The transcriptional landscape and mutational profile of lung adenocarcinoma
- Jeong-Sun Seo1,11,
- Young Seok Ju2,
- Won-Chul Lee3,
- Jong-Yeon Shin3,
- June Koo Lee4,
- Thomas Bleazard5,
- Junho Lee3,
- Yoo Jin Jung6,
- Jung-Oh Kim7,
- Jung-Young Shin7,
- Saet-Byeol Yu8,
- Jihye Kim8,
- Eung-Ryoung Lee9,
- Chang-Hyun Kang6,
- In-Kyu Park6,
- Hwanseok Rhee9,
- Se-Hoon Lee4,
- Jong-Il Kim3,
- Jin-Hyoung Kang10 and
- Young Tae Kim6
- 1 Seoul National University College of Medicine;
- 2 College of medicine, Seoul national university;
- 3 Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University;
- 4 Department of Internal Medicine, Seoul National University Hospital;
- 5 Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul 110-799,;
- 6 Dept of Thoracic and Cardiovascular Surgery, Cancer Research Institute, Seoul National University;
- 7 Div of Medical Oncology, Research Institute of Medical Science, The Catholic University of Korea;
- 8 Psoma Therapeutics Inc., Seoul 153-781, Korea;
- 9 Macrogen Inc., Seoul 153-781, Korea;
- 10 Division of Medical Oncology, Seoul St. Mary's Hospital, The Catholic University of Korea
- ↵* Corresponding author; email: jeongsun{at}snu.ac.kr
Abstract
All cancers harbor molecular alterations in their genomes. The transcriptional consequences of these somatic mutations have not yet been comprehensively explored in lung cancer. 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. Candidates for novel driver mutations were also identified in genes newly implicated in lung adenocarcinoma such as LMTK2, ARID1A, NOTCH2 and SMARCA4. We found 45 fusion genes, 8 of which were chimeric tyrosine kinases involving ALK, RET, ROS1, FGFR2, AXL and PDGFRA. Among 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 patients. We identified genomic blocks within which gene expression levels were consistently increased or decreased that could be explained by copy number alterations in samples. We also found an association between lymph node metastasis and somatic mutations in TP53. These findings broaden our understanding of lung adenocarcinoma and may also lead to new diagnostic and therapeutic approaches.
- Received July 9, 2012.
- Accepted September 7, 2012.
- © 2012, Published by Cold Spring Harbor Laboratory Press
This manuscript is Open Access.
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