Chromosome 5p aberrations are early events in lung cancer: implication of glial cell line-derived neurotrophic factor in disease progression
Chromosome 5p aberrations are early events in lung cancer: implication of glial cell line-derived neurotrophic factor in disease progression
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DOI：
10.1038/sj.onc.1208643
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发表时间：
2005-07-14
期刊：
影响因子：
8
通讯作者：
Lam, WL
中科院分区：
文献类型：
--
作者：
Garnis, C;Davies, JJ;Lam, WL
肺癌是世界上最广泛诊断的恶性肿瘤。了解早期疾病将有助于深入了解其发病机制。尽管事实上，前侵入性病变是具有挑战性的分离，并经常产生不足的DNA用于分析多个基因座，基因组亲。这种病变的定位将导致发现因果性遗传改变，否则可能被与肿瘤相关的总体不稳定性所掩盖。在这项研究中，我们报告了肺癌进展中染色体5p上多个早期遗传事件的鉴定。使用高分辨率的5p特异性基因组阵列，其中包含一个平铺路径的DNA片段的比较基因组杂交，9个新的最小区域的损失和收益被发现在支气管原位癌（CIS）标本。在这些区域内，我们确定了两个新的肺癌候选基因。5p15.2处的0.27 Mbp区域包含一个单一基因，即三重功能结构域，我们确定该基因在肿瘤中差异表达。5p13.2的0.34 Mbp区域含有胶质细胞系衍生的神经营养因子（GDNF），它是RET癌基因产物的配体，通常在肺发育过程中表达（但在成人肺组织中不表达）。我们的数据表明，GDNF不仅在转录水平上在鳞状非小细胞肺癌中过表达，而且GDNF蛋白存在于早期病变中。在早期病变中胎肺表达的GDNF的重新激活及其在CIS中的扩增表明在肿瘤发生中的早期作用。这些结果突出了在平铺分辨率下检查癌症的侵袭前阶段的基因组的价值。
Lung cancer is the most widely diagnosed malignancy in the world. Understanding early-stage disease will give insight into its pathogenesis. Despite the fact that pre-invasive lesions are challenging to isolate, and often yield insufficient DNA for the analysis of multiple loci, genomic pro. ling of such lesions will lead to the discovery of causal genetic alterations, which may be otherwise masked by the gross instability associated with tumors. In this study, we report the identification of multiple early genetic events on chromosome 5p in lung cancer progression. Using a high-resolution 5p-specific genomic array, which contains a tiling path of DNA segments for comparative genomic hybridization, nine novel minimal regions of loss and gain were discovered in bronchial carcinoma in situ (CIS) specimens. Within these regions we identified two candidate genes novel to lung cancer. The 0.27 Mbp region at 5p15.2 contains a single gene, Triple Functional Domain, which we determined to be differentially expressed in tumors. The 0.34 Mbp region at 5p13.2 contains Glial Cell Line-Derived Neurotrophic Factor (GDNF), which is a ligand for the RET oncogene product and is normally expressed during lung development (but absent in adult lung tissue). Our data showed not only that GDNF is overexpressed at the transcript level in squamous non-small-cell lung carcinoma, but also that the GDNF protein is present in early-stage lesions. Reactivation of the fetal lung expressed GDNF in early lesions and its amplification in CIS suggests an early role in tumorigenesis. These results highlight the value of examining the genomes of pre-invasive stages of cancer at tiling resolution.