IDENTIFICATION OF 3P RECESSIVE ONCOGENES IN LUNG CANCER

隐性癌基因(TSGs)在目前人类肺癌的发病机制中起主要作用，染色体3p区是肺癌中最常见的等位基因缺失部位，提示存在一个或多个新的TSGs。等位基因分型证据表明，在3p25(VHL和其他)、3p21.3(两个位点)、3pl4.2(FHIT/FRA3B)和3pl2-L3处有几个不同的推测的TSGS位点。对癌前病变的研究表明，3p等位基因的丢失是已知的癌前病变中最早的改变，甚至在吸烟者的一些组织正常上皮中也是如此。这一时机表明，一个或多个3p隐性癌基因在肺癌的分子发病机制中发挥着“把关人”的作用。我们希望识别所有这些基因，并将这些信息转化到临床上，以帮助早期诊断、监测化学预防，并可能作为开发新疗法的基础。本项目的具体目标是：(1)在肺癌3p21.3纯合子缺失区域分离出一个新的肺癌相关TSG(S)，并检测与肺癌和癌前病变相关的候选基因的突变；(2)检测导入特定候选3p TSG以及染色体3p的部分区域后，肺癌细胞系恶性转化的生长特性是否发生变化；以及(3)检测引入特异候选3p TSGs和染色体3p的部分区域后，是否能抑制肺癌细胞的端粒酶活性。最终的翻译目标是应用这些信息来开发新的方法来识别癌前病变中的基因变化，用于肺癌的早期诊断；在化学预防试验中用作替代分子标记；通过基因的胚系突变来寻找遗传易感性；以及潜在地开发肿瘤特异性治疗。因此，该项目与项目#2(肺癌的遗传易感性)、项目#3(肺癌的分子早期检测)和项目#4(肺癌的化学预防)相互作用。我们在所有目标上都取得了实质性的进展，特别是发现了具有某些突变的多个基因，几个具有生长抑制和诱导凋亡活性的基因，#3具有生长抑制的微细胞杂交，以及在癌症、癌前病变和正常上皮中发现了该区域的多个断裂点。这些精确的3p21.3断裂点与肺癌患者经BPDE治疗的淋巴细胞中的危险因素相同，因此在靶组织和外周组织之间提供了联系。

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.