Genetics Unit, Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
PLoS One. 2010 Feb 11;5(2):e9162. doi: 10.1371/journal.pone.0009162.
Non-small cell lung cancer (NSCLC) presents as a progressive disease spanning precancerous, preinvasive, locally invasive, and metastatic lesions. Identification of biological pathways reflective of these progressive stages, and aberrantly expressed genes associated with these pathways, would conceivably enhance therapeutic approaches to this devastating disease.
METHODOLOGY/PRINCIPAL FINDINGS: Through the construction and analysis of SAGE libraries, we have determined transcriptome profiles for preinvasive carcinoma-in-situ (CIS) and invasive squamous cell carcinoma (SCC) of the lung, and compared these with expression profiles generated from both bronchial epithelium, and precancerous metaplastic and dysplastic lesions using Ingenuity Pathway Analysis. Expression of genes associated with epidermal development, and loss of expression of genes associated with mucociliary biology, are predominant features of CIS, largely shared with precancerous lesions. Additionally, expression of genes associated with xenobiotic metabolism/detoxification is a notable feature of CIS, and is largely maintained in invasive cancer. Genes related to tissue fibrosis and acute phase immune response are characteristic of the invasive SCC phenotype. Moreover, the data presented here suggests that tissue remodeling/fibrosis is initiated at the early stages of CIS. Additionally, this study indicates that alteration in copy-number status represents a plausible mechanism for differential gene expression in CIS and invasive SCC.
CONCLUSIONS/SIGNIFICANCE: This study is the first report of large-scale expression profiling of CIS of the lung. Unbiased expression profiling of these preinvasive and invasive lesions provides a platform for further investigations into the molecular genetic events relevant to early stages of squamous NSCLC development. Additionally, up-regulated genes detected at extreme differences between CIS and invasive cancer may have potential to serve as biomarkers for early detection.
非小细胞肺癌（NSCLC）表现为一种进行性疾病，跨越癌前病变、癌前浸润、局部浸润和转移病变。鉴定反映这些进行性阶段的生物途径以及与这些途径相关的异常表达基因，可能会增强对这种毁灭性疾病的治疗方法。
方法/主要发现：通过构建和分析 SAGE 文库，我们确定了肺癌原位癌（CIS）和浸润性鳞状细胞癌（SCC）的转录组图谱，并使用 Ingenuity 通路分析将这些图谱与支气管上皮和癌前化生和发育不良病变的表达图谱进行比较。与表皮发育相关的基因表达和与粘液纤毛生物学相关的基因表达缺失是 CIS 的主要特征，与癌前病变有很大的共同之处。此外，与异生物质代谢/解毒相关的基因表达是 CIS 的显著特征，在浸润性癌中也得到了很大的维持。与组织纤维化和急性期免疫反应相关的基因是侵袭性 SCC 表型的特征。此外，这里提出的数据表明，组织重塑/纤维化是在 CIS 的早期阶段开始的。此外，本研究表明，拷贝数状态的改变代表了 CIS 和浸润性 SCC 中差异基因表达的一种可能机制。
结论/意义：这是首次对肺 CIS 进行大规模表达谱分析的报道。对这些癌前和浸润性病变进行无偏表达谱分析，为进一步研究与非小细胞鳞状 NSCLC 早期发展相关的分子遗传事件提供了平台。此外，在 CIS 和浸润性癌之间差异极大的上调基因可能具有作为早期检测生物标志物的潜力。
