Genetic Alterations in Lung Cancer

肺癌的基因改变

• 批准号: 7291820
• 负责人: Jonathan Scott Wiest
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7291820
• 关键词: Genetic; Alterations; Lung; Cancer

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.

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 160,000 人死于肺癌，比乳腺癌、前列腺癌和结肠癌的总和还多。大多数肺癌病例可归因于吸烟，在某些情况下还归因于其他环境危险因素。尽管戒烟者患肺癌的相对风险显着下降，但戒烟者仍然面临患肺癌的风险。最近的几项研究表明，超过 50% 的新诊断肺癌发生在戒烟者身上。在戒烟五年以上的患者中发现的肿瘤中，近 50% 发生在戒烟五年以上的患者身上。据估计，美国吸烟者和戒烟者的数量大致相等。由于戒烟是一项重大的公共卫生举措，因此戒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。 9P 染色体上的肿瘤抑制基因 (TSG)：9p 染色体缺失和改变经常发生在肺癌早期。位于 9p 的 p16/CDKN2 基因座被怀疑是该肿瘤类型中失活的主要肿瘤抑制基因。然而，我们之前在 9p 染色体短臂上的微卫星标记 D9S126 处发现了一个纯合缺失区域。检测到的最小缺失区域约为 600 Kb，与 p16/CDKN2 肿瘤抑制基因位点不同，位于近端约 2 cM。我们提出该区域含有对肺部肿瘤发生很重要的 TSG。我们通过使用免疫组织化学来分析 p16 在肺腺癌和鳞状细胞癌中的表达，并使用跨越 9 号染色体短臂的微卫星标记来分析这些肿瘤子集的杂合性丢失 (LOH)。免疫组织化学揭示了 p16 阳性肿瘤的百分比与 p16 阳性肿瘤的百分比存在显着差异。 腺癌比鳞状细胞癌具有更高的阳性染色百分比。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，p16 阳性腺癌和鳞状细胞癌之间的 LOH 分析在某些标志物上存在中等显着差异。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 9p 染色体上纯合缺失的新区域。检测到三个新的非连续纯合缺失区域，大小范围为 840 Kb 至 7.4 Mb。这些区域之一包括标记 D9S126，并且在删除中鉴定出的一个基因是 TUSC1。多重PCR和Southern印迹证实了TUSC1的纯合缺失。 TUSC1 的 Northern 印迹分析表明，两个大约 2 kb 和 1.5 kb 的转录物可能是由替代多腺苷酸化信号产生的。两种转录物均在多种人体组织中表达，并共享编码 209 个氨基酸肽的开放阅读框。分析肺癌细胞系的 RNA 和蛋白质表达表明 TUSC1 在几种细胞系中下调，表明 TUSC1 可能在肿瘤发生中发挥作用。