MOLECULAR CYTOGENETIC STUDY OF LUNG CANCER

这项研究是基于流行病学，分子和细胞遗传学数据，从一个正在进行的病例对照研究肺癌在少数民族人口。基于量化博莱霉素诱导的染色单体断裂的诱变剂敏感性与肺癌风险显著增加相关。我们还报道了这些断裂似乎优先发生在5号染色体上。我们现在计划使用中期制备物、培养的肿瘤细胞、石蜡切片和已经处理和储存的冷冻肿瘤组织将外周淋巴细胞的这些细胞遗传学发现扩展到靶（肺）组织。具体目标是： 1)比较60例肺癌患者5号染色体上的淋巴细胞与肺癌组织及癌旁正常肺组织配对标本的染色体涂染探针和Sq.工作假设是Sq对诱变损伤的偏好可能是肺癌易感性的标志。 2)为了证实我们的初步发现，Sq畸变的细胞在病例组的存活率明显高于对照组，我们用5号染色体全涂探针对100例肺癌病例和100例频率匹配的对照进行了检测。正在测试的假设是，只有那些包含重要基因的位点并在靶组织中继续存活和增殖的断裂点才可能导致肿瘤转化。 3)通过将流行病学数据与细胞遗传学、分子细胞遗传学和分子遗传学（包括代谢多态性）数据相结合，评估我们在特定目标1和2中的发现与吸烟、职业暴露、家族史和肺癌风险之间的关联。我们将检验具有一个或多个易感遗传特征和相关致癌暴露的个体患癌风险增加的假设。长期目标是进一步了解诱变剂敏感性的机制及其在肺癌发生中的意义。

This study is based upon the epidemiologic, molecular and cytogenetic data from an ongoing case-control study of lung cancer in minority populations. Mutagen sensitivity, based on quantifying bleomycin-induced chromatid breaks, was associated with significantly increased lung cancer risk. We have also reported that these breaks seem to occur preferentially on chromosome 5. We now plan to extend these cytogenetic findings in peripheral lymphocytes to target (lung) tissue using metaphase preparations, cultured tumor cells, paraffin sections, and frozen tumor tissue which have already been processed and stored. The specific aims are: 1) To compare paired specimens of lung tumor and adjacent normal tissue with lymphocytes from 60 lung cancer patients to assess concordance of abnormalities on chromosome 5 using chromosome painting probes as well as with PCR-based microsatellite repeat polymorphism (MSRP) assay on Sq. The working hypothesis is that the predilection of Sq to mutagenic damage may be a marker of susceptibility to lung cancer. 2) To confirm our preliminary findings that the survival rate of cells with Sq aberrations in cases is significantly higher than that in controls, using whole chromosome 5 painting probe in 100 lung cancer cases and 100 frequency matched controls. The hypothesis being tested is that only those breakpoints that contain the loci of important genes and continue to survive and proliferate in the target tissue could contribute to neoplastic transformation. 3) To assess the associations between our findings from specific aims 1 and 2 with cigarette smoking, occupational exposure, family history and lung cancer risk by integrating epidemiologic data with the cytogenetic, molecular cytogenetic and molecular genetic (including metabolic polymorphism) data. We will test the hypothesis that cancer risk is increased in individuals who have one or more susceptible genetic trait and the relevant carcinogenic exposures. The long term goal is to further the understanding of the mechanism of mutagen sensitivity and its implication for lung carcinogenesis.