glutathione s-transferase ml (gstm1) deficiency and lung … · the association between glutathione...

to,. 4, 589-594, .Si’pti’nther /995 Cancer Epidemiology. Biomarkers & Prevention 589

3 The abbreviations used arc: GST. glutathionc S-transfera.sc: (ISTMI. glutathioncS-tranfera.sc Ml; OR. odds ratio: CI. confidence interval.

Glutathione S-Transferase Ml (GSTM1) Deficiency and Lung

Cancer Risk1

Jeffrey E. McWilliams, Barbara J.S. Sanderson,Emily L. Harris, Kathryn E. Richert-Boe, andWilliam David Henner2

I)ivision of I-lcniatology and Medical Oncology. Oregon health Sciences

University, Mail (‘ode L5S6. Portland, Oregon 972I))-309)( IJ E. M..

K. F. R-B.. W. I). 11.1: Biotechnology Unit. School of Medicine, Flindcrs

University Of South Australia. Adelaide. Australia lB. I. S. SI: and Center for

health Research. Kaiser Permanenie. Portland, Oregon 97227 IE. L. 11.1

Abstract

The association between glutathione S-transferase Ml(GSTM1) deficiency and lung cancer risk has beencontroversial in the published literature. To examine thiscontroversy, 12 case-control studies of GSTMJ status andlung cancer risk were identified in the published Englishliterature. These studies included a total of 1593 casesand 2135 controls. We conclude that GSTM1 deficiencyis a moderate risk factor for lung cancer developmentwith an odds ratio of 1.41 (95% confidence interval1.23-1.61; P < 0.0001) by using Mantel-Haenszelmethods for stratified analysis. This increased risk is

evident for all the major histological subtypes of lungcancer. Although the increased risk is small, GSTMJ

deficiency accounts for approximately 17% of lungcancer cases because of the high prevalence of GSTMIdeficiency.

Introduction

There is a growing realization that the development of cancerresults from a complex interaction of both environmental and

genetic factors. For neoplasms such as lung cancer and non-melanoma skin cancer, the carcinogens in tobacco smoke and

sunlight, respectively, are known to be crucial environmental

factors in causation of these cancers. In addition, it is increas-ingly clear that genetic differences among individuals also

modulate the risk of developing specific forms of cancer. Insome cases, these genetic polymorphisms raise the risk ofparticular cancers to such a degree (i.e. , have a very highpenetrance) that the inheritance of the polymorphism can be traced

in family or linkage studies. Examples of polymorphisms with a

high penetrance t)f the cancer phenotype include both autosomaldominant disorders such as Li-Fraumeni syndrome and autosomalrecessive disorders such as xeroderma pigmentosum (1, 2).

However. not all genetic polymorphisms that predispose to

Received 12/22/94: revised 4/25/95: accepted 5/5/95.I This work was supported h� American Cancer Society Oregon Division and the

Anti-(’ancer Foundation of the Universities of South Australia grants and aFlinders University (if South Australia Establishment grant.2 l’o whom correspondence and reprint requests should he addressed, at Division

of Ilematologs and Medical Oncology. Oregon Health Sciences Center. 3181

Southwest Sam Jackson Park Road. Portland. OR 97201-3095.

cancer need confer a greatly increased risk or have a highpenetrance. Genetic polymorphisms that confer only a modestlyincreased risk of cancer can still he important to public health,

particularly if the polymorphism and its associated cancers arecommon. Estimates indicate that there will he 169,9(X) new

cases of lung cancer and 157,4(X) deaths due to lung cancer inthe United States in 1995 (3). For a disease with such a highincidence and mortality, even a modest increase in relative riskcan have a large impact on public health. When the penetranceof a polymorphism is low, family studies are not very helpfulin quantitating the risk conferred by such a polymorphism.Determination of whether a polymorphism confers increasedcancer risk and quantitation of this risk can he accomplishedthrough case-control studies or through large cohort studies.Several genetic polymorphisms and cancer genes have beeninvestigated in case-control studies (4, 5). Candidate polymor-phisms have been sought among the DNA repair genes, onco-genes, tumor suppressor genes. and the Phase I and Phase IImetabolic enzymes of detoxification.

