GENETIC ALTERATIONS AT MULTIPLE LOCI IN PRE-INVASIVE BRONCHIAL LESIONS

肺癌是美国和西方国家死亡的主要原因。 欧洲 目前，肺癌的诊断依赖于以下症状： 咳嗽、咯血和痰液生成，以及常规胸部X线检查， ray. 这种方法主要导致肺癌的诊断， 晚期疾病，其中至少三分之二的患者 临床可检测的区域淋巴结或远处转移。 因此本 不能依赖症状诊断策略来检测肺癌 在疾病的晚期，至少三分之二的患者 有临床可检测的区域淋巴结或远处转移。 因此，我们认为， 这种症状诊断策略不能依赖于检测肺 癌症处于早期和更容易治愈的阶段。 最近的几项研究 利用痰细胞学和支气管镜检查的现代技术， X线表现为肺部早期肿瘤。 我们建议探讨 遗传分析结合形态分析的可能性 可以增强肺癌可治愈阶段的检测， 形态学。 为了确定适当的基因测定， 将在多个位点分析肺癌的主要组织学亚型 以前与肺癌发生有关。 然后是癌前病变 将分析基因改变的组合， 在肿瘤DNA中经常检测到。 这些结果将用于设计 基因检测分析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研究机构合作进行。 在科罗拉多孢子的调查人员以及在他 约翰霍普金斯孢子。 我们已经开始分析一组44个鳞状细胞 细胞肿瘤的各种基因改变。 9号染色体分析 19个微卫星标记在分析的23个肿瘤中的22个中显示洛缺失， 约会 我们还在23个肿瘤中的14个中检测到纯合缺失。 23个肿瘤中有12个在D9 S126处含有纯合性缺失 23例中有10例含有D9 S165/263纯合缺失。 在D9 S126和D9 S165/263处的离散纯合缺失尚未被证实。 以前在肺肿瘤中报道过。 我们已经开始显微解剖 这些肿瘤的癌前病变，迄今已检测到洛合性缺失 在9号染色体上，5例增生中有2例，4例中度发育不良中有3例， 原位癌2例。 在这个实验中要检验的假设 建议是，改进的方法，检测癌前病变， 呼吸道粘膜将导致早期干预和改善 肺癌患者的生存率。 我们的目标是分析 基因改变和时间序列的事件，发生在 人类肺肿瘤的发展，以确定之间的关联， 突变事件和细胞凋亡，并进一步评估临床 支气管镜和纤维支气管镜检查中异型细胞和突变的意义 标本 对所有高血压患者进行支气管镜检查并不划算。 被诊断为中度/明显发育不良的危险患者; 然而，大约5%的中度/显著性前列腺炎患者 诊断谁已经有肿瘤将受益于立即检测， 支气管镜定位和后续治疗。

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.