Genetic changes in the pathogenesis of lung cancer

在本研究中，我们对人类肺癌的分子发病机制进行了多方面的研究。结果得到以下结果：(1)肺癌发病相关基因的鉴定：我们在17p13.3的缺失区域发现了一个纯合子缺失，提示在该基因组区域可能存在一个肿瘤抑制基因。已鉴定的纯合子缺失区域被YAC和BAC覆盖。到目前为止，一个与G2检查点相关的基因已经被确定，并正在检查肺癌中是否存在突变。本研究中调查的另一个问题是“有丝分裂检查点”。我们发现，多达40%的肺癌细胞系存在有丝分裂检查点损伤。此外，发现MAD-1有丝分裂检查点基因在肺癌中发生了低频率的突变。(2)新的转移相关基因Caspin/PEDF被研究了新的丝氨酸基因Caspin/PEDF在转移中的功能。将人Caspin/PEDF基因导入高转移性肺癌细胞系H460Lu，可减少肺血行转移，显示其抑制转移的有效性。分子流行病学分析：分子流行病学研究旨在探讨谷胱甘肽过氧化物酶和多巴胺D4受体(DRD4)基因多态性与吸烟行为或肺癌发生的可能关系。然而，我们发现，基因型与吸烟行为或肺癌发生的风险之间没有显著的相关性。

In the present study, we investigated various aspects of the molecular pathogenesis of human lung cancers. Consequently, the following results were obtained.(1) Identification of genes involved in the pathogenesis of lung cancers.We identified a homozygous deletion within a commonly deleted region at 17p 13.3, suggesting the presence of a putative tumor suppressor gene in this particular genomic region. The identified homozygously deleted region was covered by YACs and BACs. To date, a G2 checkpoint-related gene has been identified and is being examined for the presence of mutations in lung cancers.The other issue investigated in the present study was "mitotic checkpoint". We found that mitotic checkpoint impairment is present in up to 40% of lung cancer cell lines. Furthermore, MAD 1 mitotic checkpoint gene was found to be mutated in lung cancers, although at low frequency.(2) Novel metastasis related gene, CASPIN/PEDF.Functional role of a novel serpin gene, CASPIN/PEDF, was investigated in relation to metastasis. Introduction of human CASPIN/PEDF cDNA into a highly metastatic lung cancer line, H460Lu was found to reduce hematogenous metastases to the lung, showing its potency in the repression of metastasis. Together with its chromosomal assignment to 17p 13.3, this finding warrants further investigation of its involvement in the progression of lung cancers.(3) Molecular epidemiological analyses.Molecular epidemiological studies were conducted to examine possible relationship of genetic polymorphisms of the glutathione peroxydase and dopamine D4 receptor (DRD4) genes with risk for the acquisition of smoking behavior or the occurrence of lung cancer. We, however, found no significant correlations between genotypes and risk for smoking behavior or lung cancer occurrence.