Strassburg C P, Vogel A, Kneip S, Tukey R H, Manns M P
Department of Gastroenterology and Hepatology, Hannover Medical School, 30625 Hannover, Germany.
Gut. 2002 Jun;50(6):851-6. doi: 10.1136/gut.50.6.851.
Genetic polymorphisms in the human UDP-glucuronosyltransferase-1A7 (UGT1A7) gene are detected and significantly correlated with sporadic colorectal carcinoma. UGT1A7, which has recently been demonstrated to glucuronidate environmental carcinogens, is now implicated as a cancer risk gene. A silent mutation at codon 11 and missense mutations at codons 129, 131, and 208 lead to the description of three polymorphic alleles designated UGT1A72, UGT1A73, and UGT1A7*4.
UGT1A7 polymorphisms were analysed by polymerase chain reaction amplification and sequencing, as well as temperature gradient gel electrophoresis in 210 healthy blood donors and 78 subjects with colorectal cancer.
Homozygous wild-type UGT1A7 alleles were present in 20% of normal controls but were only detected in 9% of patients with colorectal carcinoma (odds ratio (OR) 0.39 (95% confidence interval (CI) 0.17-0.92); p=0.03). Analysis of individual polymorphic alleles identified a highly significant association between the presence of UGT1A7*3 alleles and colorectal cancer (OR 2.75 (95% CI 1.6 - 4.71); p<0.001). Recombinant expression of UGT1A7 polymorphic cDNA in eukaryotic cell culture showed reduced carcinogen glucuronidation activity in comparison with wild-type UGT1A7. UGT1A7 may therefore represent a modifier gene in colorectal carcinogenesis.
We have identified a potential novel risk factor in sporadic colorectal cancer which may contribute to the identification of risk groups and to the elucidation of factors involved in colon carcinogenesis.
已检测到人类尿苷二磷酸葡萄糖醛酸基转移酶-1A7（UGT1A7）基因的遗传多态性，且其与散发性结直肠癌显著相关。UGT1A7最近被证明可使环境致癌物葡萄糖醛酸化，现被认为是一种癌症风险基因。第11密码子处的沉默突变以及第129、131和208密码子处的错义突变导致了三种多态性等位基因的描述，分别命名为UGT1A72、UGT1A73和UGT1A7*4。
采用聚合酶链反应扩增和测序以及温度梯度凝胶电泳对210名健康献血者和78名结直肠癌患者的UGT1A7多态性进行分析。
纯合野生型UGT1A7等位基因在20%的正常对照中存在，但仅在9%的结直肠癌患者中检测到（优势比（OR）0.39（95%置信区间（CI）0.17 - 0.92）；p = 0.03）。对单个多态性等位基因的分析确定UGT1A7*3等位基因的存在与结直肠癌之间存在高度显著关联（OR 2.75（95% CI 1.6 - 4.71）；p < 0.001）。UGT1A7多态性cDNA在真核细胞培养中的重组表达显示，与野生型UGT1A7相比，致癌物葡萄糖醛酸化活性降低。因此，UGT1A7可能是结直肠癌发生过程中的一个修饰基因。
我们在散发性结直肠癌中发现了一个潜在的新危险因素，这可能有助于识别风险群体并阐明结肠癌发生所涉及的因素。
