Research Association between Frequency of Chromosomal Aberrations and Cancer Risk Is Not Influenced by Genetic Polymorphisms in GSTM1 and GSTT1 Anna Maria Rossi,1* Inger-Lise Hansteen,2* Camilla Furu Skjelbred,2 Michela Ballardin,1 Valentina Maggini,1 Elena Murgia,1 Antonio Tomei,1 Paolo Viarengo,3 Lisbeth E. Knudsen,4 Roberto Barale,1 Hannu Norppa,5 and Stefano Bonassi 6 1Department of Biology, Pisa University, Pisa, Italy, 2Department of Laboratory Medicine, Section of Medical Genetics, Telemark Hospital, Skien, Norway; 3Department of Aerospace Engineering, University of Naples Federico II, Naples, Italy; 4Environmental Health, Institute of Public Health, University of Copenhagen, Copenhagen, Denmark; 5New Technologies and Risks, Work Environment Development, Finnish Institute of Occupational Health, Helsinki, Finland; 6Unit of Molecular Epidemiology, National Cancer Research Institute, Genoa, Italy Background : The frequency of chromosomal aberrations (CA) in peripheral blood lymphocytes of healthy individuals has been associated with cancer risk. It is presently unclear whether this associa- tion is influenced by individual susceptibility factors such as genetic polymorphisms of xenobiotic- metabolizing enzymes. o Bjectives : To evaluate the role of polymorphisms in glutathione S-transferase (GST) M1 (GSTM1) and theta 1 (GSTT1) as effect modifiers of the association between CA and cancer risk. Methods : A case–control study was performed pooling data from cytogenetic studies carried out in 1974–1995 in three laboratories in Italy, Norway, and Denmark. A total of 107 cancer cases were retrieved from national registries and matched to 291 controls. The subjects were classified as low, medium, and high by tertile of CA frequency. The data were analyzed by setting up a Bayesian model that included prior information about cancer risk by CA frequency. r esult : The association between CA frequency and cancer risk was confirmed [ORmedium (odds ratio)medium = 1.5, 95% credibility interval (CrI), 0.9–2.5; ORhigh = 2.8, 95% CrI, 1.6–4.6], whereas no effect of the genetic polymorphism was observed. A much stronger association was seen in the Italian subset (ORhigh= 9.4, 95% CrI, 2.6–28.0), which was characterized by a lower technical vari- ability of the cytogenetic analysis. CA level was particularly associated with cancer of the respiratory tract (ORhigh= 6.2, 95% CrI, 1.5–20.0), the genitourinary tract (ORhigh = 4.0, 95% CrI, 1.4–10.0), and the digestive tract (ORhigh = 2.8, 95% CrI, 1.2–5.8). c onclusi : Despite the small size of the study groups, our results substantiate the cancer risk predictivity of CA frequency, ruling against a strong modifying effect of GSTM1 and GSTT1 polymorphisms. owrds k ey : Bayesian, biomarker, cancer risk, case–control study, chromosomal aberration, genetic polymorphism, glutathione S-transferase, GSTM1, GSTT1, Monte Carlo Markov Chain. Environ Health Perspect 117:203–208 (2009). doi:10.1289/ehp.11769 available via http://dx.doi.org/ [Online September 2008] During the last few decades, evidence con- cerning the role of chromosomal aberrations (CA) in carcinogenesis has been enriched by a number of epidemiologic studies showing that high CA frequencies in peripheral blood lymphocytes of healthy individuals are asso- ciated with increased cancer risk (Boffetta et al. 2007; Bonassi et al. 1995, 2000; 2004; Brøgger et al. 1990; Hagmar et al. 1994, 1998, 2004; Liou et al. 1999; Rossner et al. 2005). A case–control study nested within ESCH (European Study Group of Cytogenetic Biomarkers and Health) cohort studies (Bonassi et al. 1995; Hagmar et al. 1994, 1998) found that the strength of such association is not influenced by occupa- tional exposure to carcinogens or tobacco smoking (Bonassi et al. 2000). Contrasting results were reported by other investiga- tions, such as a cohort study on Czech work- ers (Smerhovsky et al. 2002) describing a stronger association between CA frequency and cancer incidence in miners exposed to radon. Whether the CA–cancer association reflects (occasionally undetected) exposure to carcinogens, individual susceptibility to carcinogens, some form of chromosomal instability, or a causal role of chromosomal rearrangements in the carcinogenic process is still an open issue. A striking amount of data supports the hypothesis that individual characteristics associated with cancer risk, such as inherited differences in metabolic enzymes or DNA repair capacity, may also modify CA occur- rence (Norppa 2004). These findings raise the obvious question of whether the association between CA and cancer risk depends on indi- vidual metabolism and DNA repair capabil- ity, so that CA would better predict cancer risk in people with an unfavorable genotype. This question can be assessed by incorporat- ing genotype data to the CA–cancer studies, but such an approach has not been applied previously, as DNA samples have not been readily available. Among the most frequently studied poly- morphisms are those concerning the metabo- lism of xenobiotics, in particular glutathione S-transferases (GSTs). GSTs catalyze the Environmental Health Perspectives • volume 117 | number 2 | February 2009 conjugation between glutathione and reac- tive xenobiotic compounds in a pathway that leads to thioethers excreted in the urine (Bolt and Thier 2006; Parl 2005). The major bio- logical function of GSTs is considered to be protection against electrophilic chemical spe- cies, although metabolic activation involving GST-mediated glutathione conjugation has also been described (e.g., for some chlorin- ated substrates) (Bolt and Thier 2006; Parl 2005). Detoxification by glutathione con- jugation can represent a minor (e.g., styrene oxide) or a major (e.g., benzo[a]pyrene) met- abolic pathway for many genotoxic agents. Given the importance of GSTs in the detoxi- fication of electrophilic carcinogens, the pos- sible influence of polymorphisms in GST genes on cancer risk has been investigated extensively (Bolufer et al. 2006; Bolt and Thier 2006; Carlsten et al. 2008; Hiyama et al. 2008; Parl 2005; Shi et al. 2008; Vineis et al. 2007; White et al. 2008). The GST M1 (GSTM1; BC036805, GenBank) and theta 1 (GSTT1; X79389, GenBank) genes have received much attention because of the high prevalence of homozygous deletions result- ing in genotypes with a decreased ability to detoxify carcinogenic compounds, plac- ing individuals at increased cancer risk (Bolufer et al. 2006; Bolt and Their 2006; Address correspondence to S. Bonassi, Unit of Molecular Epidemiology, National Cancer Research Institute, Largo Rosanna Benzi, 10, 16132 Genoa, Italy. Telephone: 390 10 5600924. Fax: 390 10-5600501. E-mail: stefano.bonassi@istge.it. *These two authors contributed equally to the present study. This work was supported by grants from the European Union 5th FP (QLRT-2000-00628) and its extension (QLK4-CT-2002-02831), the Associazione Italiana per la Ricerca sul Cancro (AIRC), the Italian Ministry of Health, the Italian Space Agency (ASI), the Telemark Hospital (Research and Development), the Fondazione Buzzi-Unicem per la Ricerca sul Mesotelioma, Casale (Italy), the Danish National Programme of Environmental Health Research on Cancer (0-302-02-4/2), and the Finnish Work Environment Fund. The Cancer Registry of Norway is not responsible for the analysis or interpretation of the data presented. The authors declare they have no competing Received 6 June 2008; accepted 16 September financial interests. 2008. 203