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Glutathione S-Transferases M1, T1, and P1 and Breast Cancer: a Pooled Analysis

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Glutathione S-Transferases M1, T1, and P1 and Breast Cancer: a Pooled Analysis Cancer Epidemiology, Biomarkers & Prevention 1473 Glutathione S-transferases M1, T1, and P1 and Breast Cancer: A Pooled Analysis Florian D. Vogl,1,2 Emanuela Taioli,3 Christine Maugard,4 Wei Zheng,5 Luis F. Ribeiro Pinto,6 Christine Ambrosone,7 Fritz F. Parl,5 Vessela Nedelcheva-Kristensen,8 Timothy R. Rebbeck,9 Paul Brennan,1 and Paolo Boffetta1,10 1IARC, Lyon, France; 2Department of Genetic Medicine, European Academy, Bolzano, Italy; 3Ospedale Policlinico IRCCS-Direzione Scientifica, Milan, Italy; 4Centre Rene´Gauducheau CRLCC Nantes, Nantes-Saint-Herblain, France; 5Vanderbilt University Medical Center, Nashville, Tennessee; 6Departamento de Bioquı´mica, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil; 7Department of Epidemiology, Roswell Park Cancer Institute, Buffalo, New York; 8Institute for Cancer Research, Norwegian Radium Hospital, Oslo, Norway; 9School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and 10German Cancer Research Center, Heidelberg, Germany Abstract The glutathione S-transferase (GST) genes are involved The relative odds ratio (95% confidence interval) of in the metabolism of various carcinogens. Deletion breast cancer was 0.98 (0.86–1.12) with the GSTM1 null, polymorphisms in the genes GSTM1 and GSTT1 and a 1.11 (0.87–1.41) with the GSTT1 null, 1.01 (0.79–1.28) base transition polymorphism at codon 105 (Ile!Val) with GSTP1 heterozygous mutants, and 0.93 (0.62–1.38) in GSTP1 were investigated in relation to breast cancer with GSTP1 homozygous mutants. Stratification by risk. Tobacco smoking and reproductive factors were smoking or reproductive factors did not reveal a examined as potential effect modifiers. Individual data modifying effect of these variables, nor was there any from seven case-control studies were pooled within the association between GSTM1 and age at diagnosis of International Collaborative Study on Genetic Suscep- breast cancer. This is the largest study investigating tibility to Environmental Carcinogens. To measure the susceptibility to breast cancer due to polymorphisms effect of GSTs on breast cancer risk, odds ratios and in the GST genes. The results conclusively show that 95% confidence intervals were computed adjusting for single gene GST polymorphisms do not confer a sub- study center and age. The modifying effect was stantial risk of breast cancer to its carriers. Further- investigated by stratification on variables of smoking more, GSTs did not interact with smoking or habits and reproductive history. A total of 2,048 cases reproductive history to modify cancer risk. (Cancer with breast cancer and 1,969 controls were analyzed. Epidemiol Biomarkers Prev 2004;13(9):1473–9) Introduction Inherited differences in the capacity of xenobiotic a functional gene product (3). Several studies have metabolizing enzymes might be an important factor of shown high agreement between the GSTM1 null geno- genetic susceptibility to cancer. Glutathione S-trans- type and a lack of GST class A function. GSTM1 is ex- ferases (GST) are phase II enzymes involved in the pressed in various tissues, mainly liver, stomach, and detoxification of a broad range of toxic and potentially brain. The frequency of the GSTM1 null genotype varies carcinogenic compounds (1). In humans, five classes of across ethnic groups and was reported to be f50% in GST enzymes have been identified (GST classes a, A, k, j, Caucasians (4-6). The GSTT1 gene (chromosome 22q11.2; and u). Each class is encoded by a separate gene or gene ref. 7) also has an inactivating homozygous deletion family. Allelic variants for each of these genes may result polymorphism (8). Homozygosity for the deletion is in less effective or absent enzymatic detoxification and present in f11% to 18% of Caucasians (9). In humans, thus increase susceptibility to cancer, although the exact the GSTT1 enzyme is primarily expressed in liver and biochemical processes are not yet fully understood. erythrocytes. In GSTP1 (chromosome 11q13; ref. 10), an The GSTM1 gene, coding for cytosolic GST class A amino acid transition has been reported at codon 105 enzyme, is located on chromosome 1p13.3 (2) and (A313G!Ile105Val), leading to expression of an active includes a deletion polymorphism that, in the homozy- but functionally different protein (11, 12). The GSTP1 gous state (GSTM1 null), results in the total absence of encoded enzyme GST class k is mainly found in spleen, heart, and lung tissue. Both GST classes k and A enzymes are also expressed in breast cancer tissue (13). Received 3/16/04; revised 8/6/04; accepted 4/12/04. Several environmental risk factors have been previ- Grant support: IARC Special Training Award (F.D. Vogl) and European ously associated with increased susceptibility to breast Commission grant CAN/96/33919. cancer. Hormonal factors that play an important role in 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 cell growth and several aspects of reproductive history, accordance with 18 U.S.C. Section 1734 solely to indicate this fact. characterized by elevated and prolonged estrogen levels, Requests for reprints: Florian D. Vogl, Department of Genetic Medicine, European are associated with breast cancer risk. Nulliparity, lack of Academy, Viale Druso 1, 39100 Bolzano, Italy. Phone: 39-0471-055-513; Fax: 39-0471-055-099. E-mail: [email protected] or reduced breast-feeding, older age at first birth, early Copyright D 2004 American Association for Cancer Research. age at menarche, and late age at menopause increase Cancer Epidemiol Biomarkers Prev 2004;13(9). September 2004 Downloaded from cebp.aacrjournals.org on September 25, 2021. © 2004 American Association for Cancer Research. 