The transcriptional landscape and mutational profile of lung adenocarcinoma

被引：484

作者：

Seo, Jeong-Sun ^{[1
,3
,4
,5
]}

Ju, Young Seok ^{[2
,4
]}

Lee, Won-Chul ^{[1
,3
]}

Shin, Jong-Yeon ^{[1
,5
]}

Lee, June Koo ^{[1
,6
]}

Bleazard, Thomas ^{[1
]}

Lee, Junho ^{[1
]}

Jung, Yoo Jin ^{[7
]}

Kim, Jung-Oh ^{[8
]}

Shin, Jung-Young ^{[8
]}

Yu, Saet-Byeol ^{[5
]}

Kim, Jihye ^{[5
]}

Lee, Eung-Ryoung ^{[4
]}

Kang, Chang-Hyun ^{[9
]}

Park, In-Kyu ^{[9
]}

Rhee, Hwanseok ^{[4
]}

Lee, Se-Hoon ^{[1
,6
,7
]}

Kim, Jong-Il ^{[1
,2
,3
,5
]}

Kang, Jin-Hyoung ^{[10
]}

Kim, Young Tae ^{[1
,7
,9
]}

机构：

[1] Seoul Natl Univ, Med Res Ctr, Genom Med Inst GMI, Seoul 110799, South Korea

[2] Seoul Natl Univ, Coll Med, Dept Biochem, Seoul 110799, South Korea

[3] Seoul Natl Univ, Grad Sch, Dept Biomed Sci, Seoul 110799, South Korea

[4] Macrogen Inc, Seoul 153781, South Korea

[5] Psoma Therapeut Inc, Seoul 153781, South Korea

[6] Seoul Natl Univ Hosp, Dept Internal Med, Seoul 110799, South Korea

[7] Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul 110799, South Korea

[8] Catholic Univ Korea, Res Inst Med Sci, Div Med Oncol, Seoul 137040, South Korea

[9] Seoul Natl Univ Hosp, Dept Thorac & Cardiovasc Surg, Seoul 110799, South Korea

[10] Catholic Univ Korea, Seoul St Marys Hosp, Div Med Oncol, Seoul 137040, South Korea

来源：

GENOME RESEARCH | 2012年 / 22卷 / 11期

基金：

新加坡国家研究基金会;

关键词：

GROWTH-FACTOR RECEPTOR; MASSIVELY-PARALLEL DNA; SOMATIC MUTATIONS; ACTIVATING MUTATIONS; CANCER GENOME; WHOLE-GENOME; GENE FUSIONS; RET; COMMON; IDENTIFICATION;

D O I：

10.1101/gr.145144.112

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：2109 / 2119

页数：11

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