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The transcriptional landscape and mutational profile of lung adenocarcinoma
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 som...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3483540/ https://www.ncbi.nlm.nih.gov/pubmed/22975805 http://dx.doi.org/10.1101/gr.145144.112 |
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author | Seo, Jeong-Sun Ju, Young Seok Lee, Won-Chul Shin, Jong-Yeon Lee, June Koo Bleazard, Thomas Lee, Junho Jung, Yoo Jin Kim, Jung-Oh Shin, Jung-Young Yu, Saet-Byeol Kim, Jihye Lee, Eung-Ryoung Kang, Chang-Hyun Park, In-Kyu Rhee, Hwanseok Lee, Se-Hoon Kim, Jong-Il Kang, Jin-Hyoung Kim, Young Tae |
author_facet | Seo, Jeong-Sun Ju, Young Seok Lee, Won-Chul Shin, Jong-Yeon Lee, June Koo Bleazard, Thomas Lee, Junho Jung, Yoo Jin Kim, Jung-Oh Shin, Jung-Young Yu, Saet-Byeol Kim, Jihye Lee, Eung-Ryoung Kang, Chang-Hyun Park, In-Kyu Rhee, Hwanseok Lee, Se-Hoon Kim, Jong-Il Kang, Jin-Hyoung Kim, Young Tae |
author_sort | Seo, Jeong-Sun |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3483540 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-34835402012-11-06 The transcriptional landscape and mutational profile of lung adenocarcinoma Seo, Jeong-Sun Ju, Young Seok Lee, Won-Chul Shin, Jong-Yeon Lee, June Koo Bleazard, Thomas Lee, Junho Jung, Yoo Jin Kim, Jung-Oh Shin, Jung-Young Yu, Saet-Byeol Kim, Jihye Lee, Eung-Ryoung Kang, Chang-Hyun Park, In-Kyu Rhee, Hwanseok Lee, Se-Hoon Kim, Jong-Il Kang, Jin-Hyoung Kim, Young Tae Genome Res Research 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. Cold Spring Harbor Laboratory Press 2012-11 /pmc/articles/PMC3483540/ /pubmed/22975805 http://dx.doi.org/10.1101/gr.145144.112 Text en © 2012, Published by Cold Spring Harbor Laboratory Press 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/. |
spellingShingle | Research Seo, Jeong-Sun Ju, Young Seok Lee, Won-Chul Shin, Jong-Yeon Lee, June Koo Bleazard, Thomas Lee, Junho Jung, Yoo Jin Kim, Jung-Oh Shin, Jung-Young Yu, Saet-Byeol Kim, Jihye Lee, Eung-Ryoung Kang, Chang-Hyun Park, In-Kyu Rhee, Hwanseok Lee, Se-Hoon Kim, Jong-Il Kang, Jin-Hyoung Kim, Young Tae The transcriptional landscape and mutational profile of lung adenocarcinoma |
title | The transcriptional landscape and mutational profile of lung adenocarcinoma |
title_full | The transcriptional landscape and mutational profile of lung adenocarcinoma |
title_fullStr | The transcriptional landscape and mutational profile of lung adenocarcinoma |
title_full_unstemmed | The transcriptional landscape and mutational profile of lung adenocarcinoma |
title_short | The transcriptional landscape and mutational profile of lung adenocarcinoma |
title_sort | transcriptional landscape and mutational profile of lung adenocarcinoma |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3483540/ https://www.ncbi.nlm.nih.gov/pubmed/22975805 http://dx.doi.org/10.1101/gr.145144.112 |
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