The human GSTs3 are a group of Phase II detoxification

enzymes encoded by a gene superfamily, each of which de-toxifies electrophilic compounds, many of which are carcino-

genie (6, 7). The enzymes detoxify these electrophilic corn-pounds by conjugating them to glutathione. Each member ofthe superfamily has a distinct, but overlapping, substrate spec-ificity. Four classes of human cytosolic GSTs have been de-

scrihed, a, ,i�, IT, and �. Within the p. class there exist at least

five genes encoding the GST isoenzymes: GSTMI-GSTM5.The gene encoding GSTMI has been of particular interest toinvestigators in the area of cancer risk because it was found tobe polymorphic. At least four alleles of GSTMI exist:

GSTMI*A, GSTMI*B, GSTMI*C, and GSTMI*O (8).

GSTM1*A and GSTMI*B differ by only one amino acid andhave no apparent differences in substrate specificity.GSTM1 *C is rather rare and is not fully characterized. TheGSTM/ �0 allele consists of a deletion of the GSTMI genesequence that can be demonstrated either by Southern blottingor PCR. Early studies of the frequency of GSTMI deficiency

using either enzyme activity assays or Southern blotting dem-onstrated that GSTMI deficiency due to homozygous GSTMI

null genotypes occurs in about one-half of the population ofEurope and the United States (9-I I).

Seideg�rd et al. (1 1) first provided evidence that GSTMIdeficiency may constitute a modest risk factor for developmentof carcinoma of the lung, particularly in smokers. Subsequent to

Seideg�rd’s report, new methods for determining the GSTMJstatus of an individual have been developed, and recently alarge number of studies comparing the frequency of GSTMI

deficiency in patients with various forms of malignancy to that

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Tal,le I (‘ase-control studies of GSTMI status

the meta-analysts

and lung cancer risk used in

Author” (‘ascs Controls Race

Alcxandric ,-t ((I. (43) 296 32’) P Caucasian

Brockmdllcr t’i (Al. (29) 1 17 355 P. I. E Caucasian

Hayashi el (Il. (25) 212 355 P Japanese

Ilcckhcrt i’i (II. (26) 1 13 12)) E Caucasian

1-lirvonen t’t ((I. (30) 135 142 P Caucasian

Kihara et ((I. (44) 175 201 P Japanese

Nakachi t’t 0/. (45) 55 17)) P Japanese

Nazar-Stewart et a!. 35 43 F, E Not indicated(37)

Seideg�lrd i’i (1/. ( 1 1 ) 66 75 E (‘aucasian

Scideg/ird t’i (Il. (21) 25 1 14 E Not indicated

Zhong i-I 0/. (24, 41) 225 225 S Caucasian

Zhimg. e( al.t99t. 1993 (24.42) I’-

BmckmbUer. ei at. t993 (29) i- I I

S#{225}ie�. ci at. l9�6 (1 1) ‘I

iicckbeit. etal, 1992 (26) I- #{149}- � I

� -IHiivonen. et a!. 1993(30)

Nazx-S*cwan. ci at. 1993 (37)

Kiliwa. ei ii. 1994 (44)

Hay�tiL el *1. 1992(25)

Sc*degkd.etai. 1990(21)

Nakachi.ctaI.. 1993(45)

Alcxandrie.ctai, 1994(43)

Me�is“ Numbers in parentheses, references.

“ P, Pc/R; I, ELISA; E, GST activity with trans-stilbene oxide substrate; S,

Southern blot.0

Odt� RatIo3 4

590 GSTM! Deficiency and Lung Cancer Risk

,l #{149}

-a--1 #{149}

- . I

in controls have appeared in the literature. Studies confirmingthe association of GSTM/ deficiency with increased risk of lungcancer and studies in which no increased risk could be dem-onstrated have appeared. This report addresses this controversy

and presents the results of a meta-analysis of published case-

control studies of lung cancer risk and GSTM/ deficiency.