1474 GSTM1, GSTT1, and GSTP1 and Breast Cancer Table 1. Studies contributing to the pooled analysis and information provided on investigated variables Reference Cases/controls Country Source of controls GSTM1 Cases (% Null) Controls (% Null) 1 (26) 283/338 USA Population 283 (51.2) 338 (50.6) 2 (30) 827/262 Norway Population 816 (51.6) 196 (45.4) 3 * 130/122 USA Population 130 (39.2) 122 (52.5) 4 (29) 361/437 France Population + Hospital 361 (55.7) 437 (51.3) 5 (27) 164/209 USA Hospital 164 (55.5) 209 (59.8) 6 (28) 79/123 Brazil Hospital 79 (41.8) 123 (52.9) 7 (31, 32) 204/478 USA Population 200 (48.5) 474 (52.5) Total 2,048/1,969 2033 (51.1) 1899 (52.0) *T. Rebbeck et al., unpublished data. breast cancer risk (14). High body mass index (BMI) and genotypes and breast cancer, which were provided by possibly low physical exercise are also risk factors of the investigators to the GSEC Study (24, 25). Investigators postmenopausal breast cancer, acting via interference who had published case-control studies on metabolic with hormonal levels (15). Cigarette smoking is an gene polymorphisms and cancer up to June 1999 were established risk factor for several cancers including the identified through Medline and invited to provide data respiratory and upper aerodigestive tract, kidney, blad- on all subjects (including published as well as unpub- der, stomach, and pancreas (16). lished data). The results of six of the seven studies Enzymes belonging to the GST classes A, k, and u are including breast cancer had been published previously involved in the detoxification of benzo(a)pyrene and (26-32). Two groups have published their results after other polycyclic aromatic hydrocarbons found in tobac- they had submitted data to the GSEC. The number of co smoke and have received considerable attention in subjects contained in the published reports may differ relation to smoking-related cancers. An association slightly from the number included in this pooled between the GST null phenotype and cancer susceptibility analysis. The present study was restricted to women of was described for lung cancer (17, 18), colorectal cancer, Caucasian origin. For every subject, case-control status and bladder cancer (19, 20). Polycyclic aromatic hydro- and genotype at the GSTM1, GSTT1, and GSTP1 loci were carbons induced mammary tumors in animal models, and submitted for the pooled analysis. All studies used PCR polycyclic aromatic hydrocarbon-DNA adducts have to detect polymorphisms. Although in some studies been identified in human mammary epithelial cells. A different PCR protocols were used, the laboratory pro- recent case-control study suggested an increased risk of cedures in general should be comparable. If available, breast cancer in relation to polycyclic aromatic hydrocar- additional information on age, anthropometric mea- bon-DNA adducts (21). Although tobacco smoking does sures (body weight and height), family history of cancer, not seem to be a risk factor of breast cancer in studies of smoking status, and reproductive factors was provided. unselected populations, the possibility of an increased Prior to analysis, the data were checked and coded in a risk in genetically predisposed groups remains (22). GSTs standard fashion and entered into a common database. are also involved in detoxifying reactive compounds Genotypes at the GSTM1 and GSTT1 loci were coded generated during estrogen metabolism. positive if at least one functional allele was present and Few studies have addressed GST polymorphisms and null in the case of a homozygous deletion. The number of breast cancer, although a meta-analysis of studies pub- homozygote and heterozygote carriers of GSTM1 and lished before 1997 has suggested a slight risk increase in GSTT1 wild-type alleles was not provided. GSTP1 carriers of the GSTM1 null polymorphism, which was genotype was classified in three categories: the homozy- only significant in the youngest age group (23). gous wild-type, the heterozygous, and the homozygous The Genetic Susceptibility to Environmental Carcino- mutant. BMI was calculated according to the standard gen (GSEC) Study, an international collaborative project, formula: weight (kg)/height (m)2. Information on cumu- has been initiated to investigate the relationships of lative tobacco smoking was expressed as pack-years polymorphisms in genes that metabolize environmental (daily amount multiplied by duration in years and carcinogens and cancers at different sites (24).
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