The transcriptional landscape and mutational profile of lung adenocarcinoma

Understanding the molecular signatures of cancer is important to apply appropriate targeted therapies. Here we present the first large scale RNA sequencing study of lung adenocarcinoma demonstrating its power to identify somatic point mutations as well as transcriptional variants such as gene fusions, alternative splicing events and expression outliers. Our results reveal the genetic basis of 200 lung adenocarcinomas in Koreans including deep characterization of 87 surgical specimens by transcriptome sequencing. We identified driver somatic mutations in cancer genes including EGFR, KRAS, NRAS, BRAF, PIK3CA, MET and CTNNB1. New cancer genes, such as LMTK2, ARID1A, NOTCH2 and SMARCA4, were also suggested as candidates for novel drivers in lung adenocarcinoma. We found 45 fusion genes, 8 of which were chimeric tyrosine kinases involving ALK, RET, ROS1, FGFR2, AXL and PDGFRA. Of 17 recurrent alternative splicing events, we identified exon 14 skipping in the proto-oncogene MET as highly likely to be a cancer driver. The number of somatic mutations and expression outliers varied markedly between individual cancers and was strongly correlated with smoking history of cancer patients. In addition, we identified genomic blocks where genes were frequently up- or down-regulated together that could be explained by copy number alterations in the cancer tissue. We also found an association between lymph node metastasis and somatic mutations in TP53. Our findings broaden our understanding of lung adenocarcinoma and may also lead to new diagnostic and therapeutic approaches. * Raw data files were submitted to EBI-SRA under accession number ERP001058.