Bell D A, Taylor J A, Paulson D F, Robertson C N, Mohler J L, Lucier G W
Laboratory of Biochemical Risk Analysis, National Institute of Environmental Health-Sciences (NIEHS), Research Triangle Park, N.C. 27709.
J Natl Cancer Inst. 1993 Jul 21;85(14):1159-64. doi: 10.1093/jnci/85.14.1159.
Numerous studies have associated bladder cancer with exposure to carcinogens present in tobacco smoke and other environmental or occupational exposures. Approximately 50% of all humans inherit two deleted copies of the GSTM1 gene which encodes for the carcinogen-detoxification enzyme glutathione S-transferase M1. Recent findings suggest that the GSTM1 gene may modulate the internal dose of environmental carcinogens and thereby affect the risk of developing bladder cancer.
We investigated whether the absence of the GSTM1 gene affects bladder cancer risk and whether there are racial differences in GSTM1 genotype frequency.
Using a polymerase chain reaction (PCR)-based method, we examined the frequency of the homozygous deleted genotype (GSTM1 0/0) in 229 patients with transitional cell carcinoma of the bladder and 211 control subjects who were enrolled from the Urology Clinics at Duke University Medical Center and the University of North Carolina Hospitals. Control subjects were urology clinic patients who primarily presented with benign prostatic hypertrophy or impotence, who had no history of any cancer other than nonmelanoma skin cancer, and who were frequency matched to case patients on race, sex, and age (10-year age intervals). In order to explore racial differences in GSTM1 gene frequency, genotype was also determined in a community-based sample of 466 paid, healthy, unrelated volunteers from Durham and Chapel Hill, N.C. The presence or absence of the GSTM1 gene locus was determined by using a differential PCR, a semiquantitative technique in which multiple genes are coamplified.
Overall, the GSTM1 0/0 genotype conferred a 70% increased risk of bladder cancer (odds ratio [OR] = 1.7; 95% confidence interval [CI] = 1.2-2.5; P = .004). Absence of the GSTM1 gene encoding the glutathione S-transferase M1 enzyme significantly increased risk to persons with exposure to the carcinogens in tobacco smoke (OR = 1.8; 95% CI = 1.2-3.0; P = .01) but poses little increased risk to persons without such exposure. Persons with smoking exposure of more than 50 pack-years who had the GSTM1 0/0 genotype had a sixfold greater risk relative to persons in the lowest risk group (i.e., nonsmokers who were GSTM1 +/+ or +/0). In the pooled clinic control and community sample groups (677 individuals), the GSTM1 0/0 genotype occurred less frequently among Blacks (35%) than among Whites (49%, P < .001).
These findings support a protective role for the GSTM1 gene in bladder cancer. From these findings, it is estimated that 25% of all bladder cancer may be attributable to the at-risk GSTM1 0/0 genotype.
大量研究表明，膀胱癌与接触烟草烟雾中的致癌物以及其他环境或职业暴露有关。大约50%的人继承了两个缺失的GSTM1基因拷贝，该基因编码致癌物解毒酶谷胱甘肽S-转移酶M1。最近的研究结果表明，GSTM1基因可能调节环境致癌物的体内剂量，从而影响患膀胱癌的风险。
我们研究了GSTM1基因缺失是否会影响膀胱癌风险，以及GSTM1基因型频率是否存在种族差异。
我们采用基于聚合酶链反应（PCR）的方法，检测了229例膀胱移行细胞癌患者和211例对照者中纯合缺失基因型（GSTM1 0/0）的频率。这些患者和对照者来自杜克大学医学中心泌尿外科诊所和北卡罗来纳大学医院。对照者为泌尿外科门诊患者，主要表现为良性前列腺增生或阳痿，除非黑色素瘤皮肤癌外无其他癌症病史，并且在种族、性别和年龄（10岁年龄间隔）上与病例患者进行频率匹配。为了探讨GSTM1基因频率的种族差异，我们还在一个基于社区的样本中确定了基因型，该样本包括来自北卡罗来纳州达勒姆和教堂山的466名有偿、健康、无亲属关系的志愿者。通过使用差异PCR（一种共扩增多个基因的半定量技术）来确定GSTM1基因位点的存在或缺失。
总体而言，GSTM1 0/0基因型使膀胱癌风险增加了70%（优势比[OR]=1.7；95%置信区间[CI]=1.2 - 2.5；P = .004）。编码谷胱甘肽S-转移酶M1酶的GSTM1基因缺失显著增加了接触烟草烟雾中致癌物的人的风险（OR = 1.8；95% CI = 1.2 - 3.0；P = .01），但对未接触此类致癌物的人风险增加不大。吸烟超过50包年且具有GSTM1 0/0基因型的人相对于风险最低组（即GSTM1 +/+或 +/0的非吸烟者）的风险高六倍。在合并的临床对照和社区样本组（677人）中，GSTM1 0/0基因型在黑人中出现的频率（35%）低于白人（49%，P < .001）。
这些发现支持GSTM1基因在膀胱癌中具有保护作用。根据这些发现估计，所有膀胱癌中约25%可能归因于有风险的GSTM1 0/0基因型。
