Genetic Alterations in Lung Cancer

肺癌是男性和女性癌症相关死亡率的主要原因， 仍然是一个重大的健康问题。2015年将有超过162，000人死于肺癌。 超过乳腺癌、前列腺癌和结肠癌的总和。大多数肺癌 这些病例可归因于吸烟，在某些情况下还可归因于其他环境风险因素。 尽管吸烟者患肺癌的相对风险在吸烟者中显著下降， 戒烟后，以前的吸烟者仍然有患这种疾病的危险。最近的几项研究表明， 超过50%的新诊断的肺癌发生在以前的吸烟者中。据估计 在美国，吸烟者和前吸烟者的数量大致相等。以来 戒烟是一项重大的公共卫生举措， 占肺癌病例的比例更高。因此，两个高危人群 存在的肺癌和改善的疾病管理可以有利于目前和 前吸烟者染色体9 p遗传改变发生在肺癌早期且经常发生; 常见于p16/CDKN 2位点。然而，我们发现了一个纯合缺失区域， 在标记D9 S126处的染色体9 p的短臂，并提出了肿瘤的存在 在该区域的肺肿瘤发生中重要的抑制基因。我们继续分析 使用30个非小细胞肺癌和12个小细胞肺癌细胞系，通过用 55个遗传标记，以确定染色体9 p上纯合缺失的新区域。三 检测到新的非连续同源缺失区。其中一个地区在 D9 S126导致鉴定为TUSC 1的基因的鉴定。多重PCR和Southern杂交 印迹分析证实了TUSC 1的纯合缺失，北方印迹分析证实了TUSC 1的纯合缺失 证明了大约2和1.5 kb的两个转录本，它们可能是由 多聚腺苷酸化信号。这两种转录本都在几种人体组织中表达 并且共享编码209个氨基酸的肽的开放阅读框。分析肺癌 RNA和蛋白质表达的细胞系证明了在几个细胞中TUSC 1的下调。 进一步表明TUSC 1可能在肿瘤发生中起作用。使用肺肿瘤的研究 用TUSC 1稳定转染的细胞系显示出体外增殖降低和肿瘤生长减少。 体内形成。总之，这些数据表明，染色体9 p可能含有其他基因。 肿瘤抑制基因在肺肿瘤发生中的重要性，TUSC 1可能是候选肿瘤 抑制基因目前的研究将采用酵母双杂交实验，以确定 TUSC 1的潜在蛋白结合伴侣。这些交互将通过以下方式进行验证： 免疫沉淀，并将导致有关的途径，其中TUSC 1 互动。TUSC 1的抗体开发将提供必要的试剂来检查 多种人肺肿瘤中的表达水平，并确定原发性肿瘤中的表达水平。的 然后，表达水平可以与临床结果相关联，以进一步确定TUSC 1作为一种免疫调节剂。 肿瘤抑制基因

Lung cancer is the leading cause of cancer related mortality in both men and women and remains a major health issue. More than 162,000 individuals will die from lung cancer in the coming year, more than breast, prostate and colon cancer combined. The majority of lung cancer cases is attributable to tobacco smoking and in some cases other environmental risk factors. Although the relative risk of developing lung cancer declines dramatically in smokers who quit, former smokers remain at risk for the disease. Several recent studies show that greater than 50% of newly diagnosed lung cancers occur in former smokers. It is estimated that there are approximately equal numbers of smokers and former smokers in the United States. Since smoking cessation is a major public health initiative, former smokers will increasingly account for a higher percentage of lung cancer cases. Thus, two high-risk population groups exist for lung cancer and improved disease management can be beneficial to both current and former smokers. Chromosome 9p genetic alterations occur early and often in lung cancer; frequently at the p16/CDKN2 locus. However, we identified a region of homozygous deletion on the short arm of chromosome 9p at the marker D9S126 and proposed the existence of a tumor suppressor gene important in lung tumorigenesis in this region. We continued our analysis using 30 non-small cell lung cancer and 12 small cell lung cancer cell lines by screening with 55 genetic markers to identify new regions of homozygous deletion on chromosome 9p. Three novel non-contiguous homozygously deleted regions were detected. One of these regions at D9S126 led to the identification of a gene identified as TUSC1. Multiplex PCR and Southern blot confirmed the homozygous deletion of TUSC1 and Northern blot analysis of TUSC1 demonstrated two transcripts of approximately 2 and 1.5 kb that are likely generated by alternative polyadenylation signals. Both transcripts are expressed in several human tissues and share an open reading frame encoding a peptide of 209 amino acids. Analyzing lung cancer cell lines for RNA and protein expression demonstrated down regulation of TUSC1 in several cell lines further suggesting TUSC1 may play a role in tumorigenesis. Studies using lung tumor cell lines stably transfected with TUSC1 show reduced proliferation in vitro and reduced tumor formation in vivo. Taken together, these data suggest that chromosome 9p may contain other tumor suppressor genes important in lung tumorigenesis and that TUSC1 may be a candidate tumor suppressor gene. Current studies will employ yeast two hybrid experiments to determine potential protein binding partners for TUSC1. These interactions will be validated using immunoprecipitation and will lead to information concerning the pathways in which TUSC1 interacts. Antibody development for TUSC1 will provide the necessary reagents to examine multiple human lung tumors and determine the expression levels in the primary tumors. The expression levels can then be correlated to clinical outcome to further establish TUSC1 as a tumor suppressor gene.