051.812.955.17 folder to Tax Return federal reserve; tax return; sandro suzart

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Notes
The following investigators compose the Skin
Cancer Prevention Study Group: E. R. Greenberg, J.
A. Baron, M. R. Karagas, M. M. Stevens, T. A.
Stukel, S. Spencer, D. Nierenberg (Dartmouth
Medical School); N. Lowe, R. Haile (The Univer-
sity of California, Los Angeles); P. Elias, V.
Emster, N. Lapins (The University of California,
San Francisco); J. Mandel, J. C. Vance, G. Bayrd
(The University of Minnesota).
Supported by Public Health Service grants
CA32934, CA23108, and CA57494 from the Na-
tional Cancer Institute, National Institutes of Health,
Department of Health and Human Services, and
ACS SIG-17 from the American Cancer Society.
We thank Leila Mott for her contribution to the
data analysis and Nicole Danforth for assisting with
the literature review.
Manuscript received April 12, 1996; revised
August 16, 1996; accepted September 13, 1996.
Glutathione 5-Transferase and
/V-Acetyltransferase Genotypes
and Asbestos-Associated
Pulmonary Disorders
Ari Hirvonen, Sirkku T.
Saarikaski, Kaija Linnainmaa,
Kari Koskinen, Kirsti
Husgafvel-Pursiainen, Karin
Mattson, Harri Vainio*
Background: Humans vary in their
ability to metabolize endogenous and
exogenous compounds. Glutathione S-
transferases (GSTs) and N-acetyltrans-
ferases (NATs) are enzymes involved in
the detoxification of hazardous agents.
The GSTM1 and GSTT1 genes exhibit
null (i.e., deletion) polymorphisms; in
specific individuals, homozygous dele-
tion (i.e., both copies lost) of these
genes can be detected. Polymorphism
of the NAT2 gene results in slow and
fast acetylators of potentially toxic sub-
stances. The GSTMl-null and the
NAT2 slow-acetylator genotypes have
been associated with increased risks for
the development of environmentally in-
duced cancers. Purpose: We assessed
whether homozygous GSTMl-null or
GSTTl-null genotypes or the NAT2
slow-acetylator genotype were asso-
ciated with increased risks for the
development of malignant and non-
malignant asbestos-related pulmonary
disorders in a cohort of Finnish con-
struction workers. Methods: The study
population consisted of 145 asbestos in-
sulators who were classified as having
been exposed to high levels of asbestos;
69 of these individuals had no pul-
monary disorders (control subjects),
and 76 had either malignant meso-
thelioma (n = 24) or nonmalignant pul-
monary disorders, such as asbestosis
and/or pleural plaques (n = 52). Lym-
phocyte DNA and the polymerase
chain reaction were used to determine
the GSTM1, GSTT1, and NAT2 geno-
types of the study subjects. Odds ratios
(ORs) and 95% confidence intervals
(CIs) estimating the relative risks of
disease associated with specific geno-
types were calculated from 2 x 2 tables
by use of Fisher's exact method.
Results: Risks for the development of
asbestos-related pulmonary disorders
were not affected significantly by
homozygous deletion of the GSTM1 or
GSTT1 genes. However, the risk of
developing both malignant and non-
malignant pulmonary disorders for in-
dividuals with a NAT2 slow-acetylator
genotype was more than twice that ob-
served for those with a NAT2 fast-
acetylator genotype (OR = 2.3; 95% CI
= 1.1-4.7); the risk of developing malig-
nant mesothelioma for NAT2 slow
acetylators was increased almost four-
fold (OR = 3.8; 95% CI = 1.2-143). In-
dividuals who lacked the GSTM1 gene
and possessed a NAT2 slow-acetylator
genotype had a risk of developing ma-
lignant and nonmalignant pulmonary
disorders that was approximately
fivefold greater than that observed for
those who had the GSTM1 gene and a
NAT2 fast-acetylator genotype (OR =
5.1; 95% CI = 1.6-17.6); these in-
dividuals had a fourfold increased risk
of developing nonmalignant pulmonary
disorders (OR = 4.1; 95% CI = 1.1-
17.2) and an eightfold increased risk of
developing malignant mesothelioma
(OR = 7.8; 95% CI = 1.4-78.7) when
compared with the same reference
group. Conclusions: Individuals with
homozygous deletion of the GSTM1
gene and a NAT2 slow-acetylator
genotype who are exposed to high
levels of asbestos appear to have en-
hanced susceptibility to asbestos-re-
lated pulmonary disorders. [J Natl
Cancer Inst 1996;88:1853-6]
Inhalation of asbestos fibers has been
shown to cause lung cancer, diffuse inter-
stitial pulmonary fibrosis (asbestosis),
*Afftlialions of authors: A. Hirvonen, K. Husgaf-
vel-Pursiainen, K. Linnainmaa, S. T. Saarikoski, H.
