IDENTIFICATION OF 3P RECESSIVE ONCOGENES IN LUNG CANCER

肺癌中 3P 隐性癌基因的鉴定

• 批准号: 6198625
• 负责人: JOHN D. MINNA
• 金额: $ 30.87万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-08 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6198625
• 关键词: SCID mouse; alleles; athymic mouse; cell line; clinical research; cytogenetics; fluorescent in situ hybridization; gene deletion mutation; gene expression; genetic mapping; genetic markers; genetic polymorphism; genetic susceptibility; human genetic material tag; human tissue; loss of heterozygosity; lung neoplasms; neoplasm /cancer genetics; neoplastic growth; nucleic acid sequence; open reading frames; polymerase chain reaction; preneoplastic state; telomerase; tumor suppressor genes

Recessive oncogenes (tumor suppressor genes, TSGs) play a major role in the pathogenesis of human lung cancel Currently, chromosome region 3p is the most frequently involved site exhibiting allele loss in lung cancer suggesting the location of one or more new TSGs. Allelotyping evidence suggests several 3p distinct putative TSGs sites located at 3p25 (VHL and others), 3p2l .3 (two sites), 3pl4.2 (FHIT/FRA3B), and 3pl2-l3. Studies of preneoplasia indicate the loss of 3p alleles is the earliest alteration known in preneoplastic lesions and even some histologically normal epithelium of smokers. The timing suggests one or more 3p recessive oncogenes function as "gatekeepers" in the molecular pathogenesis of lung cancer. We want to identify all of these genes and translate this information into the clinic to aid in early diagnosis, monitoring of chemoprevention, and potentially as a base for developing new therapies. The specific aims of this project are: (l) isolate a new lung cancer related TSG(s) in the lung cancer 3p2l .3 homozygous deletion region and to test for mutations in candidate genes in lung cancer and preneoplastic lesions; (2) test if the growth properties of lung cancer cell lines suggesting malignancy are altered following the introduction of specific candidate 3p TSGs as well as portions of chromosome 3p; and (3) test if telomerase activity can be repressed in lung cancer cells following the introduction specific candidate 3p TSGs as well as portions of chromosome 3p. The ultimate translational goals are to apply this information to develop new methods for identification of genetic changes in preneoplastic lesions for very early lung cancer diagnosis; use as surrogate molecular markers in chemoprevention trials; search for genetic predisposition via germline mutations in the gene; and potentially to develop tumor specific therapy. Thus, this project interacts with Project #2 (Genetic Susceptibility to Lung Cancer), Project #3 (Molecular early Detection of Lung Cancer) and Project #4 (Chemoprevention of Lung Cancer). We have made substantial progress on all of the aims particularly the discovery of multiple genes with some mutations, several genes with growth suppressing and apoptotic inducing activity, #3 microcell hybrids with growth suppression, and the discovery of multiple breakpoints in the region in cancers, preneoplastic lesions, and normal epithelium. These precise 3p21 .3 breakpoints are the same as those seen as risk factors in BPDE treated lymphocytes of lung cancer patients and thus provide a tie between target and peripheral tissues.

隐性癌基因（tumor suppressor genes, TSGs）在人类肺癌的发病机制中起着重要作用。目前，染色体区域3p是肺癌中最常发生等位基因丢失的位点，提示存在一个或多个新的TSGs。等位型证据表明，在3p25 （VHL和其他），3p21上有几个不同的3p推测TSGs位点。3（两个位点），3pl4.2 （FHIT/FRA3B）和3pl2-l3。对肿瘤前病变的研究表明，3p等位基因的缺失是已知的最早的肿瘤前病变，甚至是吸烟者的一些组织学正常上皮的改变。这个时间提示一个或多个3p隐性癌基因在肺癌的分子发病机制中起着“守门人”的作用。我们想要识别所有这些基因，并将这些信息转化为临床，以帮助早期诊断，监测化学预防，并潜在地作为开发新疗法的基础。本课题的具体目的是：(1)在肺癌3p2l中分离一个新的肺癌相关TSG(s)。3纯合缺失区，检测肺癌和肿瘤前病变候选基因的突变；(2)检测在引入特异性候选3p TSGs和部分3p染色体后，提示肺癌细胞系的生长特性是否发生改变；(3)检测引入特异性候选3p TSGs和部分染色体3p后，肺癌细胞端粒酶活性是否受到抑制。最终的转化目标是应用这些信息来开发新的方法来识别肿瘤前病变的遗传变化，以用于早期肺癌的诊断；在化学预防试验中用作替代分子标记物；通过基因的种系突变寻找遗传倾向；并有可能开发出肿瘤特异性治疗方法。因此，该项目与项目2（肺癌遗传易感性）、项目3（肺癌分子早期检测）和项目4（肺癌化学预防）相互作用。我们在所有目标上都取得了重大进展，特别是发现了具有某些突变的多个基因，一些具有生长抑制和诱导凋亡活性的基因，具有生长抑制的3号微细胞杂交，以及在癌症，肿瘤前病变和正常上皮中发现了多个断点。这些精确的3p21。3个断点与BPDE治疗的肺癌患者淋巴细胞中被视为危险因素的断点相同，从而在靶组织和外周组织之间提供了联系。