Materials and Methods

A search of the English literature using the National Library ofMedicine MEDLINE and search terms glutathione, glutathioneS-transferase, lung, and cancer for the years 1985-1994 wasundertaken to identify all published articles or abstracts inwhich the frequency of GSTMI positivity versus negativity was

determined for a series of human malignancies by either enzy-matic assay with trans-stilbene oxide, by immunological tech-niques (either Western blotting or ELISA), or by analysis fordeletion of the GSTMJ gene by using Southern blotting or PCR.Additional articles were identified through the references cited

in the first series of articles or through programs of recentnational or international meetings. Articles selected for analysiswere case-control in design, published in the primary literature,had no obvious overlap of subjects with other studies, and usedone of the listed methods for GSTMI typing.

Relative risk was estimated with ORs and 95% CIs. Levelof statistical significance was calculated by using the � test. P

values <0.05 were considered statistically significant. The data

from the studies identified from the published literature wereanalyzed by the Mantel-Haenszel technique for stratified data,by calculating weighted ORs and weighted � tests. Tests forheterogeneity were also performed on each group analyzed(12-14).

Results

The literature search identified 35 articles or abstracts in which

the GSTMI status of a series of tumors or tumor-bearing mdi-viduals was determined by using one or more of the above

listed methods for one or more forms of human neoplasm (4, 5,

8, 1 1, 15, 16-45). Of these 35 articles or abstracts, data from12 were ineligible for the overview; 8 were eliminated becauseno control group was included, 3 were eliminated because theywere not in the primary literature and the cases and controlsappeared to overlap with those in other publications, and 1study was eliminated because a more recent study was pub-

lished by the authors with subjects that included the older

Fig. 1. OR for all lung cancers. Bars. 95% CIs. Summary OR 1.41 (95% CI -

1.23-1.643). Box sizes arc proportional to study size.

paper. Ofthe remaining 23 publications, 1 1 (4, 8, 17, 19, 20, 23,

27, 33, 34, 39, 42) did not include cases of lung cancer and,therefore, were not included in the meta-analysis. The 12 case-control studies of lung cancer and GSTMI status are listed inTable 1 . Because two studies appeared to use the same control

group with different case groups (24, 41), these studies werecombined for analysis, resulting in 1 1 studies for the finalanalysis. Altogether, these studies included 3728 subjects (1593lung cancer cases and 2135 controls).

Of the 1 1 studies selected for meta-analysis, 3 studiesevaluated GSTMI status by phenotyping alone, and 8 studiesevaluated GSTMI status by genotyping (24, 25, 29, 30, 37, 41,43-45). Two studies (29, 37) determined GSTMI status by bothphenotyping and genotyping with highly concordant results asto GSTMI typing. When comparing studies based on pheno-typic versus genotypic determinations, these latter two studieswere treated as genotypic studies to prevent counting themtwice.

The results of the case-control studies of lung cancer and

GSTMI status are summarized in Fig. 1. In each of the studiesthere was an excess of GSTMJ-deficient individuals among thelung cancer cases compared to the controls. However, thisexcess reached statistical significance in only four of the mdi-vidual studies. The Mantel-Haenszel summary OR was 1.41,which was significantly different than 1.0 by using a � test

(P < 0.0001). CIs (95%) for the ORs for each of the individualstudies all overlapped with the most likely estimate of 1.41. Atest for heterogeneity suggested no significant heterogeneity(P = 0. 176). On the basis of these data, there is a 95%likelihood that the true OR for GSTMI deficiency and lung

cancer is between 1.23 and 1.61, confirming a relationshipbetween GSTMI deficiency and the risk of developing lung

cancer.

To determine the effect of GSTM1 deletion on the risk ofdeveloping specific histological types of lung cancer, we ex-amined each of the three major histological forms of lungcancer by using data from studies, which included histologicalinformation. The analyses included a total of 591 squamouscell, 482 adenocarcinoma, and 122 small cell carcinoma casesand are shown in Figs. 2-4. GSTM1 deficiency was associatedwith increased risk for all types of lung cancer: squamous cell

(OR = 1.49; 95% CI 1.22-1.80; P < 0.0001), adenocarci-



I: I

RI

Zhong,etal, 1991, 1993(24.41)

Brockn,bllcr. etal, 1993 (29)

Seidegkd.etal. 1986(11)

t{#{233}rvonen. et at. 1993 (30)

Kihaza.etai. 1994(44)

Hayashi. ci a!. 1992(25)

