The PstI/RsaI and DraI polymorphisms of CYP2E1 and head and neck cancer risk: a meta-analysis based on 21 case-control studies

Kefu Tang 0 2 Yang Li 0 2 Zhao Zhang 0 2 Yunmin Gu 0 Yuyu Xiong 0 2 Guoyin Feng 3 Lin He 0 1 2 Shengying Qin 0 2 0 Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University , Shanghai , China 1 Institutes of Biomedical Sciences, Fudan University , Shanghai , China 2 Institute for Nutritional Sciences, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences , Shanghai , China 3 Shanghai Institute of Mental Health , Shanghai , China Background: CYP2E1 encodes a member of the cytochrome P450 superfamily of enzymes which play a central role in activating and detoxifying many carcinogens and endogenous compounds thought to be involved in the development of cancer. The PstI/RsaI and DraI polymorphism are two of the most commonly studied polymorphisms of the gene for their association with risk of head and neck cancer, but the results are conflicting. Methods: We performed a meta-analysis using 21 eligible case-control studies with a total of 4,951 patients and 6,071 controls to summarize the data on the association between the CYP2E1 PstI/RsaI and DraI polymorphism and head and neck cancer risk, especially by interacting with smoking or alcohol. Results: Compared with the wild genotype, the OR was 1.96 (95% CI: 1.33-2.90) for PstI/RsaI and 1.56 (95% CI: 1.06-2.27) for DraI polymorphism respectively. When stratified according to ethnicity, the OR increased in the Asians for both polymorphisms (OR = 2.04, 95% CI: 1.32-3.15 for PstI/RsaI; OR = 2.04, 95% CI: 1.27-3.29 for DraI), suggesting that the risk is more pronounced in Asians. Conclusion: Our meta-analysis suggests that individuals with the homozygote genotypes of PstI/RsaI or DraI polymorphism might be associated with an increased risk of head and neck cancer, especially in Asians. - Background Squamous cell carcinoma of head and neck (HNSCC), including the oral cavity, pharynx, and larynx, is the sixth most common cancer in the world [1]. Epidemiological studies have shown that this type of cancer is one of those most strongly related to environmental factors, such as tobacco smoking and alcohol consumption. Many chemical carcinogens present in tobacco and alcohol undergo metabolic activation by phase I enzymes, in particular the cytochrome P450 (CYP). The activated metabolites are subsequently subjected to other detoxification steps by phase II enzymes such as glutathione S-transferases (GSTs) and N-acetyltransferases (NATs). It is hypothesized that part of the susceptibility to head and neck cancer may be determined by the inter-individual differences in the bioactivation of procarcinogens and detoxification of carcinogens. CYP2E1, which is a major component of the microsomal system involved in the metabolism of ethanol and acetone among phase I enzymes, has been widely studied as a cause of susceptibility to head and neck cancer [2,3]. The CYP2E1 gene, located on chromosome 10q26.3, is constitutively expressed in human liver and is responsible for the catalysis of xenobiotic. The protein encoded by this gene specifically activates N-nitrosamines and benzene, contained in cigarette smoke [4], and catalyses molecular oxygen to active oxygen forms (e.g., superoxide anion radical, hydrogen peroxide, etc.), which lead to intensified lipid and protein peroxidation, DNA damage, and ultimately carcinogenesis [5]. Several functional polymorphisms have been reported for the CYP2E1 gene. Two point mutations in the 5-flanking region (PstI, RsaI), which are in complete linkage disequilibrium, was found to be associated with higher-transcription and increased enzyme activity [6]. These mutations generate the CYP2E1 wild (c1) allele and the less common (c2) allele and have been reported as conferring higher risk for developing oral, pharyngeal [7] and lung cancer [8]. Another important polymorphism detectable with DraI in intron 6 is T7632A (rs6413432), a mutation of T to A, which is reported to enhance transcription of the CYP2E1 gene [9]. Polymorphisms in CYP2E1 are therefore believed to be risk factors for HNSCC. A number of studies have investigated the associations between CYP2E1 polymorphisms and HNSCC susceptibility. However, these studies have yielded contradictory results, with some studies showing a significant association, while others showing no such association. Such inconsistency could be due to the small effect of the polymorphism on HNSCC risk and the relatively small sample-size in each of the published studies. We therefore performed a meta-analysis of the published studies to clarify this inconsistency and to establish a comprehensive picture of the relationship between CYP2E1 and HNSCC. Methods Identification and eligibility of relevant studies The literature included in the current analysis was selected using PubMed with keywords head and neck or oral-neoplasms or larynx or pharynx and cancer or carcinoma, HNSCC or SCCHN, cytochrome p45 (...truncated)