Association between GSTM1*0 and squamous dysplasia of the esophagus in the high risk region of Linxian, China
Introduction
Linxian, China has some of the highest incidence rates of esophageal squamous cell carcinoma (ESCC) in the world [1]. Although the etiology for these high rates remains unknown, studies suggest that they may be associated with exposure to environmental carcinogens, including polycyclic aromatic hydrocarbons and nitrosamines [2], [3], [4], [5], [6]. The biologic consequences of carcinogenic environmental exposures may be modulated by polymorphisms in carcinogen metabolism and detoxification genes, which may result in differences in esophageal cancer risk among individuals with similar carcinogen exposures. Phase I enzymes metabolically activate parent compounds and pro-carcinogens to reactive species that exert their tumorigenic potential through binding to cellular macromolecules. These Phase I enzymes include cytochrome P450s such as CYP1A1 and CYP2E1 [7]. Aryl hydrocarbon hydroxylase, or CYP1A1, is believed to be responsible for the metabolic activation of benzo(a)pyrene and other polycyclic aromatic hydrocarbons. Two recent Japanese studies found no association between CYP1A1 polymorphisms and ESCC [8], [9], while a third found an increased frequency of the at risk CYP1A1*2B genotype in ESCC cases [10]. CYP2E1 is believed to be responsible for the metabolic activation of various N-nitrosamines, and contains both RsaI (CYP2E1*5B) and DraI (CYP2E1*6) polymorphisms. Studies correlating the CYP2E1*5B genotype to ESCC risk have reported inconsistent results. A study in a Japanese population found no difference in allele frequencies between ESCC cases and controls [9], but another study from Linxian found a significantly increased risk of developing ESCC or esophageal adenocarcinoma among persons with a CYP2E1*5B genotype [11]. The only study to date examining the CYP2E1*6 polymorphism found no association with ESCC or esophageal adenocarcinoma risk [11].
In addition to activation, carcinogens may be detoxified by Phase II enzymes such as the glutathione-S-transferases which include mu-(GSTM1) and theta-(GSTT1) isoforms. GSTM1 detoxifies the reactive metabolites of benzo(a)pyrene and other polycyclic aromatic hydrocarbons [12]. A homozygous deletion in the coding region of GSTM1 has been associated with an increased risk of breast cancer and squamous cell carcinoma of the lung [13], [14]. Also, heavy smokers with combined CYP1A1 valine homozygous (CYP1A1*2B) and GSTM1 null genotypes have been found to be at a statistically higher risk for esophageal cancer than control subjects [10]. GSTT1 detoxifies smaller reactive compounds, such as ethylene oxide and diepoxybutane [15]. A homozygous coding region deletion results in a deficient genotype that has been associated with gastric cancer [16], an early age of onset of colon cancer [17], and with the myelodysplastic syndrome [18]. In addition, compared with healthy controls, a combination of GSTM1 and GSTT1 null genotypes has been found in higher frequency in patients with squamous cell carcinomas of the head and neck, or lung, cancer types that are histolopathologically and etiologically similar to squamous cell carcinoma of the esophagus [19], [20].
Thus, evidence suggests that an exposed individual with specific Phase I and Phase II enzyme genotypes may have an increased risk of developing squamous esophageal carcinoma. It is yet unknown if an association exists between specific genotypes of these xenobiotic enzymes and preneoplastic squamous lesions of the esophagus. Understanding these early relationships may help us to better explain the gene-environment interactions associated with esophageal cancer initiation and promotion. These interactions may be especially important in high risk regions such as Linxian.
Previous studies from our group have shown that squamous dysplasia is the near-term histologic precursor of esophageal squamous carcinoma in Linxian. This is true both for moderate and severe dysplasia [21] and for mild dysplasia (Dawsey, unpublished data). We have also shown that endoscopic biopsy sampling directed by mucosal iodine staining is an accurate way of distinguishing patients with and without esophageal squamous dysplasia [22]. The current study examines whether certain genetic variants of CYP1A1, CYP2E1, GSTM1, and GSTT1, independently or in combination, are associated with increased risk of biopsy-proven squamous dysplasia of the esophagus in asymptomatic adults in Linxian.
