Genomic Landscape of Non-Small Cell Lung Cancer in Smokers and Never-Smokers

被引：980

作者：

Govindan, Ramaswamy ^{[1
,2
]}

Ding, Li ^{[2
,3
,4
]}

Griffith, Malachi ^{[3
,4
]}

Subramanian, Janakiraman ^{[1
,2
]}

Dees, Nathan D. ^{[3
]}

Kanchi, Krishna L. ^{[3
]}

Maher, Christopher A. ^{[1
,2
,3
]}

Fulton, Robert ^{[3
,4
]}

Fulton, Lucinda ^{[3
,4
]}

Wallis, John ^{[3
,4
]}

Chen, Ken ^{[8
]}

Walker, Jason ^{[3
]}

McDonald, Sandra ^{[1
,6
]}

Bose, Ron ^{[1
,2
]}

Ornitz, David ^{[5
]}

Xiong, Donghai ^{[7
]}

You, Ming ^{[7
]}

Dooling, David J. ^{[3
,4
]}

Watson, Mark ^{[1
,6
]}

Mardis, Elaine R. ^{[1
,3
,4
]}

Wilson, Richard K. ^{[1
,3
,4
]}

机构：

[1] Washington Univ, Sch Med, Siteman Canc Ctr, St Louis, MO 63110 USA

[2] Washington Univ, Sch Med, Dept Internal Med, Div Oncol, St Louis, MO 63110 USA

[3] Washington Univ, Sch Med, Genome Inst, St Louis, MO 63110 USA

[4] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA

[5] Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO 63110 USA

[6] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA

[7] Med Coll Wisconsin, Dept Pharmacol & Toxicol, Milwaukee, WI 53226 USA

[8] Univ Texas MD Anderson Canc Ctr, Div Quantitat Sci, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA

来源：

CELL | 2012年 / 150卷 / 06期

关键词：

MUTATIONAL SIGNIFICANCE; SOMATIC MUTATIONS; GENE FUSIONS; IDENTIFICATION; REARRANGEMENTS; HETEROGENEITY; TRANSCRIPTION; EXPRESSION; EVOLUTION; ARID1A;

D O I：

10.1016/j.cell.2012.08.024

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：

We report the results of whole-genome and transcriptome sequencing of tumor and adjacent normal tissue samples from 17 patients with non-small cell lung carcinoma (NSCLC). We identified 3,726 point mutations and more than 90 indels in the coding sequence, with an average mutation frequency more than 10-fold higher in smokers than in never-smokers. Novel alterations in genes involved in chromatin modification and DNA repair pathways were identified, along with DACH1, CFTR, RELN, ABCB5, and HGF. Deep digital sequencing revealed diverse clonality patterns in both never-smokers and smokers. All validated EFGR and KRAS mutations were present in the founder clones, suggesting possible roles in cancer initiation. Analysis revealed 14 fusions, including ROS1 and ALK, as well as novel metabolic enzymes. Cell-cycle and JAK-STAT pathways are significantly altered in lung cancer, along with perturbations in 54 genes that are potentially targetable with currently available drugs.

引用

页码：1121 / 1134

页数：14

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