Genetic Alterations in Lung Cancer

肺癌是男性和女性癌症相关死亡的主要原因，并且仍然是一个主要的健康问题。明年将有超过16万人死于肺癌，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。虽然戒烟者患肺癌的相对风险大幅下降，但前吸烟者仍有患肺癌的风险。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。在前吸烟者中发现的肿瘤中，近50%发生在戒烟超过五年的患者中。据估计，在美国，吸烟者和前吸烟者的人数大致相同。由于戒烟是一项重大的公共卫生举措，因此前吸烟者在肺癌病例中所占的比例将越来越高。因此，存在两个肺癌高危人群，改善疾病管理对当前和以前的吸烟者都有益。此外，肺癌患者的预后非常差，总体5年生存率仅为14%。肺癌患者预后不良的部分原因是历史上缺乏有效的早期检测措施。染色体9 p上的肿瘤支持基因（TSG）：染色体9 p缺失和改变发生在肺癌的早期和经常发生。p16/CDKN 2位点位于9 p，被怀疑是该肿瘤类型中失活的主要抑癌基因。然而，我们以前已经确定了一个区域的纯合性缺失的短臂染色体9 p的微卫星标记D9 S126。检测到的最小缺失区域约为600 Kb，与p16/CDKN 2肿瘤抑制基因位点不同，位于近端约2 cM处。我们提出，该地区窝藏TSG在肺肿瘤发生的重要。我们通过免疫组化进一步分析了p16在肺腺癌和鳞状细胞癌中的表达，并利用跨越9号染色体短臂的微卫星标记分析了这些肿瘤的亚群的杂合性丢失（洛）。免疫组化结果显示，腺癌p16蛋白阳性率高于鳞癌。杂合性丢失分析表明，p16阳性和阴性鳞状细胞癌之间的丢失模式相似。然而，在p16阳性的腺癌和鳞状细胞癌之间的洛分析中，在某些标志物上存在中度显著差异。最近，用55个标记筛选了30个非小细胞肺癌和12个小细胞肺癌细胞系，以鉴定染色体9 p上纯合缺失的新区域。检测到三个新的非连续同源性缺失区域，大小范围从840 Kb到7.4 Mb。这些区域之一包括标记D9 S126，并且在缺失中鉴定的一个基因是TUSC 1。多重PCR和Southern杂交证实了TUSC 1基因的纯合性缺失。TUSC 1的北方印迹分析证明了两个大约2和1.5 kb的转录本，它们可能是由备选的多聚腺苷酸化信号产生的。这两种转录物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。分析肺癌细胞系的RNA和蛋白质表达表明，TUSC 1在几种细胞系中下调，表明TUSC 1可能在肿瘤发生中起作用。

Lung cancer is the leading cause of cancer related mortality in both men and women and remains a major health issue. More than 160,000 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. Of the tumors detected in former smokers, nearly 50% occurred in patients who had quit for more than five years. 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. Additionally the prognosis for lung cancer patients is very poor, as reflected by an overall, 5-year survival rate of only 14%. The poor prognosis for lung cancer patients is due, in part, to the historical lack of effective early detection measures. TUMOR SUPPRESSOR GENES (TSG) ON CHROMOSOME 9P: Chromosome 9p deletions and alterations occur early and often in lung cancer. The p16/CDKN2 locus, located on 9p, is suspected to be the major tumor suppressor gene inactivated in this tumor type. However, we have previously identified a region of homozygous deletion on the short arm of chromosome 9p at the microsatellite marker D9S126. The minimal region of deletion detected was approximately 600 Kb, is distinct from the p16/CDKN2 tumor suppressor gene locus, and lies approximately 2 cM proximal. We proposed that the region harbors a TSG important in lung tumorigenesis. We furthered our analysis by using immunohistochemistry to analyze the expression of p16 in adenocarcinomas and squamous cell carcinomas of the lung and subsets of these tumors were analyzed for loss of heterozygosity (LOH) with microsatellite markers spanning the short arm of chromosome 9. The immunohistochemistry revealed a significant difference in the percent of tumors positive for p16 with the adenocarcinomas having a higher percentage of positive staining than the squamous cell carcinomas. Loss of heterozygosity analysis demonstrated that the pattern of loss was similar between p16 positive and negative squamous cell carcinomas. However, there were moderately significant differences in the LOH analysis between p16 positive adenocarcinomas and squamous cell carcinomas at some of the markers. More recently, 30 non-small cell lung cancer and 12 small cell lung cancer cell lines were screened with 55 markers to identify new regions of homozygous deletion on chromosome 9p. Three novel non-contiguous homozygously deleted regions were detected and ranged in size from 840 Kb to 7.4 Mb. One of these regions included the marker D9S126 and one gene identified in the deletion was TUSC1. Multiplex PCR and Southern blot confirmed the homozygous deletion of TUSC1. 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 suggesting TUSC1 may play a role in tumorigenesis.