Elsevier

Oral Oncology

Volume 42, Issue 6, July 2006, Pages 632-637
Oral Oncology

Influence of CYP1A1, CYP2E1, GSTM3 and NAT2 genetic polymorphisms in oral cancer susceptibility: Results from a case-control study in Rio de Janeiro

https://doi.org/10.1016/j.oraloncology.2005.11.003Get rights and content

Summary

Xenobiotic metabolizing enzymes are involved in the detoxification of many carcinogens and may be important in modulating cancer susceptibility. CYP1A1, CYP2E1, GSTM3, and NAT2 polymorphisms were determined in peripheral blood DNA of 231 oral cancer patients and 212 hospital controls in Rio de Janeiro, Brazil, using the PCR–RFLP technique. NAT2 polymorphism distribution was different between cases and controls (P = 0.035), with an overrepresentation of NAT211 mutant allele in controls. Risk analysis showed that NAT2 4/4 individuals (OR = 1.95, 95% CI = 1.05–3.60) and combined GSTM3 and NAT2 heterozygotes (OR = 1.94, 95% CI = 1.04–3.66) were at increased oral cancer risk. No statistically significant association was observed for CYP1A1 and CYP2E1 polymorphisms. Our results suggest that NAT2 polymorphism, alone or combined with GSTM3, may modulate susceptibility to oral cancer in Rio de Janeiro.

Introduction

Oral cancer is a serious public health problem, with over 200,000 new cases reported annually worldwide, two-thirds of which occur in developing countries, and with an overall 5-year mortality rate of approximately 50%.1 In Brazil, it is the seventh most incident cancer type, with over 11,000 new cases in 2002.2 Molecular epidemiology has shown strong evidence for the contribution of both environmental and genetic risk factors in human cancers.3 Tobacco and alcohol consumption are major environmental risk factors for oral cancer, and a dose–effect relationship has been observed.2, 4 Several common genetic polymorphisms may modify the multi-step carcinogenic process, including the genes involved in xenobiotic biotransformation, DNA repair, hormone metabolism, immune system regulation and development, apoptosis, and cell cycle control.5, 6 Biotransformation processes include detoxification pathways, but sometimes the reactive intermediates can bind to DNA or other macromolecules,7 leading to cellular and genetic damage, initiating carcinogenesis.8 Genetic polymorphisms in xenobiotic metabolizing enzymes (XMEs) may contribute to the individual variability in the metabolism of chemical substances which have been associated with cancer.9 The higher activity of phase I enzymes, such as the ones coded by the cytochrome P450 (CYP) family, and/or lower activity of phase II enzymes, coded by glutathione S-transferase (GST) and N-acetyltransferase (NAT), may have implications for the metabolism of tobacco-specific nitrosamines and polycyclic aromatic hydrocarbons (PAHs), alcohol, and other carcinogenic substances.5 Despite the biological plausibility, inconsistent associations have been described for polymorphic XMEs and cancer, with controversial results.10

In the last decade, considerable progress has been made in understanding the genetic basis of the development of oral cancer as it results from an accumulation of genetic alterations.6 However, little is known about which genes are involved and how important they are, or which can be used as predictive or informative risk factors for early detection, prognosis, and treatment management. Few studies have been conducted in this area, especially in developing countries.

The identification of genes modulating cancer risk may have several implications, including the possibility of developing chemoprevention programs for highly sensitive individuals, allowing early intervention and the implementation of efficient prevention and treatment strategies. The objectives of this study were to determine the allelic and genotypic frequencies of CYP1A1, CYP2E1, GSTM3, and NAT2 polymorphisms in a case-control sample from Rio de Janeiro, Brazil, and investigate their role as molecular markers for oral cancer risk.

Section snippets

Subjects and methods

Cases were 15–79 year-old patients with histopathological confirmation, mainly of squamous cell carcinoma, with no previous treatment, diagnosed at the Hospital of the National Cancer Institute (INCA), Rio de Janeiro, between 1999 and 2002. Controls were selected from two public hospitals near the INCA, with non-tumor pathologies (excluding those related to alcohol and tobacco consumption), and were frequency-matched to cases in relation to age, gender, and skin color. Individuals were

Results

Table 2 shows the distribution of 231 oral cancer cases and 212 controls, according to sex, age, skin color, and genotypes in the study sample. Mean age was 56.6 years (±0.64) among cases and 55.3 years (±0.77) among controls (P = 0.47). Smoking and alcohol consumption were more frequent among oral cancer cases (77% and 66%) than among controls (42% and 51%). A more comprehensive analysis of the association between the studied genetic polymorphisms, smoking, and alcohol intake has been developed,

Discussion

Oral cancer is a complex disease resulting from both gene–gene and gene–environment interactions.2 Cytochrome P450, GST, and NAT are families of enzymes involved in the metabolism of many environmental agents, including tobacco and alcohol, and there is growing evidence for their role as cancer susceptibility factors.3, 5

Allelic frequencies for CYP1A12C, CYP2E15B, GSTM3B, and NAT211 were in agreement with literature reports, presenting intermediate values between those of major ethnic

Acknowledgments

We are grateful to Jane Capelli, Maria Beatriz Kneipp, Flávia Rajoy, and Monica Romero for their dedicated and skilled work. This work was supported by grants from the Brazilian National Research Council (CNPq), State of Rio de Janeiro Research Foundation (FAPERJ), and European Community (DG XII).

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