Array CGH-based Characterization of Genetic Alterations in Pulmonary Neuroendocrine Tumors

The goal of this study was to characterize and classify pulmonary neuroendocrine tumors based on Array Comparative Genomic Hybridization (aCGH). Using aCGH, we performed karyotype analysis of 33 small cell lung cancer (SCLC) tumors, 13 SCLC cell lines, 19 bronchial carcinoids, and 9 gastrointestinal (GI) carcinoids. In contrast to the relatively stable karyotypes of carcinoid tumors, the karyotypes of SCLC tumors and cell lines were highly aberrant. High copy number (CN) gains were detected in SCLC tumors and cell lines in cytogenetic bands encoding JAK2, FGFR1, and MYC family members. In some of those samples, the CN of these genes exceeded 100, suggesting that they could represent driver alterations and potential drug targets in subgroups of SCLC patients. Recurrent CN alterations of a total of 203 genes, including the RB1 gene, and 59 microRNAs, most of which locate in the DLK1-DIO3 domain, were observed in SCLC tumors, bronchial carcinoids and carcinoids of GI origin; in contrast, CN alterations of the TP53 gene and the MYC family members were observed more frequently in SCLC. These findings suggest the existence of partially shared tumor-specific CN alterations in these tumors. Furthermore, we demonstrated that the aCGH profile of SCLC cell lines highly resemble that of clinical SCLC specimens. Finally, by analyzing potential drug targets, we provide a genomics based rationale for targeting the AKT-mTOR and apoptosis pathways in SCLC. Carcinoids, including 19 bronchial carcinoids and 9 carcinoid of gastrointestinal origin, and small cell lung cancer, including 33 patients' tumor samples and 13 cell line samples, were compared.

本研究旨在基于阵列比较基因组杂交（Array Comparative Genomic Hybridization，aCGH）技术，对肺神经内分泌肿瘤进行特征表征与分类。我们利用aCGH技术，对33例小细胞肺癌（small cell lung cancer, SCLC）肿瘤样本、13株SCLC细胞系、19例支气管类癌及9例胃肠道（gastrointestinal, GI）类癌开展了核型分析。与核型相对稳定的类癌不同，SCLC肿瘤及细胞系的核型呈现高度异常。在编码JAK2、FGFR1及MYC家族成员的细胞遗传学染色体带区中，于SCLC肿瘤及细胞系内检测到高水平的拷贝数（copy number, CN）扩增；部分样本中上述基因的拷贝数超过100，提示其可能为SCLC患者亚群中的驱动性变异及潜在药物靶点。在SCLC肿瘤、支气管类癌及胃肠道类癌中，共观察到203个基因（含RB1基因）及59个微小RNA（microRNAs）的复发性拷贝数变异，其中绝大多数位于DLK1-DIO3区域；与之相反，TP53基因及MYC家族成员的拷贝数变异在SCLC中更为频发。上述发现提示，此类肿瘤中存在部分共有的肿瘤特异性拷贝数变异。此外，我们证实SCLC细胞系的aCGH图谱与临床SCLC标本高度相似。最后，通过对潜在药物靶点的分析，我们为SCLC中靶向AKT-mTOR通路及细胞凋亡通路提供了基于基因组学的理论依据。本研究对两类受试样本进行了对比：一类为类癌（含19例支气管类癌与9例胃肠道类癌），另一类为小细胞肺癌（含33例患者肿瘤样本与13株细胞系样本）。