Abstract 1112: Whole exome and whole genome sequence analysis of lung adenocarcinoma.
Authors: Chmielecki Juliann , Rosenberg Mara , Imielinski Marcin , Hernandez Bryan , Lawrence Michael , Sivachenko Andrey , Cibulskis Kristian , Voet Douglas , Sougnez Carrie , Gabriel Stacey , Getz Gad , Meyerson Matthew ,   The Cancer Genome Atlas Research Network
Published: August 2014

Lung adenocarcinoma is the leading cause of cancer-related death worldwide. Recent molecular characterization of this disease through large-scale sequencing efforts has identified distinct subsets driven by mutant oncogenes or kinase fusion proteins, many of which can be inhibited with targeted therapies. Despite these advances, almost half of all lung cancers still lack an identifiable driver. Here, we describe the genomic profiling of 230 normal-paired lung adenocarcinoma samples included as part of The Cancer Genome Atlas (TCGA) effort. All samples were subjected to whole exome analysis, copy number profiling and a subset were also subjected to whole genome sequencing. Mutation calling was performed with the MuTect algorithm. To identify significantly mutated genes, we used the MutSig CV algorithm, a statistically rigorous analysis that takes into account nucleotide context, gene-expression, replication time, and somatic background mutation rate. Mutation rate in lung adenocarcinoma was quite high with an average of 242 mutations/tumor observed (median: 161, range: 11-1328). In total, we identified mutations in over 13,500 genes of which 10 genes reached statistical significance (q&lt;0.1). One significant gene was excluded from further analyses as it was not expressed in RNA-seq data. In addition to mutant genes with established roles in lung adenocarcinoma (e.g. TP53, KRAS, STK11, EGFR, RB1, KEAP1, and BRAF), we also identified other statistically significant mutant genes whose role in lung tumorigenesis is presently unclear. These included mutations in the RNA-binding protein RBM10, and the integrin protein ITGAL. Although statistically insignificant by a small degree, we also identified mutations in the splicing factor U2AF1, and the SWI/SNF complex proteins SMARCA4 and ARID1A. We are currently analyzing whole genome sequences to confirm these events, and identify known and novel fusion events that may be contributing to tumorigenesis. In conclusion, we have analyzed the exomes of 230 lung adenocarcinoma samples and identified known and unknown mutations in this disease. Ultimately, these data will be integrated with ongoing expression, methylation, pathway, miRNA, and proteomic analyses. At its conclusion, this effort will represent the most comprehensive profiling of lung adenocarcinoma samples to date, and will provide a detailed integrative picture of the molecular mechanisms contributing to this disease.

Citation Format: Juliann Chmielecki, Mara Rosenberg, Marcin Imielinski, Bryan Hernandez, Michael Lawrence, Andrey Sivachenko, Kristian Cibulskis, Douglas Voet, Carrie Sougnez, Stacey Gabriel, Gad Getz, Matthew Meyerson, The Cancer Genome Atlas Research Network. Whole exome and whole genome sequence analysis of lung adenocarcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1112. doi:10.1158/1538-7445.AM2013-1112