Cancer Risk and GSTM1 and GSTT1 Polymorphisms
Environ Health Perspect. doi:10.1289/ehp.0900829 available via http://dx.doi.org [Online 23 June 2009]
Referencing: Association between Frequency of Chromosomal Aberrations and Cancer Risk Is Not Influenced by Genetic Polymorphisms in GSTM1 and GSTT1
Rossi et al. (2009) stated in their conclusion that “GSTM1 [glutathione S-transferase 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.”
We agree with these statements from a general point of view. However, it is one thing to suggest that an evident pathologic marker, such as CA frequency in peripheral lymphocytes, could be an expression of cancer (like elevated carcinoembryonic antigen or other biomarkers) and another to exclude any influence of a genetic polymorphism on the occurrence of a specific type of cancer on the basis of a study that is basically not suitable to answer the question.
We will not address the advantages of the Bayesian approach versus the classic frequentist model. However, as clinicians, we would like to comment on epidemiologic studies on cancer, in particular those concerning the possible effects of complex causative factors such as environmental pollution. We also will discuss issues concerning patients and outcomes of the article by Rossi et al. (2009). In particular, we will focus on issues that are often considered by epidemiologists and those interested in statistical analysis to be pathophysiologic or pathogenetic details, but are, on the contrary, basic issues for those examining clinical and pathological findings.
Although the combination of bone and skin cancers (cancers that originate from different tissues and are related to completely different pathogenetic agents and pathophysiologic mechanisms) could be acceptable from a statistical point of view, this practice creates a methodologic bias from pathophysiologic and pathogenetic points of view. Because Rossi et al. (2009) included a large number of bone and skin cancer cases in their study (n = 20 in their Table 2), it is of paramount importance to state whether cytochrome P451 A1 (CYP1A1) is a basic factor in the occurrence of these cancers. For lung and respiratory tract cancer, the role of CYP1A1 has been tested; however, it is not appropriate to use these polymorphisms, which are specific for the metabolism of some xenobiotics, as a marker of all cancers.
Our team has long been involved in the detection of cause and effect relationships between presumed causative factors and cancer, in particular, concerning the relative role of inherited predisposition and environmental factors, the relative impact of intrinsic toxicity or carcinogenicity, and the role of host susceptibility and response (Cetta et al. 2007, 2009a).
In a genome-wide analysis of copy numbers in couples in which either husbands had been occupationally exposed to asbestos but did not have mesothelioma or spouses with mesothelioma who had not been occupationally exposed to asbestos, we reported a panel of differently expressed genes that could be responsible for a different inherited susceptibility. This panel of differently expressed genes sometimes included genes involved in the control of major histocompatibility systems, in the production of drug-metabolizing enzymes, or of X-ray repair or mismatch repair genes (Cetta F. Dhamo A, Zangari R, unpublished data).
Therefore, it is plausible that genetic polymorphisms in GSTM1 and GSTT1 may be part (if not the main determinant) of a panel of genes that define the individual susceptibility of some subjects to interact differently with a given environmental agent; this interaction would lead to cancer as a final outcome only in the susceptible individuals and not in others, even if the nonsusceptible individuals are more exposed to the same toxic or carcinogenic agent.
We suggest that the pathogenetic task (i.e., a better knowledge of the variable impact of the same toxic agent on different individuals) requires very specific and focused studies and not generic studies that combine skin and bone cancer grouped by the same code.
We suggest that studies rely less on the statistical power of numbers (cases and controls) and pay more attention to the homogeneity of populations, groups, or subgroups. These studies should focus not only on the biological but also on the pathophysiologic and pathogenetic plausibility of observed data; they should avoid mixing “apples and oranges.”
We suggest that researchers examine data carefully before they state that one event is influenced or not influenced by a causative or facilitating agent, namely when interactions between cause and effect are very complex and the causative relationship is not clear-cut (Cetta et al. 2007, 2009b). This is even more important when attempting to establish the relative impact of inherited or environmental factors in the occurrence of various types of cancers, each of which has its own peculiarity and wide variations, even within the range of tumors affecting the same organ or tissue (Cetta et al. 2007, 2009a).
In the future, there will be a major need for improved knowledge of causative and pathophysiologic mechanisms and for more strict adherence to this knowledge before designing epidemiologic or pathogenetic studies. These studies must rely more on the homogeneity of the enrolled population and on the direct cause and effect relationship between the causative agent and the expected outcome, and less on the number of enrolled subjects (if subjects are not appropriate for the scope of the study, their inclusion is potentially misleading. Panel studies in smaller but well-selected groups will give more useful information than large population studies that are missing the pathophysiologic and causative targets, in particular when large studies are based on too many inferences and/or extrapolations from old or inhomogeneous data.
This work was supported by the Flagship Project, PROLIFE, City of Milan, Italy.
The authors declare they have no competing financial interests.
Francesco Cetta*
Armand Dhamo
Laura Moltoni
Rosalia Zangari
Department of Surgery
Research Doctorate in Oncology and Genetics
University of Siena
Siena, Italy
*PAT Geriatric Institute, Milan, Italy
E-mail: cetta@unisi.it
References
Cetta F, Dhamo A, Azzarà A, Moltoni L. 2009a. The role of inherited predisposition and environmental factors in the occurrence of multiple different solid tumors in the same individual. The experience of the University Hospital of Siena. In: Multiple Primary Malignancies (Renda A, ed). Milan:Springer Verlag, 157–178.
Cetta F, Dhamo A, Moltoni L, Bolzacchini E. 2009b. Adverse health effects from combustion derived nanoparticles: the relative role of intrinsic particle toxicity and host response [Letter]. Environ Health Perspect 117:A190.
Cetta F, Dhamo A, Schiraldi G, Camatini M. 2007. Particulate matter, science and European Union policy. Eur Respir J 10:805–806.
Rossi AM, Hansteen IL, Skjelbred CF, Ballardin M, Maggioi V, Murgia E, et al. 2009. Association between frequency of chromosomal aberrations and cancer risk is not influenced by genetic polymorphisms in GSTM1 and GSTT1. Environ Health Perspect 117:203–208.
Cancer Risk and GSTM1 and GSTT1 Polymorphisms: Hansteen et al. Respond
Environ Health Perspect. doi:10.1289/ehp.0900829R available via http://dx.doi.org [Online 23 June 2009]
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 of 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 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 (Hirschhorn 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 CA (indicating individual susceptibility to 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.
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. Knudsen
Environmental Health
Institute of Public Health
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
E-mail: stefano.bonassi@istge.it
References
Bonassi S, Hagmar L, Strømberg 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, Strømberg U, Vermeulen R, Znaor A, et al. 2008. Chromosomal aberration frequency in lymphocytes predicts the risk of cancer: results from a pooled cohort study of 22,358 subjects in 11 countries. Carcinogenesis 29:1178–1183.
Hagmar L, Strømberg 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 in 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 GSTM1 and GSTT1. Environ Health Perspect 117:203–208.
