Jain Meenu, Tilak Anup Raj, Upadhyay Rohit, Kumar Ashwani, Mittal Balraj
Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareilly Road, Lucknow-226014, India.
Toxicol Appl Pharmacol. 2008 Jul 15;230(2):247-51. doi: 10.1016/j.taap.2008.02.023. Epub 2008 Mar 5.
Genetic polymorphisms in xenobiotic metabolizing enzymes may alter risk of various cancers. Present case-control study evaluated the influence of EPHX1 genetic variations on squamous cell esophageal cancer (ESCC) susceptibility in 107 patients and 320 controls. EPHX1 polymorphic alleles were genotyped by direct sequencing (exon 3, Tyr113His) or PCR-RFLP (exon 4, His139Arg). Patients with exon 3 genotypes (Tyr113His, His113His) and 113His allele were at risk of ESCC (OR(Tyr113His) 2.0, 95% CI=1.2-3.4, p=0.007; OR(His113His) 2.3 95% CI=1.0-5.2, p=0.03 and OR(His) 1.5, 95% CI=1.0-2.1, p=0.01). In contrast, individuals with exon 4, 139Arg allele were at low risk of cancer (OR 0.34, 95% CI=0.20-0.56, p=0.001). However, none of haplotype combinations of exon 3 (Tyr113His) and exon 4 (His139Arg) polymorphisms showed modulation of risk for ESCC. Sub-grouping of patients based on anatomical location of tumor predicted that patients with exon 3, His113His and Tyr113His genotypes were at higher risk for developing ESCC tumor at upper and middle third locations (OR 4.4, 95% CI=1.0-18.5, p=0.04; OR 2.5, 95% CI=1.3-5.0, p=0.005 respectively). The frequency of exon 4, His139Arg genotype was significantly lower in ESCC patients with lower third tumor location as compared to controls (14.8% vs. 36.3%, p=0.02). In case-only study, gene-environment interaction of EPHX1 genotypes with tobacco, alcohol and occupational exposures did not appear to modulate the cancer susceptibility. In conclusion, exon 3, Tyr113His genotype was associated with higher risk of ESCC particularly at upper and middle-third anatomical locations of tumor. However, His139Arg genotype of exon 4, exhibited low risk for ESCC as well as its clinical characteristics.
外源性物质代谢酶的基因多态性可能会改变患各种癌症的风险。目前的病例对照研究评估了EPHX1基因变异对107例患者和320例对照者鳞状细胞食管癌（ESCC）易感性的影响。通过直接测序（外显子3，Tyr113His）或PCR-RFLP（外显子4，His139Arg）对EPHX1多态性等位基因进行基因分型。外显子3基因型（Tyr113His、His113His）和113His等位基因的患者有患ESCC的风险（OR(Tyr113His) 2.0，95%CI = 1.2 - 3.4，p = 0.007；OR(His113His) 2.3，95%CI = 1.0 - 5.2，p = 0.03；OR(His) 1.5，95%CI = 1.0 - 2.1，p = 0.01）。相比之下，具有外显子4、139Arg等位基因的个体患癌风险较低（OR 0.34，95%CI = 0.20 - 0.56，p = 0.001）。然而，外显子3（Tyr113His）和外显子4（His139Arg）多态性的单倍型组合均未显示对ESCC风险的调节作用。根据肿瘤的解剖位置对患者进行亚组分析预测，外显子3、His113His和Tyr113His基因型的患者在食管上三分之一和中三分之一部位发生ESCC肿瘤的风险较高（OR分别为4.4，95%CI = 1.0 - 18.5，p = 0.04；OR 2.5，95%CI = 1.3 - 5.0，p = 0.005）。与对照组相比，肿瘤位于食管下三分之一部位的ESCC患者中外显子4、His139Arg基因型的频率显著较低（14.8%对36.3%，p = 0.02）。在仅病例研究中，EPHX基因型与烟草、酒精和职业暴露之间的基因-环境相互作用似乎并未调节癌症易感性。总之，外显子3、Tyr113His基因型与ESCC的较高风险相关，尤其是在肿瘤的食管上三分之一和中三分之一解剖部位。然而，外显子4的His139Arg基因型显示出ESCC风险较低及其临床特征。
