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 Boffetta 1,10 1 IARC, Lyon, France; 2 Department of Genetic Medicine, European Academy, Bolzano, Italy; 3 Ospedale Policlinico IRCCS-Direzione Scientifica, Milan, Italy; 4 Centre Rene ´ Gauducheau CRLCC Nantes, Nantes-Saint-Herblain, France; 5 Vanderbilt University Medical Center, Nashville, Tennessee; 6 Departamento de Bioquı ´mica, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil; 7 Department of Epidemiology, Roswell Park Cancer Institute, Buffalo, New York; 8 Institute for Cancer Research, Norwegian Radium Hospital, Oslo, Norway; 9 School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and 10 German Cancer Research Center, Heidelberg, Germany Abstract The glutathione S -transferase (GST ) genes are involved in the metabolism of various carcinogens. Deletion polymorphisms in the genes GSTM1 and GSTT1 and a base transition polymorphism at codon 105 (Ile!Val) in GSTP1 were investigated in relation to breast cancer risk. Tobacco smoking and reproductive factors were examined as potential effect modifiers. Individual data from seven case-control studies were pooled within the International Collaborative Study on Genetic Suscep- tibility to Environmental Carcinogens. To measure the effect of GSTs on breast cancer risk, odds ratios and 95% confidence intervals were computed adjusting for study center and age. The modifying effect was investigated by stratification on variables of smoking habits and reproductive history. A total of 2,048 cases with breast cancer and 1,969 controls were analyzed. The relative odds ratio (95% confidence interval) of breast cancer was 0.98 (0.86 – 1.12) with the GSTM1 null, 1.11 (0.87 – 1.41) with the GSTT1 null, 1.01 (0.79 – 1.28) with GSTP1 heterozygous mutants, and 0.93 (0.62 – 1.38) with GSTP1 homozygous mutants. Stratification by smoking or reproductive factors did not reveal a modifying effect of these variables, nor was there any association between GSTM1 and age at diagnosis of breast cancer. This is the largest study investigating susceptibility to breast cancer due to polymorphisms in the GST genes. The results conclusively show that single gene GST polymorphisms do not confer a sub- stantial risk of breast cancer to its carriers. Further- more, GSTs did not interact with smoking or reproductive history to modify cancer risk. (Cancer Epidemiol Biomarkers Prev 2004;13(9):1473 – 9) Introduction Inherited differences in the capacity of xenobiotic metabolizing enzymes might be an important factor of genetic susceptibility to cancer. Glutathione S -trans- ferases (GST) are phase II enzymes involved in the detoxification of a broad range of toxic and potentially carcinogenic compounds (1). In humans, five classes of GST enzymes have been identified (GST classes a, A, k, j, and u). Each class is encoded by a separate gene or gene family. Allelic variants for each of these genes may result in less effective or absent enzymatic detoxification and thus increase susceptibility to cancer, although the exact biochemical processes are not yet fully understood. The GSTM1 gene, coding for cytosolic GST class A enzyme, is located on chromosome 1p13.3 (2) and includes a deletion polymorphism that, in the homozy- gous state (GSTM1 null), results in the total absence of a functional gene product (3). Several studies have shown high agreement between the GSTM1 null geno- type and a lack of GST class A function. GSTM1 is ex- pressed in various tissues, mainly liver, stomach, and brain. The frequency of the GSTM1 null genotype varies across ethnic groups and was reported to be f 50% in Caucasians (4-6). The GSTT1 gene (chromosome 22q11.2; ref. 7) also has an inactivating homozygous deletion polymorphism (8). Homozygosity for the deletion is present in f 11% to 18% of Caucasians (9). In humans, the GSTT1 enzyme is primarily expressed in liver and erythrocytes. In GSTP1 (chromosome 11q13; ref. 10), an amino acid transition has been reported at codon 105 (A313G!Ile105Val), leading to expression of an active but functionally different protein (11, 12). The GSTP1 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). Several environmental risk factors have been previ- ously associated with increased susceptibility to breast cancer. Hormonal factors that play an important role in cell growth and several aspects of reproductive history, characterized by elevated and prolonged estrogen levels, are associated with breast cancer risk. Nulliparity, lack of or reduced breast-feeding, older age at first birth, early age at menarche, and late age at menopause increase Received 3/16/04; revised 8/6/04; accepted 4/12/04. Grant support: IARC Special Training Award (F.D. Vogl) and European Commission grant CAN/96/33919. 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. Requests for reprints: Florian D. Vogl, Department of Genetic Medicine, European Academy, Viale Druso 1, 39100 Bolzano, Italy. Phone: 39-0471-055-513; Fax: 39-0471-055-099. E-mail: florian.vogl@eurac.edu Copyright D 2004 American Association for Cancer Research. 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