GENETIC ALTERATIONS AT MULTIPLE LOCI IN PRE-INVASIVE BRONCHIAL LESIONS

肺癌是美国和西方国家的头号死因 欧洲。目前，肺癌的诊断依赖于 咳嗽、咯血、咳痰，以及常规的胸部X- 雷。这种方法主要导致对#年肺癌的诊断。 疾病的晚期，至少三分之二的患者有 临床上可检测到的区域结节或远处转移。因此，这 不能依靠对症诊断策略来检测肺癌 在疾病的晚期，至少三分之二的患者 有临床可检测到的区域结节或远处转移。因此， 不能依靠这种症状诊断策略来检测肺部 癌症处于早期和更可治愈的阶段。最近的几项研究 利用现代痰细胞学和支气管镜检查技术检测 X线隐匿性肺早期肿瘤。我们建议探讨 基因分析与形态分析相结合的可能性 可以提高对肺癌可治愈阶段的检测 仅仅是形态上的。为了确定适当的遗传分析， 肺癌的主要组织学亚型将在多个部位进行分析 此前曾被认为与肺癌的发生有关。然后是癌前病变 将对这些基因改变的组合进行分析 经常在肿瘤DNA中检测到。这些结果将被用于设计 用遗传分析方法分析痰和支气管镜检查中的非典型细胞 标本。这些基因分析将与其他 科罗拉多孢子菌的调查人员以及他与调查人员的合作 约翰霍普金斯大学的孢子。我们已经开始分析一组44个鳞片 细胞肿瘤的各种基因改变。9号染色体的分析 19个微卫星标记在分析的23个肿瘤中有22个显示杂合性缺失 约会。我们还在23个肿瘤中的14个检测到纯合子缺失。 23例肿瘤中有12例存在D9S126纯合子缺失 23例中有10例在D9S165/263有纯合子缺失。 D9S126和D9S165/263的离散纯合子缺失尚未 此前报道的是肺部肿瘤。我们已经开始显微解剖 这些肿瘤的癌前病变，到目前为止已经检测到LOH 位于9号染色体上的5例增生症中2例，4例中度不典型增生中3例，2例 2例原位癌病变。这里要检验的假设是 建议改进检测癌前病变的方法 呼吸道粘膜将导致早期干预和改善 肺癌患者的存活率。我们的目标是分析组合 关于基因改变和发生在 人类肺癌的发展，以确定两者之间的关联 突变事件和细胞异型性，并进一步评估临床 痰和支气管镜检查中非典型细胞和突变的意义 标本。做支气管镜检查并非完全符合成本效益 痰被诊断为中度/显著异型增生的高危患者； 然而，这些患者中约5%的患者有中度/明显的痰 已经患有肿瘤的诊断将受益于立即检测和 支气管镜定位及后续治疗。

Lung cancer is the leading cause of death in the United States and Western Europe. Currently, the diagnosis of lung cancer relies on the symptoms of cough, hemoptysis and production of sputum, and the conventional chest x- ray. This approach mainly results in the diagnosis of lung cancer in advanced stages of disease where at least two thirds of the patients have clinically detectable regional node or distant metastases. Therefore, this symptomatic diagnosis strategy cannot be relied upon to detect lung cancer in advanced stages of disease where at least two-thirds of the patients have clinically detectable regional node or distant metastases. Therefore, this symptomatic diagnosis strategy cannot be relied upon to detect lung cancer in its early and more curable stages. Several recent studies utilized modern techniques of sputum cytology and bronchoscopy to detect x-ray occult lung early stage tumors. We propose to explore the possibility that genetic analysis in conjunction with morphologic analysis can enhance the detection of curable stages of lung cancer compared to morphology alone. To determine the appropriate genetic assays, sets of the major histologic subtypes of lung cancer will be analysis at multiple loci previously implicated in lung carcinogenesis. Then premalignant lesions will be analyses for the combinations of the genetic alterations which were frequently detected in the tumor DNA. These results will be used to design genetic assays to analyze atypical cells in sputa and bronchoscopy specimens. These genetic analyses will be done in collaboration with other investigators in the Colorado SPORE as well as with investigators int he Johns Hopkins SPORE. We have begun to analyze a set of forty-four squamous cell tumors for the various genetic alterations. Analysis of chromosome 9 and 19 microsatellite markers showed LOH in 22 of the 23 tumors analyzed to date. We have also detected a homozygous deletion in 14 of the 23 tumors. Twelve of the twenty-three tumors contained a homozygous deletion at D9S126 and ten of the twenty-three contained a homozygous deletion at D9S165/263. Discrete homozygous deletions at D9S126 and D9S165/263 have not been previously reported in lung tumors. We have begun to microdissect preneoplastic lesions from these same tumors and to date have detected LOH on chromosome 9 in 2 of 5 hyperplasias, 3 of 4 moderate dysplasias, and 2 of 2 carcinoma in situ lesions. The hypothesis to be tested in this proposal is that improved methods of detection of preneoplastic changes in respiratory mucosa will result in earlier intervention and improved survival in lung cancer patients. The goals are to analyze the combination of genetic alterations and temporal sequence of events that occur in the development of human lung tumors, to determine the association between the mutational events and cellular atypia, and to further evaluate the clinical significance of atypical cells and mutations in sputa and bronchoscopic specimens. It is not cost effective to perform bronchoscopy on all high risk patients whose sputa are diagnosed as moderate/marked dysplasia; however, the approximate 5% of these patients with moderate/marked sputa diagnosis who already have a tumor would benefit by immediate detection and localization by bronchoscopy and subsequent treatment.