Identification of somatic mutations in non-small cell lung carcinomas using whole-exome sequencing

Lung cancer is the leading cause of cancer-related death, with non-small cell lung cancer (NSCLC) being the predominant form of the disease. Most lung cancer is caused by the accumulation of genomic alterations due to tobacco exposure. To uncover its mutational landscape, we performed whole-exome se...

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Vydáno v:	Carcinogenesis (New York) Ročník 33; číslo 7; s. 1270
Hlavní autoři:	Liu, Pengyuan, Morrison, Carl, Wang, Liang, Xiong, Donghai, Vedell, Peter, Cui, Peng, Hua, Xing, Ding, Feng, Lu, Yan, James, Michael, Ebben, John D, Xu, Haiming, Adjei, Alex A, Head, Karen, Andrae, Jaime W, Tschannen, Michael R, Jacob, Howard, Pan, Jing, Zhang, Qi, Van den Bergh, Francoise, Xiao, Haijie, Lo, Ken C, Patel, Jigar, Richmond, Todd, Watt, Mary-Anne, Albert, Thomas, Selzer, Rebecca, Anderson, Marshall, Wang, Jiang, Wang, Yian, Starnes, Sandra, Yang, Ping, You, Ming
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	England 01.07.2012
Témata:	Carcinoma, Non-Small-Cell Lung - genetics Cell Line, Tumor Exons Humans Lung Neoplasms - genetics Mutation
ISSN:	1460-2180, 1460-2180
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Abstract	Lung cancer is the leading cause of cancer-related death, with non-small cell lung cancer (NSCLC) being the predominant form of the disease. Most lung cancer is caused by the accumulation of genomic alterations due to tobacco exposure. To uncover its mutational landscape, we performed whole-exome sequencing in 31 NSCLCs and their matched normal tissue samples. We identified both common and unique mutation spectra and pathway activation in lung adenocarcinomas and squamous cell carcinomas, two major histologies in NSCLC. In addition to identifying previously known lung cancer genes (TP53, KRAS, EGFR, CDKN2A and RB1), the analysis revealed many genes not previously implicated in this malignancy. Notably, a novel gene CSMD3 was identified as the second most frequently mutated gene (next to TP53) in lung cancer. We further demonstrated that loss of CSMD3 results in increased proliferation of airway epithelial cells. The study provides unprecedented insights into mutational processes, cellular pathways and gene networks associated with lung cancer. Of potential immediate clinical relevance, several highly mutated genes identified in our study are promising druggable targets in cancer therapy including ALK, CTNNA3, DCC, MLL3, PCDHIIX, PIK3C2B, PIK3CG and ROCK2.
AbstractList	Lung cancer is the leading cause of cancer-related death, with non-small cell lung cancer (NSCLC) being the predominant form of the disease. Most lung cancer is caused by the accumulation of genomic alterations due to tobacco exposure. To uncover its mutational landscape, we performed whole-exome sequencing in 31 NSCLCs and their matched normal tissue samples. We identified both common and unique mutation spectra and pathway activation in lung adenocarcinomas and squamous cell carcinomas, two major histologies in NSCLC. In addition to identifying previously known lung cancer genes (TP53, KRAS, EGFR, CDKN2A and RB1), the analysis revealed many genes not previously implicated in this malignancy. Notably, a novel gene CSMD3 was identified as the second most frequently mutated gene (next to TP53) in lung cancer. We further demonstrated that loss of CSMD3 results in increased proliferation of airway epithelial cells. The study provides unprecedented insights into mutational processes, cellular pathways and gene networks associated with lung cancer. Of potential immediate clinical relevance, several highly mutated genes identified in our study are promising druggable targets in cancer therapy including ALK, CTNNA3, DCC, MLL3, PCDHIIX, PIK3C2B, PIK3CG and ROCK2.Lung cancer is the leading cause of cancer-related death, with non-small cell lung cancer (NSCLC) being the predominant form of the disease. Most lung cancer is caused by the accumulation of genomic alterations due to tobacco exposure. To uncover its mutational landscape, we performed whole-exome sequencing in 31 NSCLCs and their matched normal tissue samples. We identified both common and unique mutation spectra and pathway activation in lung adenocarcinomas and squamous cell carcinomas, two major histologies in NSCLC. In addition to identifying previously known lung cancer genes (TP53, KRAS, EGFR, CDKN2A and RB1), the analysis revealed many genes not previously implicated in this malignancy. Notably, a novel gene CSMD3 was identified as the second most frequently mutated gene (next to TP53) in lung cancer. We further demonstrated that loss of CSMD3 results in increased proliferation of airway epithelial cells. The study provides unprecedented insights into mutational processes, cellular pathways and gene networks associated with lung cancer. Of potential immediate clinical relevance, several highly mutated genes identified in our study are promising druggable targets in cancer therapy including ALK, CTNNA3, DCC, MLL3, PCDHIIX, PIK3C2B, PIK3CG and ROCK2. Lung cancer is the leading cause of cancer-related death, with non-small cell lung cancer (NSCLC) being the predominant form of the disease. Most lung cancer is caused by the accumulation of genomic alterations due to tobacco exposure. To uncover its mutational landscape, we performed whole-exome sequencing in 31 NSCLCs and their matched normal tissue samples. We identified both common and unique mutation spectra and pathway activation in lung adenocarcinomas and squamous cell carcinomas, two major histologies in NSCLC. In addition to identifying previously known lung cancer genes (TP53, KRAS, EGFR, CDKN2A and RB1), the analysis revealed many genes not previously implicated in this malignancy. Notably, a novel gene CSMD3 was identified as the second most frequently mutated gene (next to TP53) in lung cancer. We further demonstrated that loss of CSMD3 results in increased proliferation of airway epithelial cells. The study provides unprecedented insights into mutational processes, cellular pathways and gene networks associated with lung cancer. Of potential immediate clinical relevance, several highly mutated genes identified in our study are promising druggable targets in cancer therapy including ALK, CTNNA3, DCC, MLL3, PCDHIIX, PIK3C2B, PIK3CG and ROCK2.
Author	Liu, Pengyuan Jacob, Howard Zhang, Qi Andrae, Jaime W You, Ming Xu, Haiming Watt, Mary-Anne Adjei, Alex A Lo, Ken C Pan, Jing Patel, Jigar Ding, Feng Head, Karen Tschannen, Michael R Wang, Jiang Anderson, Marshall Albert, Thomas Vedell, Peter Richmond, Todd Cui, Peng Van den Bergh, Francoise Morrison, Carl Xiong, Donghai Yang, Ping Hua, Xing Lu, Yan Xiao, Haijie James, Michael Starnes, Sandra Wang, Liang Wang, Yian Selzer, Rebecca Ebben, John D
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Snippet	Lung cancer is the leading cause of cancer-related death, with non-small cell lung cancer (NSCLC) being the predominant form of the disease. Most lung cancer...
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SubjectTerms	Carcinoma, Non-Small-Cell Lung - genetics Cell Line, Tumor Exons Humans Lung Neoplasms - genetics Mutation
Title	Identification of somatic mutations in non-small cell lung carcinomas using whole-exome sequencing
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Volume	33
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