Seidegkd. ci at. 1990 (21) i-. lu I

Nak�in.eta1.. 1993(45) I I

Atexandrie. et at.. 1994(43) � � I

Meta.analysis I � I

BroclanOller. ci al, 1993 (29)

S#{224}dcg#{225}rd.etal,1986(lt) �

KthUa. etat 994(44)

Alexandrie,etal., 1994(43)

Met*-ana1)i�s I $�. I

0 1 2 3 4

Odds RatIo

Fig. 4. ORs for small cell carcinoma. Bars, 95% CIs. Summary OR 1 .9() (95%

CI = 1.27-2.84). Box sizes are proportional to study size.

�t- .�1

Kihmo.etaL 1994 (44)

Hayashi. ci al. 1992(25)

Nak�I#{252}.�a1.. 1993(45)

Japsnese stodics

Zbong.ctai. 1991. 1993 (24.41) 8-

0 1 2 3 4

Odck Ratio

/�ig. 2. ORs for squamous cell carcinoma. Bars, 95% CIs. Summary OR 1.49

(95% CI = 1.22-1.80). Box sizes are proportional to study size.

7.iioog. ci al. 1991. 1993 (24.41) I . #{149}

Brocknsallc. ci a). :�3 (29) I - � . I

Seidcglrd, ci at. 1986(1 0 I I U �

Hircooen,ctaI. )993(30) I #{149} � - I

Kihoa.rsal.1994(44)

Haysahi. ci al. 1992(25) 8-

S.e)dcgicd, eta), 1990 (Zt) I I I

A1c�iand#{241}r; �I at,, 1994443) I

Meta-analysis

0 2 3 4

Od� Ratio

Fig. 3. ORs for adenocarcinoma. Bars, 95% CIs. Summary OR 1.53 (95% CI =

1.26-1.85). Box sizes are proportional to study size.

�

�i �

-rRxockmtllcr, clot. 1993 (29) I - ) I I

S#{225}Iegbd. ci at, 1986 (3 1) 4-Hockbcsi. stat. (992 (26) ,-

Havoncn.ctai.t99300) I�

Akaandneetal., 1994(43) 8-

Caucasian studies

Meta.anaI�

0 2 3 4

Odds RatIo

Cancer Epidemiology, Biomarkers & Prevention 59/

‘I #{149} I

noma (OR = 1.53; 95% CI = 1.26-1.85; P < 0.0001), andsmall cell carcinoma (OR = 1.90; 95% CI = 1.27-1.85;P = 0.001). Likewise, if “Kreyberg type I cancers” are exam-med (squamous and small cell carcinomas, the two histologicaltypes most closely linked to smoking as a risk factor), the OR

is 1.56 (95% CI = 1.30-1.86; P < 0.0001). Tests for hetero-geneity in each of the subgroups analyzed showed no signifi-

cant heterogeneity except in the adenocarcinoma group(P = 0.016).

One potential source of bias in case-control studies of

GSTMJ deficiency and cancer risk is the imbalance of racialgroups among cases and controls. Different racial and ethnic

populations have different frequencies of GSTMJ deficiency(10). Nine ofthe studies included individuals ofonly one racialgroup. Three included only Japanese cases and controls (25, 44,45), and six were limited to Caucasians (11, 26, 29, 30, 41, 43).The results for GSTMJ deficiency and lung cancer risk strati-fied by race are shown in Fig. 5. GSTMJ was deleted in 47 and49% of the Japanese and Caucasian control populations, re-spectively. The OR for lung cancer and GSTMI deficiency in

I.

U

Fig. 5. ORs stratified by race. Bars, 95% CIs. Summary OR I .34 (95%

CI = 1.19-1.58). OR for Japanese studies 1.60 (95% CI = 1.25-2.13). OR for

Caucasian studies 1.17 (95% CI = 0.98-1.40). Box sizes are proportional to study

size.

Japanese cases compared to controls was I .60 (95%

Cl = 1.25-2.13; P = 0.002), and in Caucasians, 1. 17 (95%CI = 0.98-1.40; P = 0.037). When these studies were exam-med as a group, the risk for lung cancer with GSTMI deficiencywas 1.37 (95% CI = 1.19-1.58; P = 0.0002).

