in normal lung tissue from 70 cases. DNA
adducts were evaluated by stratifying adducts into tertiles. The
highest adduct tertile had the highest LOH prevalence when looking at
all cases with both measurements, and there was a dose-related increase
in 3p21 LOH with increasing adduct tertiles overall that was highly
significant in the squamous cell carcinoma cases
(P < 0.05; Fig. 2
).
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Fig. 2. The prevalence of LOH at 3p21 in NSCLC stratified by lung
polynuclear aromatic adduct tertiles for all cases
(n = 70) and restricted to histologies
(n = 43 for adenocarcinoma and
n = 22 for squamous cell carcinoma).
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Finally, 3p21 LOH was analyzed stratified by p53 and K-ras
mutation status. There was no apparent association between LOH and
induction of mutation at the K-ras locus (Table 2)
. The prevalence of 3p21 LOH was borderline significantly higher in
those tumors with mutated p53. As shown in Table 2
, 47.6% of p53
mutant adenocarcinoma cases had 3p21 LOH compared with 26.7% of the
wild-type cases (P < 0.08). In squamous cell
carcinoma, 53.9% of p53 mutated case showed LOH, compared with 37% in
wild-type cases.
When logistic models were used to examine these data, the association
of p53 mutation and LOH was significant after adjustment for pack-years
of smoking and histology (squamous versus adenocarcinoma;
P < 0.03; odds ratio, 2.6). Additional
modeling of the association of age at smoking initiation, DNA adduct
level, and LOH was not done, because these variables are colinear and
the number of subjects studied was limited.
For 73 of the 219 cases, we also examined tumor tissue for instability
at the BAT-26 locus and found no tumors with any evidence of
changes in allele length (Table 1)
.
|
Discussion
|
|---|
Deletion of one copy of the short arm of chromosome 3 is observed
frequently in lung cancer. 3p LOH has been reported to be a relatively
early event in lung carcinogenesis (7
, 8
, 13)
and has been
detected in preneoplastic epithelial lesions (13)
. The
frequency of 3p LOH in lung cancer has been reported to be 49–86%
(13)
. The prevalence of LOH at 3p has also been observed
to be higher in squamous cell carcinoma than in adenocarcinoma:
50–83% in squamous cell carcinoma versus 36–61% in
adenocarcinoma (20)
. We have detected LOH at 3p in 33.6%
of 143 informative NSCLC cases, and the presence of LOH was more
frequent in squamous cell carcinoma cases (44.2%) than in
adenocarcinoma cases (30.2%). The somewhat lower prevalence of LOH
observed in our study may be attributable to our use of only one
marker, or it might also be attributable to differences in study
design. We used a prospective enrollment strategy, whereas previous
investigations used primarily retrospective and convenience designs. In
addition, the enrollment criterion for our study was strictly surgical,
and our use of a conservative method for detecting LOH may also account
for the lower prevalence of LOH at 3p.
In our study, although the prevalence of 3p21 LOH increased with
cumulative smoking dose, there was a strong significant association
between 3p21 LOH and increasing PAH-DNA adducts levels. In addition,
there was a higher prevalence of 3p21 LOH in individuals who started
smoking at younger ages. Our result, showing that 3p LOH is associated
with measurable PAH-DNA adducts implies that 3p21 LOH is clearly
induced by tobacco carcinogens. These observations are consistent with
previous work of other investigators (14
, 15)
and indicate
that deletion of 3p is an important and early event in lung
carcinogenesis.
Although different measures of tobacco smoke exposure are related, we
found the strongest association of LOH at 3p21 to be with the age of
onset of smoking. One novel interpretation of this data is that LOH
induced in lungs that are still developing can result in propagation of
this lesion and yield large fields of cells with LOH. Field effects are
well described for the squamous cell histology and less well documented
for adenocarcinomas. This mirrors our finding that early smoking is
more strongly associated with LOH at 3p21 in squamous cell carcinoma.
Hence, we believe that developmental factors may account for the higher
prevalence of LOH at 3p21 among patients who begin smoking early in
life.
The association of an early age of initiation of smoking, DNA adduct
persistence, and LOH at 3p could further indicate that a gene in this
region is important in facilitating DNA damage repair, either directly
or indirectly. The hMLH1 gene is located at 3p21, but this
protein is not likely to be responsible for bulky DNA adduct repair. In
addition, the absence of BAT-26 instability in these tumors
suggests that hMLH1 is not the gene responsible for the
associations we observed with tobacco carcinogen exposure and DNA
adducts. However, because DNA repair genes cluster on some chromosomes
(21)
and there is a recent report of a novel DNA repair
gene in the precise locus (3p21) that we examined (22)
, it
is possible that an important gene of this sort is located in this
region. Further speculation on this possibility awaits cloning of the
gene(s) at this locus that is important in the genesis of lung cancer.
One candidate gene located on the short arm of chromosome 3, at 3p25,
the von Hipple-Lindau tumor suppressor gene, appeared to
have association with renal cell carcinoma but has been found to be
involved only infrequently in lung cancer. Several studies have
examined associations of another 3p region, including the
FHIT locus and p53 status. Horio et al.
(23)
reported that there was a significant association
between the presence of p53 mutation and 3p deletions in 71 NSCLCs.
Burke et al. (24)
studied 106 NSCLCs and found
that 3p14 LOH was associated with p53 missense mutations, whereas
Geradts et al. (25)
, in 103 resected NSCLCs,
found no correlation of 3p LOH with abnormality in p53
immunohistochemical staining. In our study, there was an increasing
prevalence of 3p21 LOH among cases with p53 mutations, which is
consistent with a role of p53 in the maintenance of genetic stability.
Of interest, the histological differences in various genetic
alterations have been observed within NCSLC; p53 mutations are more
prevalent in squamous cell carcinomas, ras mutations are
more common in adenocarcinomas, and 3p LOH is more frequently seen in
squamous cell carcinomas (20
, 26)
. The induction of
mutations at these loci in specific tissues is likely to occur in a
specific order but possibly at varying intervals of time. The order may
differ in different histological tissue types and may thereby represent
a differing pathogenesis and progression toward frank malignancy.
However, large-scale chromosome loss does not seem likely to be
associated with genomic instability in NSCLC.
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FOOTNOTES
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Supported by Grants ES08357, ES00002, ES04705,
CA74386, CA09078, and ES/CA06409. 
2 To whom requests for reprints should be
addressed, at Department of Cancer Cell Biology, Harvard School of
Public Health, 665 Huntington Avenue, Boston, MA 02115-6021.
3 The abbreviations used are: PAH, polynuclear
aromatic hydrocarbon; LOH, loss of heterozygosity; NSCLC, non-small
cell lung cancer.
Received 4/26/00.
Accepted 11/20/00.
|
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ABSTRACT
INTRODUCTION
