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CORRESPONDENCE Most cancers can be attributed to environmental factors
that act in conjunction with both genetic and acquired
susceptibility.1 It has been suggested that individuals
possessing a modified ability to metabolize carcinogens are at
increased risk for cancer.1 In fact, germ-line
polymorphisms of genes encoding carcinogen-metabolizing enzymes,
namely, phase I cytochromes P-450 (CYPs) and phase II glutathione S-transferases (GSTs), have been shown to influence the
risk of a variety of disorders thought to be caused by environmental exposure to toxic agents, including Parkinson disease2 and cancers of the gastrointestinal tract, skin, bladder, cervix, and
lung.1,3 In contrast to these solid tumors, the etiologic role of chemical carcinogens is less obvious for many hematologic malignancies. Nevertheless, Krajinovic et al4 reported the GSTM1 null and CYP1A1*2A genotypes to be risk
factors for childhood acute lymphoblastic leukemia (ALL), and
myelodysplastic syndromes (MDSs) seem to be associated with the
GSTT1 null genotype.5 For chronic myelogenous leukemia (CML), a malignancy of the
hematopoietic stem cell characterized by the Philadelphia chromosome and the hybrid BCR-ABL fusion gene, epidemiologic
studies have failed to find any reproducible, significant association
with either genetic or environmental factors except for ionizing
radiation and benzene. In order to find new evidence for the hypothesis that CML is a combined result of environmental exposure and genetic susceptibility, we used the polymerase chain reaction (PCR)-based genotyping approach described by Krajinovic et al4 to
examine the relationship between BCR-ABL+ CML
and genetic polymorphisms in the CYP1A1, GSTM1, and
GSTT1 gene loci. Genomic DNA of 141 BCR-ABL+ CML cases (78 males,
63 females) was randomly selected from a large institutional DNA bank
where DNA of German CML Study Group patients is collected. Diagnosis of
BCR-ABL+ CML was confirmed according to the
criteria of the German CML Study Group. Informed consent was obtained
from all participating individuals. For a general population control
group, peripheral blood samples of 150 randomly selected, anonymous,
healthy blood donors (97 males, 53 females) were collected. After
isolation of purified genomic DNA, PCR-based genotyping was performed
as described.4 Whereas no significant differences between cases and controls were
found in the frequencies of heterozygous or homozygous presence of the
mutant alleles CYP1A1*2B and CYP1A1*4 and of
homozygous deletions of GSTM1 and GSTT1, the
mutant allele CYP1A1*2A was significantly underrepresented
among CML cases (6.4% versus 16.0%, P < .01).
The significance was calculated using the These data indicate a reduced risk for CML in individuals carrying the mutant allele CYP1A1*2A. This is, to our knowledge, the first report of a protective role of this allele, which is a risk factor for childhood ALL according to Krajinovic et al.4 The latter finding is explained by the elevated metabolizing activity associated with CYP1A1*2A, which results in enrichment of reactive intermediates of some carcinogens, for example, polycyclic aromatic hydrocarbons (PAHs), in phase I of metabolism.1 These intermediates must be detoxified by the phase II enzymes such as GSTs. Accordingly, homozygous GSTM1 or GSTT1 deletions are risk factors for childhood ALL and several other neoplasias.1,4,5 In contrast, the relevant carcinogens for CML seem to be detoxified by CYP1A1. This should mean that the phase II metabolism is not needed for detoxification of these carcinogens, which is in accordance with our observation that there is no association between GSTM1 or GSTT1 deletions and CML risk. Our result that CYP1A1*2A is a protective factor against CML means (1) that genetic susceptibility may be relevant for CML risk, (2) that environmental carcinogens seem to play a role in the etiology of CML, and (3) that the carcinogens relevant for CML risk might differ from carcinogens relevant for other malignancies, for example, PAHs. Moreover, even different hematologic malignancies seem to be preferentially attributed to different chemical carcinogens. Taken together with other results, the available knowledge of inherited genetic and environmentally acquired susceptibility might be relevant for predicting individual risk patterns for hematologic and other malignancies. Acknowledgments. We thank Ms Susanne Brendel for excellent technical assistance, Dr H. P. Altenburg for statistical analysis, and the DRK-Blutspendezentrale Mannheim for collecting samples of healthy donors.
Harald Löffler, Jörg Bergmann, Andreas Hochhaus, Rüdiger Hehlmann, Alwin Krämer, and the German CML Study Group Supported by the Deutsche Krebshilfe (grant no. 10-1179-Kr1), the Deutsche José Carreras Leukämie-Stiftung eV, and the Forschungsfonds, Fakultät für Klinische Medizin Mannheim, Universität Heidelberg, Germany (grant no. 0022/97) References
1.
Perera FP.
Environment and cancer: who are susceptible?
Science.
1997;278:1068-1073 2. Smith CAD, Gough AC, Leigh PN, et al. Debrisoquine hydroxylase gene polymorphism and susceptibility to Parkinson's disease. Lancet. 1992;339:1375-1377[CrossRef][Medline] [Order article via Infotrieve].
3.
Kawajiri K, Eguchi H, Nakachi K, Sekiya T, Yamamoto M.
Association of CYP1A1 germ line polymorphisms with mutations of the p53 gene in lung cancer.
Cancer Res.
1996;56:72-76
4.
Krajinovic M, Labuda D, Richer C, Karimi S, Sinnett D.
Susceptibility to childhood acute lymphoblastic leukemia: influence of CYP1A1, CYP2D6, GSTM1, and GSTT1 genetic polymorphisms.
Blood.
1999;93:1496-1501 5. Chen H, Sandler DP, Taylor JA, et al. Increased risk for myelodysplastic syndromes in individuals with glutathione transferase theta 1 (GSTT1) gene defect. Lancet. 1996;347:295-297[CrossRef][Medline] [Order article via Infotrieve].   CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
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| Copyright © 2001 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
2 test and
confirmed by using the Bonferroni correction for multiple testing
(k = 5). As an estimate for the relative risk, the crude odds ratio
for CYP1A1*2A was 0.36 with a 95% confidence interval of
0.16-0.80 (Table