Because the studies included in the analysis differed inmethods of determination of GSTMJ status, we calculated sep-arate summary ORs for phenotypic or genotypic methods. Theresults are presented in Fig. 6. The studies, which determinedGSTMJ status by phenotyping only, included 304 cases and 312

controls and yielded a summary OR for all lung cancers of I .80(95% CI = 1.29-2.50; P = 0.0004). Studies examiningGSTMJ status by genotyping included 1254 cases and 1780controls and yielded a summary OR of 1.34 (95%CI = 1.16-1.55; P = 0.0001).

Discussion

On the basis of our expanding knowledge of the moleculargenetic changes that occur during carcinogenesis, it isnot surprising that cancer risk for an individual would be



Seidegkd. ci at. 1986(11)

Hukbat. ci al. 1992(26)

Sudteg6rd.elaL, 1990)21)

Phenotyping

- I I

I #{149} I

I � I

Thong. ci *1.1991, 1993 (24.41) 8- �-4

Brudunbiler. ci al. 1993 (29) 8- #{149}-I

11,xvonen. et a!. 1993 (30) I

Kilsarn.eial. 1994(44)

Mayenlil. et at. 1992(25)

NakachLctaL. 1993(45)

Naz�-Stewan. ci at. 1993 (37)

Alexaidrle. a al.. 1994(43) 8-

I

#{149} I

UI

U I

I�I

0

Odda Ratio

Genotyp’ng

Fi,�’. 6. ORs stratified by GSTM/ typing method, liars, 95% CIs. Summary OR

for phcnotyping studies 1.8)) (Cl 1.29-2.50). Summary OR for genotyping

studies 1.34 (95’�; = 1.15-1.55).

determined both by exposure to environmental carcinogens

and by heredity. Genes determine the individual’s levels ofdetoxification enzymes, DNA repair enzymes, and perhapsthe stability of oncogenes and tumor suppressor genes. Some

gene mutations confer a very high risk of cancer and, there-fore, result in well-known familial cancer syndromes. Incontrast, other mutations in cancer susceptibility genesmight confer only a moderate excess cancer risk. Suchmutations would not he readily apparent in family studiesbut would be detectable in large case-control or cohortstudies. These “moderate risk” cancer genes are likely main-

tamed in the population because there is no reproductive

disadvantage.The known biochemical function of the GSTs and, more

specifically, of GSTMI, suggests a plausible biochemical ra-tionale for individual differences in susceptibility to certainkinds of cancer, particularly those due to exposure to chemicalcarcinogens. Individuals with both copies of the GSTMJ genedeleted are totally deficient in this GST isoenzyme (genotype

GSTMI -I--) and, therefore, a greater fraction of the relevantchemical carcinogens from cigarette smoke can penetrate to

cellular DNA and form carcinogenic adducts. According to thismodel, individuals with one or two copies of the GSTMJ gene

(genotype GSTMI +1+ or GSTM/ +1-) express this GSTisozyme and detoxify a greater fraction of the carcinogen or

carcinogens before adduct formation. Because the GSTMJ +1+individuals have approximately twice the levels of GSTMI thando GSTMJ +1- individuals (46), it should be possible tofurther subdivide the cancer risk among GSTMJ-positive mdi-viduals by determining the risk of cancer in GSTMI +1+

individuals and GSTM/ +1- individuals. However, becausethe methods used for determining GSTMJ status in most of the

examined case-control studies do not distinguish the GSTMI+1+ and +/- genotypes, this question cannot be addressed in

the present meta-analysis.

592 GSTMI Deficiency and Lung Cancer Risk

Lung cancer, a leading cause of death from cancer in the

United States and worldwide, is largely due to exposure tochemical carcinogens in tobacco smoke (47). Therefore, a de-

ficiency of an enzyme that detoxifies carcinogenic compoundsin tobacco smoke has the potential to be an important publichealth issue. Case-control studies of GSTMI deficiency and

lung cancer have consistently shown ORs of > I but havesuffered from poor power because of insufficient sample size.