Vainio (Department of Industrial Hygiene and
Toxicology), K. Koskinen (Uusimaa Regional In-
stitute), Finnish Institute of Occupational Health,
Helsinki, Finland; K. Mattson, Department of Inter-
nal Medicine, Helsinki University Central Hospital,
Finland.
Correspondence to: Ari Hirvonen, Ph.D., Depart-
ment of Industrial Hygiene and Toxicology,
Molecular Epidemiology Group, Finnish Institute of
Occupational Health, FIN-00250 Helsinki, Finland.
See "Notes" section following "References."
Journal of the National Cancer Institute, Vol. 88, No. 24, December 18, 1996 REPORTS 1853

2. malignant mesothelioma of the pleura and
peritoneum, and several other pleura! dis-
eases such as pleural plaques (7). Since
the causal relationship between asbestos
exposure and pulmonary diseases was es-
tablished, much work has been under-
taken to understand the mechanisms of
fiber-induced pathogenesis. According to
present knowledge, both direct and in-
direct cellular effects of fibers may con-
tribute to disease outcome. These effects
include the generation of reactive free
radicals, which result from interactions of
fibers and target cells or are generated
following the phagocytosis of fibers by
inflammatory cells (2). The other factors
(e.g., individual susceptibility) that could
contribute to the development of asbes-
tos-related diseases have not yet been
identified.
Humans vary in their ability to metabo-
lize exogenous and endogenous com-
pounds, and individuals with a genetically
determined reduced capacity to detoxify
hazardous compounds may be at in-
creased risk of adverse health effects
compared with those with unaltered meta-
bolic capacity (3). In this respect, con-
jugation of electrophilic compounds to
glutathione, mediated by glutathione S-
transferases (GSTs), may be of great im-
portance (4). The GST Ml and Tl genes
are polymorphic in humans, and a pheno-
typic absence of enzyme activity results
from the homozygous deletion of the re-
spective genes (i.e., the null genotypes)
(5,6). About 50% of Caucasians have the
GSTMl-null genotype, which has been
suggested in several studies (7-70) to
pose an increased risk for the develop-
ment of environmentally induced cancers.
To date, there are no studies on the as-
sociation between the GSTTl-null geno-
type, which putatively has a frequency of
10%-25% in Caucasians, and individual
cancer risk. However, lack of the GSTT1
gene was recently associated with an en-
hanced susceptibility to myelodysplastic
syndromes, which are clonal proliferative
disorders of bone marrow that often
progress to acute myeloid leukemia (77).
In addition to glutathione conjugation,
acetylation by N-acetyltransferase 2
(NAT2) is an important detoxification
pathway in humans (J). Consequently,
the slow-acetylation-associated NAT2
genotypes, which have a frequency of
about 50% among Caucasians, have been
suggested to modulate individual risk for
the development of, for example, en-
vironmentally induced bladder and colon
cancers (5).
We previously found an association be-
tween the occurrence of malignant meso-
thelioma and GSTM1 and NAT2
genotypes among workers who were
highly exposed to asbestos (70). How-
ever, only a population-based control
group without occupational exposure data
was available, and mesothelioma was the
sole asbestos-related pulmonary disorder
studied. We therefore substituted the
population-based control subjects with a
carefully characterized group of workers
who had a history of high asbestos ex-
posure but no pulmonary disorders, and
we extended the study to cover workers
with two other asbestos-caused disorders,
asbestosis and pleural plaques. We also
assessed the recently described GSTT1
gene polymorphism (<5) to clarify further
the potential role of GST genes in asbes-
tos-associated pulmonary disorders.
Subjects and Methods
Study Subjects
The study subjects were selected from a cohort
of approximately 1500 construction workers who
were recruited for a health-screening survey carried
out at the Finnish Institute of Occupational Health.
