Dataset Information

Integrative analysis of small cell lung cancer

ABSTRACT: Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype. We conducted integrated analysis of genome sequencing, transcriptome, and copy number analysis and found an extremely high mutation rate of 7.4±1 protein-changing mutations per million basepairs. Evidence for inactivation of TP53 and RB1 was found in all sequenced cases. Furthermore, we identified recurrent mutations in CREBBP, EP300, and MLL, observed mutations in PTEN, in SLIT2, and EPHA7, as well as focal amplifications of the FGFR1 locus. As a major feature of SCLC we found mutation in histone modifying genes, observed genome alterations that are therapeutically tractable, and provide a framework for identifying biologically relevant genes in the context of a high mutation rate. Peifer et al., 2012, Nature Genetics.

PROVIDER: EGAS00001000299 | EGA |

REPOSITORIES: EGA

ACCESS DATA

Publications

Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer.

Peifer Martin M Fernández-Cuesta Lynnette L Sos Martin L ML George Julie J Seidel Danila D Kasper Lawryn H LH Plenker Dennis D Leenders Frauke F Sun Ruping R Zander Thomas T Menon Roopika R Koker Mirjam M Dahmen Ilona I Müller Christian C Di Cerbo Vincenzo V Schildhaus Hans-Ulrich HU Altmüller Janine J Baessmann Ingelore I Becker Christian C de Wilde Bram B Vandesompele Jo J Böhm Diana D Ansén Sascha S Gabler Franziska F Wilkening Ines I Heynck Stefanie S Heuckmann Johannes M JM Lu Xin X Carter Scott L SL Cibulskis Kristian K Banerji Shantanu S Getz Gad G Park Kwon-Sik KS Rauh Daniel D Grütter Christian C Fischer Matthias M Pasqualucci Laura L Wright Gavin G Wainer Zoe Z Russell Prudence P Petersen Iver I Chen Yuan Y Stoelben Erich E Ludwig Corinna C Schnabel Philipp P Hoffmann Hans H Muley Thomas T Brockmann Michael M Engel-Riedel Walburga W Muscarella Lucia A LA Fazio Vito M VM Groen Harry H Timens Wim W Sietsma Hannie H Thunnissen Erik E Smit Egbert E Heideman Daniëlle A M DA Snijders Peter J F PJ Cappuzzo Federico F Ligorio Claudia C Damiani Stefania S Field John J Solberg Steinar S Brustugun Odd Terje OT Lund-Iversen Marius M Sänger Jörg J Clement Joachim H JH Soltermann Alex A Moch Holger H Weder Walter W Solomon Benjamin B Soria Jean-Charles JC Validire Pierre P Besse Benjamin B Brambilla Elisabeth E Brambilla Christian C Lantuejoul Sylvie S Lorimier Philippe P Schneider Peter M PM Hallek Michael M Pao William W Meyerson Matthew M Sage Julien J Shendure Jay J Schneider Robert R Büttner Reinhard R Wolf Jürgen J Nürnberg Peter P Perner Sven S Heukamp Lukas C LC Brindle Paul K PK Haas Stefan S Thomas Roman K RK

Nature genetics 20120902 10

Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor prognosis. We sequenced 29 SCLC exomes, 2 genomes and 15 transcriptomes and found an extremely high mutation rate of 7.4±1 protein-changing mutations per million base pairs. Therefore, we conducted integrated analyses of the various data sets to identify pathogenetically relevant mutated genes. In all cases, we found evidence for inactivation of TP53 and RB1 and identified recurrent mutations in the CREBBP, EP300 and MLL ...[more]

PMID: 22941188

Similar Datasets

Project description:The study was designed to identify the molecular changes that occur in EGFR mutant NSCLCs that become resistant to TKI by transforming to SCLC. Tyrosine kinase inhibitors (TKIs) are effective treatments for non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, they do not lead to cures, and, on average, relapse occurs after one year of continuous treatment. In a subset of patients, a fundamental histological transformation from NSCLC to small cell lung cancer (SCLC) is observed in the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of a cohort of tumor samples and cell lines derived from resistant EGFR mutant patients with SCLC transformation revealed that RB is lost in 100% of these cases, but rarely in those that remain NSCLC. Global changes in gene expression, including increased neuroendocrine marker expression and absence of EGFR expression, are observed in cancers that transformed to SCLC. Consistent with their genetic and epigenetic similarities to classical SCLC, cell lines derived from resistant EGFR mutant SCLC biopsies are substantially more sensitive to ABT-263 treatment compared to those derived from resistant EGFR mutant NSCLCs. Together, these findings suggest that despite developing initially as EGFR mutant adenocarcinomas, this subset of resistant cancers ultimately take on many of the molecular and phenotypic characteristics of classical SCLC. The patient-derived cell line models MGH119, MGH121, MGH125, MGH126, MGH131-1, MGH131-2, MGH134 and MGH156 were developed on collagen coated plates in ACL4 medium and transferred to RPMI. MGH157 was developed initially in RPMI. The cell line MGH141 was derived using the feeder system with irradiated fibroblasts (5000 rad) from normal patient tissue. When a tumor cell majority was observed it was passaged off of the feeder layer and later transferred to RPMI medium for experiments. The development of a model was considered complete when it was independent of the feeder system, free of stromal cells, and determined to maintain known patient tumor mutations. MGH119-R was derived in vitro from the treatment naive model, MGH119, through in vitro exposure to gefitinib, escalating from 10nM to a final concentration of 1Î¼M.

Dataset Information

Integrative analysis of small cell lung cancer

Publications

Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets