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Free keywords:
Amino Acid Substitution
Animals
CREB-Binding Protein/genetics
Cell Line, Tumor
DNA Copy Number Variations
DNA Mutational Analysis
E1A-Associated p300 Protein/genetics
Gene Expression Profiling
Gene Regulatory Networks
*Genome, Human
Genome-Wide Association Study
Humans
Intercellular Signaling Peptides and Proteins/genetics
Lung Neoplasms/*genetics
Mice
Mice, Knockout
Models, Molecular
Mutation
Myeloid-Lymphoid Leukemia Protein/genetics
Nerve Tissue Proteins/genetics
Oligonucleotide Array Sequence Analysis
PTEN Phosphohydrolase/genetics
Polymorphism, Single Nucleotide
Protein Processing, Post-Translational/genetics
Retinoblastoma Protein/genetics
Small Cell Lung Carcinoma/*genetics
Tumor Suppressor Protein p53/genetics
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.