All of the workers were interviewed for detailed oc-
cupational and smoking histories by a physician
who was specialized in occupational medicine. The
degree of asbestos exposure, on the basis of all
available data (e.g., personal interview and measure-
ments of lung fiber burden from some of the patients
with mesothelioma), was classified as 1) definite or
probable, 2) possible, and 3) unlikely/unknown. On
the basis of the data, individuals were classified to
high, moderate, or low asbestos-exposure groups. A
subcohort of asbestos insulators who were classified
to the high asbestos-exposure group comprised the
present study population consisting of 145 workers,
69 of whom had no pulmonary disorders detectable
in thorax x rays (mean subject age, 52.8 years
[standard deviation, 9.0 years]) and 76 of whom had
developed either malignant mesothelioma (n = 24)
or nonmalignant pulmonary disorders (asbestosis
and/or pleural plaques) (n = 52) (mean subject age,
55.7 years [standard deviation, 9.3 years]). The dis-
tribution of years of known asbestos exposure was
as follows: 1-9 years (n = 29); 10-19 years (n = 17);
20-29 years (n = 54); and 30 years or more (n = 45).
A minority of the study subjects were never
smokers, both among the healthy workers (25 of 76
[33%]) and among the workers with pulmonary dis-
orders (16 of 69 [23%]). The rest were either ex-
smokers (23 of 76 [30%] and 33 of 69 [48%],
respectively) or current smokers (28 of 76 [37%]
and 20 of 69 [29%], respectively), with mean
cumulative tobacco smoke doses of 28 (standard
deviation, 20) pack-years and 27 (standard devia-
tion, 18) pack-years in the two groups, respectively.
The more specific tobacco smoke dose distribution
for the study population was as follows: 0 pack-
years (n = 41); 1-19 pack-years (n = 36); 20-39
pack-years (n = 48); and 40 or more pack-years (n =
20).
All of the patients with mesothelioma had been
admitted to the Department of Pulmonary Medicine
at the Helsinki University Central Hospital between
1985 and 1993 and were subsequently diagnosed as
having malignant mesothelioma. The tumors were
classified as having epithelial, mixed, or fibroma-
tous histology. The diagnoses were confirmed by
both the Finnish National Mesothelioma Panel and
the European Organization for Research and Treat-
ment of Cancer Mesothelioma Panel. The diagnoses
of asbestosis and pleural plaques were determined
first by conventional chest x rays, using the Interna-
tional Labour Office classification of Radiographs
of Pneumoconiosis. The diagnoses of asbestosis
were subsequently confirmed by the Finnish Nation-
al Panel of Pneumoconiosis by use of high-resolu-
tion central tomography.
Determination of Genetic
Polymorphisms
Genomic DNA was extracted from lymphocytes
by the use of standard techniques. A multiplex
polymerase chain reaction (PCR) method was used
to detect the presence or absence of the GSTM1 and
GSTT1 genes as described by Chen et al. (//). This
modified PCR method (5,6,9,12) had both GST-
specific pnmer pairs in the same amplification mix-
ture and included a third primer pair for f5-globin.
The PCR mixture was composed of 100 ng genomic
DNA template, 30 pmol of each GST primer (G5-
5'GAA CTC CCT GAA AAG CTA AAG C3' and
G6-5'GTT GGG CTC AAA TAT ACG GTG G3',
for amplifying GSTM1; gsttF-5TTC CTT ACT
GGT CCT CAC ATC TC3' and gsttR-5TCA CCG
GAT CAT GGC CAG CA3', for amplifying GSTT1
[primers synthesized by the Institute of Biotechnol-
ogy, Helsinki, Finland]), 10 pmol p-globin gene
primers (BG1-5'CAA CTT CAT CCA CGT TCA
CC3' and BG2-5'GAA GAG CCA AGG ACA GGT
AC3' [primers synthesized by the Institute of
Biotechnology]), 200 ujnol deoxynucleoside tri-
phosphates (dNTPs) (Boehnnger Mannheim GmbH,
Federal Republic of Germany), 1 U Taq polymerase
(Promega Corp., Madison, WI), and 3.3 mM MgCl2
(stock solution, 25 mM; Promega Corp.) in a final
volume of 30 uL with the PCR buffer (final con-
centrations: 16.6 mA/ [NH4]2SO4, 50 mM fJ-mercap-
toethanol, 6.8 |lM EDTA, 67 mM Tris [pH 8.8], and
80 (ig/mL bovine serum albumin). The reaction
mixture was assembled at 85 "C, placed in a Perkin-
Elmer 9600 thermal cycler (Perkin-Elmer Cetus,
Norwalk, CT) for 3 minutes at 94 "C, and then sub-
jected to 30 cycles of 94 "C for 10 seconds, 60 'C
for 20 seconds, and 72 'C for 45 seconds. The ther-
mal cycling program was followed by a final step at
72 "C for 5 minutes. The GSTT1 (480 base pair
[bp]), P-globin (268 bp), and GSTM1 (215 bp)
amplification products were resolved in an ethidium
bromide-stained 4% 3:1 NuSieve/agarose gel (FMC
