title: Comprehensive genomic profiles of small cell lung cancer.
abstract: We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
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authors.affiliation: Computational Molecular Biology Group, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
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authors.affiliation: Department of Pathology, CHU Grenoble INSERM U823, University Joseph Fourier, Institute Albert Bonniot 38043, CS10217 Grenoble, France.
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authors.forename: Martin
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authors.lastname: Sage
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mesh_terms: D000483:Alleles; D000818:Animals; D045744:Cell Line, Tumor; D056905:Chromosome Breakpoints; D019938:Cyclin D1 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009490:Neurosecretory Systems / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D051880:Receptors, Notch; D016160:Retinoblastoma Protein; C495901:TP53 protein, human; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1