Our meta-analysis is, therefore, useful in clarifying the issue:GSTM/ deficiency is associated with a modest increase in lungcancer risk. In addition, our results indicate that GSTMI-defi-

cient individuals have an elevated risk of developing each of thethree major histological types of lung cancer, including the twotypes most strongly linked to smoking, squamous cell and small

cell carcinoma.When performing a meta-analysis, one must consider p0-

tential biases that might confound the results of the analyses.We are able to eliminate three of these potential biases: (a)variation in the distribution of histological types of lung cancer

among the studies may introduce bias because the GSTMIdeletion may impart different risks for different histological

___________ types. We were able to address this issue in a subgroup of the� . . � �. -it included studies. When ORs were calculated for individual

histological types, in each case a significantly positive associ-ation existed. This implies that variation in histological sub-

types of cancer among the studies did not introduce significantbias; (b) differences in racial distribution between case and

control groups among the studies may be a source of bias. Nineof our studies enrolled subjects of only one race and so elim-mated this bias. A significantly increased risk of lung cancer

existed in both Japanese and Caucasian GSTM/-deficient mdi-viduals. When these single-race studies are taken together, the

summary OR obtained was similar to that obtained with all theincluded studies; and (c) bias may have been introduced bymisclassification of GSTMJ status by the techniques used for

genotyping or phenotyping. This does not appear to be animportant bias in our meta-analysis because two of the included

studies determined GSTM1 status by genotyping and pheno-typing with highly concordant results, and the positive associ-

ation held up when either genotyping or phenotyping studieswere examined alone.

There were, however, two potential biases that we were

unable to address in the meta-analysis: (a) variation in genderdistribution among the studies. Most of the included studies didnot give information on the gender of their subjects and so wewere unable to examine this potential bias adequately; and (b)variation in smoking among the study subjects. Most lung

cancers are caused by smoking and, therefore, the exact natureof the interaction of the excess risks conferred by smoking and

GSTMI deficiency is of interest. For example, is the excess riskconferred by GSTMJ deficiency additive or multiplicative with

the excess risk conferred by smoking? Although some of theindividual case-control studies have approached this question,we were not able to further elucidate this issue because infor-mation regarding smoking history was either not presented orwas not uniformly collected in the analyzed studies. Becausemost lung cancer patients are smokers, it is likely that the OR

of 1.41 presented here is most relevant for lung cancer devel-oping in smokers. Because lung cancer is rare in nonsmokers,it would be difficult to collect enough nonsmoking lung cancerpatients to determine the risk of GSTMJ deficiency in that

group.Although the overall risk for developing lung cancer in

GSTM/-deficient individuals is small, lung cancer is sucha common malignancy that even a small increase in risk



Cancer Epidemiology, Blomarkers & Prevention 593

translates to a large number of excess lung cancer cases at thepopulation level. On the basis of the results of our meta-analysis, we calculate that GSTMI deficiency is implicated inapproximately 17% of new lung cancers annually. In the UnitedStates, this increased risk would account for approximately

29,000 new cases of lung cancer each year. Therefore, GSTMJ

deficiency is an important public health issue.This meta-analysis has addressed only the question of the

risk of lung cancer in GSTMI-deficient individuals. However,

GSTMI deficiency may also confer an altered risk for thedevelopment of other malignancies. Case-control studies ofGSTMJ status and other smoking related cancers such as squa-

mous cell carcinoma of the head and neck (33) and carcinomaof the bladder (4, 19, 33, 42) have estimated ORs in the rangeof 1.7-2.0. Reports that GSTMJ deficiency either is, or is not,associated with an altered risk of developing other malignan-cies, such as carcinoma of the breast (17, 39, 42, 48) or colon(20, 23, 42), have been published, but the role of GSTMIdeficiency in these cancers is not yet fully defined.

The results of this meta-analysis confirm that GSTMJ

deficiency is a risk factor in the development of lung cancer.GSTM1 deficiency is one of several common genetic polymor-phisms that confer a moderate excess risk of lung cancer.Examples of other common polymorphisms that confer a mod-

erately increased risk for lung cancer include polymorphisms inthe CYPIA/ gene and the p53 gene, as well as rare alleles ofHRASI (5, 49). Future studies will be needed to examine andquantitate the interactions between the excess lung cancer riskconferred by GSTMJ deficiency and these other polymor-phisms.

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