한빛사 논문
Abstract
Jeong-Sun Seo1,2,3,4,5,$,#, Young Seok Ju4,$, Won-Chul Lee1,3,$, Jong-Yeon Shin1,5, June Koo Lee1,6, Thomas Bleazard1, Junho Lee1, Yoo Jin Jung7, Jung-Oh Kim9, Jung-Young Shin9, Saet-Byeol Yu5, Jihye Kim5, Eung-Ryoung Lee4, Chang-Hyun Kang8, In-Kyu Park8, Hwanseok Rhee4, Se-Hoon Lee1,6,7, Jong-Il Kim1,2,3,5, Jin-Hyoung Kang10,# and Young Tae Kim1,7,8,#
1. Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul 110-799, Korea
2. Department of Biochemistry, Seoul National University College of Medicine, Seoul 110-799, Korea
3. Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 110-799, Korea
4. Macrogen Inc., Seoul 153-781, Korea
5. Psoma Therapeutics Inc., Seoul 153-781, Korea
6. Department of Internal Medicine, Seoul National University Hospital, Seoul 110-799, Korea
7. Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea
8. Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, Seoul 110-799, Korea
9. Division of Medical Oncology, Research Institute of Medical Science, The Catholic University of Korea, Seoul 137-040, Republic of Korea
10. Division of Medical Oncology, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul 137-040, Korea
$ These authors contributed equally to this work
# Corresponding authors : Jeong-Sun Seo, Jin-Hyoung Kang, Young Tae Kim
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.
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