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Cancer risk and GSTM1 and GSTT1 polymorphisms: Hansteen et al. respond.

doi: 10.1289/ebp.0900829R

We thank Cetta et al. for the interesting comments regarding our article (Rossi et al. 2009). In their letter they address two main issues. The first refers to the role of genetic polymorphisms in the causal relationships between exposure to carcinogens and cancer occurrence. The second is more conceptual and criticizes the evolution of association studies, claiming a decreased attention to pathogenetic mechanisms in favor of an indiscriminate increase of the study size, with a consequent lack of biological plausibility.

We agree that these are important issues. We have addressed the problem of inherited predisposition for DNA damage from a different angle, namely using the frequency of chromosomal aberration (CA) as a response indicator for occupational and environmental exposure to genotoxic agents. An increase in CA level in exposed individuals compared with controls has been documented since the 1990s (Nordic Study Group 1990). The conceptual basis for using this assay has been the hypothesis that the extent of genetic damage in peripheral lymphocytes reflects critical events for the carcinogenic process in target tissues.

The key issue--whether the association with cancer risk is attributable to exposure to carcinogenic agents or reflects inherited susceptibility and accumulated damages--was addressed with a nested case-control study on incident and deceased cancer cases in the Nordic and Italian cohorts (Bonassi et al. 2000). The main findings of that study indicated an increase in cancer risk for subjects with high CA levels compared with those with low levels. This increase was independent of exposure history, as further verified in follow-up studies (Bonassi et al. 2008; Hagmar et al. 2004).

In all these studies, cancer has been studied as one entity. This summarization was mostly due to statistical needs, although the very early occurrence of chromosome damage in the carcinogenic pathway of most solid cancers provided a valuable rationale (Mitelman et al. 2004). A further reason for summarizing data by cancer type was that damages were measured in surrogate tissues and not in the target, providing only an indirect measure of cancer-related events. However, studying the cancer site in relation to CA frequency was a major interest of our group, because different types of cancers have different pathogenetic models. In our recent article (Rossi et al. 2009), we grouped cancer types into three groups, and we showed for all of these groups that subjects with high levels of CAs are more susceptible to developing cancer than are subjects with low or medium levels for CAs; this indicates that CA is an inherited susceptibility marker for cancer regardless of cancer type.

The beginning of Cetta et al.'s letter is misleading. The statement from our article (Rossi et al. 2009) that "GSTM1 [glutathione S-transferase theta M1] and GSTT1 [glutathione S-transferase theta 1] polymorphisms [as all individual polymorphisms] ... are not expected to have a dramatic influence on baseline CA [chromosomal aberration] or overall cancer risk" is not a conclusion of the study, but describes the conclusions of the extensive literature supporting this evidence (Hirchhorn 2009). We agree that it is important to examine the cause of different types of cancer and the role(s) of the different modifying enzymes, including GSTM1 and GSTT1. However, the present study was designed to evaluate a possible modifying effect of GSTM1 and GSTT1 on the cancer predictivity of developing cancer). Our main concern was identify individuals more susceptible to damage from known genotoxic exposure. Because only GSTM1 and GSTT1 polymorphisms have been extensively evaluated in human surveillance studies, we tested only these genotypes. Within the consortium of studies included in this project (Bonassi et al. 2008), further follow-up studies to differentiate cancer types or include other genotypes are possible, providing adequate financial support.

The issue raised by Cetta et al. of decreased attention to pathogenetic mechanisms in favor of larger studies, with a consequent lack of biological plausibility, is only partially correct. Actually, in association studies that link a genetic polymorphism to the effect of exposure or to the risk of cancer, the lack of specificity is the main reason for failure. Another reason for their failure is small study size, which generates meaningless and often contrasting results. The conflict noted by Cetta et al. is apparent because, as demonstrated by the success of genome-wide association studies, the need of reaching a proper statistical power is as important as studying a genetic polymorphism in a specific pathway.

The authors declare they have no competing financial interests.


Bonassi S, Hagmar L, Stromberg U, Montagud AH, Tinnerberg H, Forni A, et al. 2000. Chromosomal aberrations in lymphocytes predict human cancer independently of exposure to carcinogens. Cancer Res 60:1619-1625.

Bonassi S, Norppa H, Ceppi M, Stromberg U, Vermeulen R, Znaor A, et al. 2008. Chromosomal aberration frequency in lymphocytes predicts the risk of cancer: result from a pooled cohort study of 22,358 subjects in 11 countries. Carcinogenesis 29:1178-1183.

Hagmar L, Stromberg U, Bonassi S, Hansteen IL, Knudsen LE, Lindholm C, et al. 2004. Impact of types of lymphocyte chromosomal aberrations on human cancer risk: results from Nordic and Italian cohorts. Cancer Res 64:2258-2263.

Hirschhorn JN. 2009. Genomewide association studies--illuminating biologic pathways. N Engl J Med 360:1699-1701.

Mitelman F, Johansson B, Mertens F. 2004. Fusion genes and rearranged genes as a linear function of chromosome aberrations m cancer. Nat Genet 36:331-334.

Nordic Study Group on the Health Risk of Chromosome Damage 1990. A Nordic data base on somatic chromosome damage in humans. Mutat Res 241:325-337.

Rossi AM, Hansteen IL, Skjelbred CF, Ballardin M, Maggini V, Murgia E, et al. 2009. Association between frequency of chromosomal aberrations and cancer risk is not influenced by polymorphisms in GSTMl and GSTT1. Environ Health Perspect 117:203-208.

Inger-Lise Hansteen

Department of Laboratory Medicine

Section of Medical Genetics

Telemark Hospital

Skien, Norway

Anna Maria Rossi

Roberto Barale

Department of Biology

Pisa University

Pisa, Italy

Lisbeth E. Knudesen

Environmental Health

Institute of Public Heath

University of Copenhagen

Copenhagen, Denmark

Hannu Norppa

New Technologies and Risks

Work Environment Development

Finnish Institute of Occupational Health

Helsinki, Finland

Stefano Bonassi

Unit of Molecular Epidemiology

National Cancer Research Institute

Genoa, Italy

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Title Annotation:Correspondence
Author:Hansteen, Inger-Lise; Rossi, Anna Maria; Barale, Roberto; Knudesen, Lisbeth E.; Norppa, Hannu; Bonas
Publication:Environmental Health Perspectives
Article Type:Report
Date:Jul 1, 2009
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