Corp., Rockland, ME). The absence of the GSTM1-
1854 REPORTS Journal of the National Cancer Institute, Vol. 88, No. 24, December 18, 1996

3. Table 1. Distribution of glutathione 5-transferase (GST) and A'-acetyltransferase (NAT) genotypes in workers exposed to asbestos in relation to
pulmonary disorders*
End point
No pulmonary disorders
Pulmonary disorders (all)
Nonmalignant
Malignantt
No. of
patients
69
76
52
24
GSTM1 genotype
%null
46
61
58
67
OR (95% CI)
1.0
1.8(0.3-3.4)
1.5(0.8-3.3)
2.3(0.8-7.1)
No. of
patients
69
76
52
24
GSTT1 genotype
% null
10
8
8
8
OR (95% CI)
1.0
0.8 (0.2-2.8)
0 7(0.2-3.1)
0.8(0.1-4.7)
No. of
patients
68
75
51
24
NAT2 genotype
%slow
50
69
65
79
OR(95%CI)
1.0
2.3(1.1-4.7)
1.8(0.8-4.2)
3.8(1.2-14.3)
*OR = odds ratio; CI = confidence interval; null = absence of the gene; slow = slow acetylator.
tMalignant mesothelioma.
or the GSTT1-specific fragment indicated the cor-
responding null genotype, whereas the p^-globin-
specific fragment confirmed the presence of
amplifiable DNA in die reaction mixture (//). To
verify the GSTTl-null genotype further and to en-
sure that DNA degradation did not influence the
results, a second PCR was performed that yielded a
112-bp fragment (data not shown).
The NAT2 allele corresponding to the fast-
acetylator phenotype and the four slow-acetylator
phenotype-associated alleles were distinguished by
use of pnmers specific for the NAT2 gene in a PCR
reaction and restriction enzyme digestion of the
resulting amplification product as described by Bell
et al. (13). A single PCR was earned out using 50
pmol of the primers (N5-5'GGA ACA AAT TGG
ACT TGG3' and N4-5TCT AGC ATG AAT CAC
TCT GC3' [synthesized by Institute of Biotechnol-
ogy]), 200 umol dNTPs (Boehringer Mannheim
GmbH), 1 U Taq polymerase (Promega Corp.), and
2.0 nW MgCl2 (Promega Corp.) in a volume of 50
uL with the above-described PCR buffer. After
PCR, which was performed as indicated for the GST
analyses, except that an annealing temperature of
57 'C was used, 7.5-|iL aliquots were removed and
subjected to restriction digestion with Kpn I (for the
M1 allele), Taq I (for the M2 allele), BamHl (for the
M3 allele), or Msp UAlu I (for the M4 allele). (The
restriction enzymes were from New England
Biolabs, Inc., Beverly, MA.) The digests were sub-
jected to electrophoresis in 4% agarose gels. The ab-
sence of a restriction site indicated the presence of a
defective NAT2 allele, and the presence of two
defective alleles identified the slow acetylators (13)
Statistical Methods
The odds ratio (OR) is an estimate of the rela-
tive risk of disease associated with specific
genotypes and is defined as the odds of a case
patient having the at-risk genotype divided by the
odds of a control subject having the same
genotype. ORs and 95% confidence intervals (CIs)
were calculated from 2 x 2 tables with the Fisher's
exact model, and Pearson coefficients of correla-
tion were calculated between determinants and
potential confounders (14).
Results and Discussion
When the three genes were studied
separately (Table 1), no statistically sig-
nificant differences were observed for the
GST genotypes, although the frequency
of the GSTM 1-null genotype was clearly
higher among the patients with malignant
mesothelioma (67%) and somewhat
higher among the asbestos workers with
nonmalignant pulmonary disorders (58%)
than among workers who lacked evidence
of these disorders (46%). In contrast, the
NAT2 slow-acetylator genotypes were
significantly more prevalent among the
workers with pulmonary disorders (69%)
than among those lacking them (50%)
(OR = 2.3; 95% CI = 1.1-4.7). The fre-
quency of NAT2 slow-acetylator geno-
types was highest among the patients with
malignant mesothelioma (79%) (OR =
3.8; 95% CI = 1.2-14.3). Moreover, the
slow acetylators lacking the GSTM 1 gene
had nearly an eightfold higher risk of
mesothelioma (OR = 7.8; 95% CI = 1.4-
78.7) compared with those who had the
gene and the NAT2 fast-acetylator
genotype (Table 2). They were also at a
fourfold higher risk of nonmalignant pul-
monary disorders (OR = 4.1; 95% CI =
1.1-17.2) and, consequently, at about a
fivefold higher risk overall (OR = 5.1;
95% CI = 1.6-17.6) of developing one of
the pulmonary disorders studied. As ex-
pected, correlations between the geno-
types and age, pack-years of cigarette
smoking, duration of smoking, and dura-
tion of asbestos exposure were negligible,
with correlation coefficients ranging from
-0.05 to 0.12. Therefore, no adjustment
of the ORs by these factors was needed.
