Somatic mutations affect key pathways in lung adenocarcinoma

被引：2120

作者：

Ding, Li ^{[1
]}

Getz, Gad ^{[2
]}

Wheeler, David A. ^{[3
]}

Mardis, Elaine R. ^{[1
]}

McLellan, Michael D. ^{[1
]}

Cibulskis, Kristian ^{[2
]}

Sougnez, Carrie ^{[2
]}

Greulich, Heidi ^{[2
,4
]}

Muzny, Donna M. ^{[3
]}

Morgan, Margaret B. ^{[3
]}

Fulton, Lucinda ^{[1
]}

Fulton, Robert S. ^{[1
]}

Zhang, Qunyuan ^{[5
]}

Wendl, Michael C. ^{[1
]}

Lawrence, Michael S. ^{[2
]}

Larson, David E. ^{[1
]}

Chen, Ken ^{[1
]}

Dooling, David J. ^{[1
]}

Sabo, Aniko ^{[3
]}

Hawes, Alicia C. ^{[3
]}

Shen, Hua ^{[3
]}

Jhangiani, Shalini N. ^{[3
]}

Lewis, Lora R. ^{[3
]}

Hall, Otis ^{[3
]}

Zhu, Yiming ^{[3
]}

Mathew, Tittu ^{[3
]}

Ren, Yanru ^{[3
]}

Yao, Jiqiang ^{[3
]}

Scherer, Steven E. ^{[3
]}

Clerc, Kerstin ^{[3
]}

Metcalf, Ginger A. ^{[3
]}

Ng, Brian ^{[3
]}

Milosavljevic, Aleksandar ^{[3
]}

Gonzalez-Garay, Manuel L. ^{[3
]}

Osborne, John R. ^{[1
]}

Meyer, Rick ^{[1
]}

Shi, Xiaoqi ^{[1
]}

Tang, Yuzhu ^{[1
]}

Koboldt, Daniel C. ^{[1
]}

Lin, Ling ^{[1
]}

Abbott, Rachel ^{[1
]}

Miner, Tracie L. ^{[1
]}

Pohl, Craig ^{[1
]}

Fewell, Ginger ^{[1
]}

Haipek, Carrie ^{[1
]}

Schmidt, Heather ^{[1
]}

Dunford-Shore, Brian H. ^{[1
]}

Kraja, Aldi ^{[5
]}

Crosby, Seth D. ^{[1
]}

Sawyer, Christopher S. ^{[1
]}

机构：

[1] Washington Univ, Sch Med, Dept Genet, Genome Ctr, St Louis, MO 63108 USA

[2] Broad Inst Harvard & MIT, Canc Program, Genome Biol Program, Cambridge, MA 02142 USA

[3] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[4] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[5] Washington Univ, Sch Med, Div Stat Genom, Dept Genet, St Louis, MO 63108 USA

[6] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[7] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA

[8] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA

[9] Max Planck Soc, Max Planck Inst Neurol Res, Klaus Joachim Zulch Labs, D-50931 Cologne, Germany

[10] Univ Cologne, Fac Med, D-50931 Cologne, Germany

[11] Univ Cologne, Ctr Integrated Oncol, D-50931 Cologne, Germany

[12] Univ Cologne, Dept Internal Med 1, D-50931 Cologne, Germany

[13] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA

[14] Univ Michigan, Thorac Surg Sect, Dept Surg, Ann Arbor, MI 48109 USA

[15] Univ Texas Houston, MD Anderson Canc Ctr, Dept Thorac & Cardiovasc Surg, Houston, TX 77030 USA

[16] Univ Texas Houston, MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA

[17] Univ Texas Houston, MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[18] NHGRI, NIH, Bethesda, MD 20892 USA

[19] Washington Univ, Dept Pathol & Immunol, St Louis, MO 63108 USA

[20] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA

[21] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA

[22] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA

[23] Mem Sloan Kettering Canc Ctr, Dept Computat Biol, New York, NY 10065 USA

[24] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[25] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA

来源：

NATURE | 2008年 / 455卷 / 7216期

关键词：

D O I：

10.1038/nature07423

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well- classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers - including NF1, APC, RB1 and ATM - and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.

引用

页码：1069 / 1075

页数：7

共 51 条

[31] KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib
Pao, W
Wang, TY
Riely, GJ
Miller, VA
Pan, QL
Ladanyi, M
Zakowski, MF
Heelan, RT
Kris, MG
Varmus, HE
[J]. PLOS MEDICINE, 2005, 2 (01) : 57 - 61
[32] Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain
Pao, W
Miller, VA
Politi, KA
Riely, GJ
Somwar, R
Zakowski, MF
Kris, MG
Varmus, H
[J]. PLOS MEDICINE, 2005, 2 (03) : 225 - 235
[33] EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib
Pao, W
Miller, V
Zakowski, M
Doherty, J
Politi, K
Sarkaria, I
Singh, B
Heelan, R
Rusch, V
Fulton, L
Mardis, E
Kupfer, D
Wilson, R
Kris, M
Varmus, H
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (36) : 13306 - 13311
[34] Global cancer statistics, 2002
Parkin, DM
Bray, F
Ferlay, J
Pisani, P
[J]. CA-A CANCER JOURNAL FOR CLINICIANS, 2005, 55 (02) : 74 - 108
[35] Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors
Pollack, JR
Sorlie, T
Perou, CM
Rees, CA
Jeffrey, SS
Lonning, PE
Tibshirani, R
Botstein, D
Borresen-Dale, AL
Brown, PO
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (20) : 12963 - 12968
[36] RODENHUIS S, 1988, CANCER RES, V48, P5738
[37] Sanchez-Cespedes M, 2002, CANCER RES, V62, P3659
[38] Nucleophosmin mediates mammalian target of rapamycin-dependent actin cytoskeleton dynamics and proliferation in neurofibromin-deficient astrocytes
Sandsmark, Danielle K.
Zhang, Huabiao
Hegedus, Balazs
Pelletier, Corey L.
Weber, Jason D.
Gutmann, David H.
[J]. CANCER RESEARCH, 2007, 67 (10) : 4790 - 4799
[39] Sasaki H, 2007, ONCOL REP, V18, P623
[40] EVIDENCE FOR MENDELIAN INHERITANCE IN THE PATHOGENESIS OF LUNG-CANCER
SELLERS, TA
BAILEYWILSON, JE
ELSTON, RC
WILSON, AF
ELSTON, GZ
OOI, WL
ROTHSCHILD, H
[J]. JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1990, 82 (15) : 1272 - 1279

← 1 2 3 4 5 6 →