食管癌遗传易感性分子基础的探讨
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摘要
食管癌(esophageai cancer，EC)是我国的—种常见肿瘤，尤其是在北方某些地区EC发病率是世界上最高的。多年来对EC的发病原因进行了大量的研究工作，调查显示EC具有独特的流行学特征，如明显的地区分布差异和家族聚集现象等。目前认为EC的发生是遗传因素和环境因素共同作用的结果。我室前期工作已经证实除EC具有明显的家族聚集现象外，EC患者及其血缘亲属表现出明显的遗传不稳定性和DNA修复能力低下，胡楠等对221个EC核心家族的分析提示人类基因组中存在潜在的EC易感基因。EC高发区调查还显示，环境中亚硝胺含量较高是EC发生的主要因素之一。亚硝胺是一种烷化剂，可作用于DNA分子形成各种烷基加成物，其中O~(5-)烷基鸟嘌吟被认为是主要的致癌致突变前损伤。O~(5-)甲基鸟嘌呤-DNA甲基转移酶(O~(6-)methy Lguanine-DNA methyltransfersae，MGMT)是一种DNA修复酶，可特异性地修复烷化的碱基。据报道EC高发区居民食管上皮DNA中O~(6-)甲基鸟嘌呤明显升高，这就提出一个问题：升高的O~(6-)甲基鸟嘌呤是遗传性MGMT功能降低造成的?还是环境中亚硝胺作用的结果?或两者皆有?为此，我们用PCR-SSCP及直接测序技术以及Southern Bloc和Western Blot法，对6个EC高危家族成员的淋巴细胞和70例EC组织(40例石蜡包埋组织和30例新鲜组织)的MGMT基因进行了分析。
Esophageal Cancer(EC) is a very common disease in many areas of China. The reported mortality rates in North China are the highest in the world. A nationwide survey of mortality identified EC as the second most common cause of cancer death in China.
Over the past two decades, many studies have been conducted on the etiologic factors associated with EC. Our previous work had demonstrated that EC patients and their blood-relatives showed genetic instability and DNA repair defects caused by N-nitroso-compounds and other genotoxic agents. Surveys in high EC areas suggested that many of EC patients had family history and some autosomal recessive (and even dominant) genes might play an important role in the EC pathogenesis.
Epidemiologic studies in China have implicated environmental factors in the etiology of EC. One of the main factors is the exposure of the inhabitants living in these areas to high level nitroso-compounds. N-nitroso-compounds are alkylating agents that can produce various alkyladducts in DNA and induce tumors directly in experimental animals. Among those. O~6-alklguanine appears to be primarily
Esophageal Cancer(EC) is a very common disease in many areas of China. The reported mortality rates in North China are the highest in the world. A nationwide survey of mortality identified EC as the second most common cause of cancer death in China.
Over the past two decades, many studies have been conducted on the etiologic factors associated with EC. Our previous work had demonstrated that EC patients and their blood-relatives showed genetic instability and DNA repair defects caused by N-nitroso-compounds and other genotoxic agents. Surveys in high EC areas suggested that many of EC patients had family history and some autosomal recessive (and even dominant) genes might play an important role in the EC pathogenesis.
Epidemiologic studies in China have implicated environmental factors in the etiology of EC. One of the main factors is the exposure of the inhabitants living in these areas to high level nitroso-compounds. N-nitroso-compounds are alkylating agents that can produce various alkyladducts in DNA and induce tumors directly in experimental animals. Among those. O~6-alklguanine appears to be primarily
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