Section snippets
Materials and methods
The general design of this study was to analyze frozen cell samples collected as part of an esophageal cytologic screening study (described in greater detail in Roth et. al. [23] for associations between CYP1A1, CYP2E1, GSTM1 and GSTT1 genotypes and the presence of biopsy proven squamous dysplasia in asymptomatic individuals. This study was approved by the Institutional Review Boards of the collaborating institutions, the Cancer Institute of the Chinese Academy of Medical Sciences (CICAMS), and
Results
The 112 participants had a mean age (SD) of 60.7 (6.2) years. Histologically, the controls consisted almost entirely of subjects with a worst overall squamous endoscopic biopsy diagnosis of normal and the cases consisted predominantly of subjects with a worst overall squamous endoscopic biopsy diagnosis of moderate dysplasia. Due to the limited amount of DNA obtained from some of the frozen cell samples, not all markers could be analyzed for all specimens. The number of successes as a
Discussion
Linxian, China has epidemic rates of squamous esophageal cancer, the causes of which remain to be identified. Many previous studies in Linxian have focused on environmental risk factors, and a few have investigated genetic risk factors, but only recently have studies begun to evaluate the possible significance of gene-environment interactions. One potentially important gene-environment interaction is the effect that genetic polymorphisms of carcinogen metabolizing enzymes may have on the cancer
Acknowledgements
The authors thank Wing Quan of the Laboratory of Cellular Carcinogenesis and Tumor Promotion, Division of Biological Sciences, National Cancer Institute, NIH, Bethesda, Maryland for his technical assistance.
References (33)
- et al.
Histopathologic changes seen in esophagectomy specimens from the high risk region of Linxian, China: potential clues to an etiologic exposure?
Hum. Pathol.
(1998) - et al.
Increased risk for myelodysplastic syndromes in individuals with glutathione transferase theta 1 (GSTT1) gene defect
Lancet
(1996) - et al.
Glutathione s-transferase genotypes as risk factors for head and neck cancer
Am. J. Surg.
(1995) - et al.
Ethnic susceptibility to lung cancer: differences in CYP2E1, CYP1A1 and GSTM1 genetic polymorphisms between French, Caucasians and Chilean populations
Cancer Lett.
(1999) - et al.
In vitro kinetics of individual differences in cancer susceptibility
Biochem. Biophys. Res. Commun.
(1997) - et al.
Esophageal cancer
- et al.
High levels of carcinogenic polycyclic aromatic hydrocarbons present within food from Linxian
China may contribute to that region's high incidence of esophageal cancer, Eur. J. Cancer
(1998) - Roth, M.J., Qiao, Y-L., Rothman, N., Dawsey, S.M., Strickland, P.T., High urine 1-hydroxypyrene glucuronide...
- et al.
Characterization of xenobiotic-metabolizing enzymes and nitrosamine metabolism in the human esophagus
Carcinogenesis
(1998) Research on esophageal cancer in China: a review
Cancer Res.
(1980)
Genetic polymorphism of CYP genes, alone or in combination, as a risk modifier of tobacco-related cancers
Cancer Epidemiol. Biomarkers Prev.
Genetic polymorphisms of tobacco- and alcohol related metabolizing enzymes and human esophageal squamous cell carcinoma susceptibility
J. Clin Gastroenterol.
CYP1A1 CYP2E1 and GSTM1 polymorphisms are not associated with susceptibility to squamous cell carcinoma of the esophagus
Int. J. Cancer
Genotyping of the CYP1A1 and GSTM1 genes in esophageal carcinoma patients with special reference to smoking
Cancer
Susceptibility to esophageal cancer and genetic polymorphisms in glutathione S-transferases T1, P1, and M1 and Cytochrome P450 2E1
Cancer Epidemiol. Biomarkers Prev.
Isoenzyme(s) of glutathione transferase (class Mu) as a marker of susceptibility to lung cancer: a follow up study
Carcinogenesis
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