title: Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer.
abstract: 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 genes that encode histone modifiers. Furthermore, we observed mutations in PTEN, SLIT2 and EPHA7, as well as focal amplifications of the FGFR1 tyrosine kinase gene. Finally, we detected many of the alterations found in humans in SCLC tumors from Tp53 and Rb1 double knockout mice. Our study implicates histone modification as a major feature of SCLC, reveals potentially therapeutically tractable genomic alterations and provides a generalizable framework for the identification of biologically relevant genes in the context of high mutational background.
authors.affiliation: Department of Translational Genomics, University of Cologne, Cologne, Germany.
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mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D050882:CREB-Binding Protein / Q000235:genetics; D045744:Cell Line, Tumor; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D050881:E1A-Associated p300 Protein / Q000235:genetics; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D015894:Genome, Human; D055106:Genome-Wide Association Study; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D051059:PTEN Phosphohydrolase / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011499:Protein Processing, Post-Translational / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics; D055752:Small Cell Lung Carcinoma / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000098552:Slit Homolog 2 Protein
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; C497422:KMT2A protein, human; D009419:Nerve Tissue Proteins; D016160:Retinoblastoma Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000098552:Slit Homolog 2 Protein