In contrast to the effects shown by com-
binations of GSTM1 and NAT2 geno-
types, other combinations of the studied
genotypes showed no additive effects.
Table 2. Combinations of GSTM 1 and NAT2 genotypes in workers exposed to asbestos in relation to pulmonary disorders*
End point
NAT2 slow acetylators NAT2 fast acetylators
GSTM 1-null
No. of
patients %
GSTM 1-positive
No. of
patients %
GSTM I-null
No. of
patients %
GSTM 1-positive
No. of
patients % ORt 95% CI*
No pulmonary disorders
Pulmonary disorders (all)
Nonmalignant
Malignant§
15
30
17
13
22
40
33
54
19
22
16
6
28
29
31
25
16
16
13
3
24
21
26
13
18
7
5
2
27
9
10
8
1.0
5.1
4.1
7.8
1.6-17.6
1.1-17.2
1.4-78.7
•Null = absence of the gene; positive = presence of the gene.
tOR = odds ratio. OR shown is for the NAT2 slow-acetylator and GSTM 1 -null genotype combination compared with the NAT2 fast-acetylator and GSTM 1 -posi-
tive genotype combination; reference group consists of subjects with no pulmonary disorders.
pZl = confidence interval.
§Malignant mesothelioma.
Journal of the National Cancer Institute, Vol. 88, No. 24, December 18, 1996 REPORTS 1855

4. The lack of effect of smoking in this
study stands in contrast to previous
analyses of the GSTM1 gene and cancer
susceptibility, where the risk associated
with the GSTM 1-null genotype was
mostly attributable to smoking (7-9). In
the previous analyses, the associations
appeared, however, to be heavily influ-
enced by the asbestos exposure levels, in
agreement with two more recent studies.
An association was reported between the
GSTM 1-null genotype and the risk of
developing asbestosis among highly ex-
posed asbestos workers (15), whereas no
association was found between radiograph-
ic or lung function changes and GSTM1
genotype in a group of asbestos workers
with mostly low or moderate exposure
levels (16).
Certain GST isoenzymes are con-
sidered to be part of a system required for
the repair of free-radical-induced lipid
peroxidation (4), which is considered to
be one possible mechanism in the multi-
step process of asbestos carcinogenesis
(2). Therefore, the observed association
between the GSTM 1-null genotype and
asbestos-associated pulmonary disorders
was not surprising, whereas the remark-
able impact of the NAT2 genotype ob-
served both in this study and in our
previous study (10) was rather unex-
pected. However, asbestos fibers are able
to induce ornithine decarboxylase en-
zyme activity, resulting in increased cell
proliferation as a consequence of en-
hanced polyamine synthesis (17). Since
an acetylation step is known to be in-
volved in the catabolism of polyamines
(18), the slow NAT2 acetylators may ac-
cumulate greater amounts of polyamines
than the fast acetylators. This could ex-
plain, in part, the modulating effect of
NAT2 polymorphism in individual re-
sponses to asbestos exposure.
In conclusion, we found that, among
workers with high levels of asbestos ex-
posure, individuals concurrently having a
NAT2 slow-acetylator genotype and
homozygous deletion of the GSTM 1 gene
showed a marked excess of asbestos-as-
sociated pulmonary disorders. Even if the
present study size is relatively small, the
high prevalence of these potential at-risk
genotypes indicates that our observations
may have important implications for
public health.
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Notes
Supported in part by the Finnish Academy of
Sciences grants 8566 and 29456 and by the Finnish
Work Environment Fund grant 93384.
We thank Drs. Antti Karjalainen and Timo Par-
tanen for helping in the statistical analyses and
Maria Reinikainen for her skillful technical assis-
tance.
Manuscript received April 18, 1996; revised July
23, 1996; accepted September 25, 1996.
1856 REPORTS Journal of the National Cancer Institute, Vol. 88, No. 24, December 18, 1996