The transcriptional landscape and mutational profile of lung adenocarcinoma
- Jeong-Sun Seo1,2,3,4,5,11,12,
- Young Seok Ju4,11,
- Won-Chul Lee1,3,11,
- Jong-Yeon Shin1,5,
- June Koo Lee1,6,
- Thomas Bleazard1,
- Junho Lee1,
- Yoo Jin Jung7,
- Jung-Oh Kim8,
- Jung-Young Shin8,
- Saet-Byeol Yu5,
- Jihye Kim5,
- Eung-Ryoung Lee4,
- Chang-Hyun Kang9,
- In-Kyu Park9,
- Hwanseok Rhee4,
- Se-Hoon Lee1,6,7,
- Jong-Il Kim1,2,3,5,
- Jin-Hyoung Kang10,12 and
- Young Tae Kim1,7,9,12
- 1Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul 110-799, Korea;
- 2Department of Biochemistry, Seoul National University College of Medicine, Seoul 110-799, Korea;
- 3Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 110-799, Korea;
- 4Macrogen Inc., Seoul 153-781, Korea;
- 5Psoma Therapeutics Inc., Seoul 153-781, Korea;
- 6Department of Internal Medicine, Seoul National University Hospital, Seoul 110-799, Korea;
- 7Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea;
- 8Division of Medical Oncology, Research Institute of Medical Science, The Catholic University of Korea, Seoul 137-040, Korea;
- 9Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, Seoul 110-799, Korea;
- 10Division of Medical Oncology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul 137-040, Korea
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↵11 These authors contributed equally to this work.
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, eight 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.
Footnotes
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↵12 Corresponding authors
E-mail jeongsun{at}snu.ac.kr
E-mail jinkang{at}catholic.ac.kr
E-mail ytkim{at}snu.ac.kr
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.145144.112.
Freely available online through the Genome Research Open Access option.
- Received July 9, 2012.
- Accepted September 7, 2012.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported License), as described at http://creativecommons.org/licenses/by-nc/3.0/.
