Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, United Kingdom.
Tumor Genomics Unit, Milan, Italy.
EBioMedicine. 2015 Jul 8;2(8):831-40. doi: 10.1016/j.ebiom.2015.07.001. eCollection 2015 Aug.
Although screening programmes of smokers have detected resectable early lung cancers more frequently than expected, their efficacy in reducing mortality remains debatable. To elucidate the biological features of computed tomography (CT) screening detected lung cancer, we examined the mRNA signatures on tumours according to the year of detection, stage and survival.
Gene expression profiles were analysed on 28 patients (INT-IEO training cohort) and 24 patients of Multicentre Italian Lung Detection (MILD validation cohort). The gene signatures generated from the training set were validated on the MILD set and a public deposited DNA microarray data set (GSE11969). Expression of selected genes and proteins was validated by real-time RT-PCR and immunohistochemistry. Enriched core pathway and pathway networks were explored by GeneSpring GX10.
A 239-gene signature was identified according to the year of tumour detection in the training INT-IEO set and correlated with the patients' outcomes. These signatures divided the MILD patients into two distinct survival groups independently of tumour stage, size, histopathological type and screening year. The signatures can also predict survival in the clinically detected cancers (GSE11969). Pathway analyses revealed tumours detected in later years enrichment of the PI3K/PTEN/AKT pathway, with up-regulation of PDPK1, ITGB1 and down-regulation of FOXO1A. Analysis of normal lung tissue from INT-IEO cohort produced signatures distinguishing patients with early from late detected tumours.
The distinct pattern of "indolent" and "aggressive" tumour exists in CT-screening detected lung cancer according to the gene expression profiles. The early development of an aggressive phenotype may account for the lack of mortality reduction by screening observed in some cohorts.
虽然对吸烟者的筛查项目比预期更频繁地发现了可切除的早期肺癌，但它们在降低死亡率方面的效果仍存在争议。为了阐明计算机断层扫描（CT）筛查发现的肺癌的生物学特征，我们根据检测年份、分期和生存情况检查了肿瘤的 mRNA 特征。
在 28 名患者（INT-IEO 培训队列）和 24 名多中心意大利肺癌检测（MILD 验证队列）患者中分析了基因表达谱。从训练集中生成的基因特征在 MILD 集中进行了验证，并在公共存放的 DNA 微阵列数据集（GSE11969）中进行了验证。通过实时 RT-PCR 和免疫组织化学验证了选定基因和蛋白质的表达。通过 GeneSpring GX10 探索了丰富的核心途径和途径网络。
根据培训 INT-IEO 组中肿瘤检测的年份，确定了一个 239 个基因的特征，该特征与患者的结果相关。这些特征将 MILD 患者分为两个不同的生存组，与肿瘤分期、大小、组织病理学类型和筛查年份无关。该特征也可预测临床上发现的癌症（GSE11969）的生存率。通路分析显示，在检测年份较晚的肿瘤中，PI3K/PTEN/AKT 通路被富集，PDPK1、ITGB1 上调，FOXO1A 下调。对 INT-IEO 队列的正常肺组织进行分析，产生了区分早期和晚期检测肿瘤患者的特征。
根据基因表达谱，在 CT 筛查发现的肺癌中存在“惰性”和“侵袭性”肿瘤的不同模式。侵袭性表型的早期发展可能是某些队列中观察到的筛查未能降低死亡率的原因。
