title: Array comparative genomic hybridization-based characterization of genetic alterations in pulmonary neuroendocrine tumors.
abstract: 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 carcinoids. In contrast to the relatively conserved 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. In SCLC tumors, as well as bronchial carcinoids and carcinoids of gastrointestinal origin, recurrent CN alterations were observed in 203 genes, including the RB1 gene and 59 microRNAs of which 51 locate in the DLK1-DIO3 domain. These findings suggest the existence of partially shared CN alterations in these tumor types. In contrast, CN alterations of the TP53 gene and the MYC family members were predominantly observed in SCLC. Furthermore, we demonstrated that the aCGH profile of SCLC cell lines highly resembles 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.
authors.affiliation: Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Johannes
authors.initials: J
authors.lastname: Voortman
authors.forename: Jih-Hsiang
authors.initials: JH
authors.lastname: Lee
authors.forename: Jonathan Keith
authors.initials: JK
authors.lastname: Killian
authors.forename: Miia
authors.initials: M
authors.lastname: Suuriniemi
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Wang
authors.forename: Marco
authors.initials: M
authors.lastname: Lucchi
authors.forename: William I
authors.initials: WI
authors.lastname: Smith
authors.forename: Paul
authors.initials: P
authors.lastname: Meltzer
authors.forename: Yisong
authors.initials: Y
authors.lastname: Wang
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giaccone
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001984:Bronchial Neoplasms / Q000188:drug therapy / Q000235:genetics; D002276:Carcinoid Tumor / Q000235:genetics; D045744:Cell Line, Tumor; D055028:Comparative Genomic Hybridization / Q000379:methods*; D020732:Cytogenetic Analysis; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D055752:Small Cell Lung Carcinoma / Q000235:genetics