Somatic mutations affect key pathways in lung adenocarcinoma

Li Ding; Gad Getz; David A. Wheeler; Elaine R. Mardis; Michael D. McLellan; Kristian Cibulskis; Carrie Sougnez; Heidi Greulich; Donna M. Muzny; Margaret B. Morgan; Lucinda Fulton; Robert S. Fulton; Qunyuan Zhang; Michael C. Wendl; Michael S. Lawrence; David E. Larson; Ken Chen; David J. Dooling; Aniko Sabo; Alicia C. Hawes; Hua Shen; Shalini N. Jhangiani; Lora R. Lewis; Otis Hall; Yiming Zhu; Tittu Mathew; Yanru Ren; Jiqiang Yao; Steven E. Scherer; Kerstin Clerc; Ginger A. Metcalf; Brian Ng; Aleksandar Milosavljevic; Manuel L. Gonzalez-Garay; John R. Osborne; Rick Meyer; Xiaoqi Shi; Yuzhu Tang; Daniel C. Koboldt; Ling Lin; Rachel Abbott; Tracie L. Miner; Craig Pohl; Ginger Fewell; Carrie Haipek; Heather Schmidt; Brian H. Dunford-Shore; Aldi Kraja; Seth D. Crosby; Christopher S. Sawyer; Tammi Vickery; Sacha Sander; Jody Robinson; Wendy Winckler; Jennifer Baldwin; Lucian R. Chirieac; Amit Dutt; Tim Fennell; Megan Hanna; Bruce E. Johnson; Robert C. Onofrio; Roman K. Thomas; Giovanni Tonon; Barbara A. Weir; Xiaojun Zhao; Liuda Ziaugra; Michael C. Zody; Thomas Giordano; Mark B. Orringer; Jack A. Roth; Margaret R. Spitz; Ignacio I. Wistuba; Bradley Ozenberger; Peter J. Good; Andrew C. Chang; David G. Beer; Mark A. Watson; Marc Ladanyi; Stephen Broderick; Akihiko Yoshizawa; William D. Travis; William Pao; Michael A. Province; George M. Weinstock; Harold E. Varmus; Stacey B. Gabriel; Eric S. Lander; Richard A. Gibbs; Matthew Meyerson; Richard K. Wilson

doi:10.1038/nature07423

Somatic mutations affect key pathways in lung adenocarcinoma

Li Ding, Gad Getz, David A. Wheeler, Elaine R. Mardis, Michael D. McLellan, Kristian Cibulskis, Carrie Sougnez, Heidi Greulich, Donna M. Muzny, Margaret B. Morgan, Lucinda Fulton, Robert S. Fulton, Qunyuan Zhang, Michael C. Wendl, Michael S. Lawrence, David E. Larson, Ken Chen, David J. Dooling, Aniko Sabo, Alicia C. HawesHua Shen, Shalini N. Jhangiani, Lora R. Lewis, Otis Hall, Yiming Zhu, Tittu Mathew, Yanru Ren, Jiqiang Yao, Steven E. Scherer, Kerstin Clerc, Ginger A. Metcalf, Brian Ng, Aleksandar Milosavljevic, Manuel L. Gonzalez-Garay, John R. Osborne, Rick Meyer, Xiaoqi Shi, Yuzhu Tang, Daniel C. Koboldt, Ling Lin, Rachel Abbott, Tracie L. Miner, Craig Pohl, Ginger Fewell, Carrie Haipek, Heather Schmidt, Brian H. Dunford-Shore, Aldi Kraja, Seth D. Crosby, Christopher S. Sawyer, Tammi Vickery, Sacha Sander, Jody Robinson, Wendy Winckler, Jennifer Baldwin, Lucian R. Chirieac, Amit Dutt, Tim Fennell, Megan Hanna, Bruce E. Johnson, Robert C. Onofrio, Roman K. Thomas, Giovanni Tonon, Barbara A. Weir, Xiaojun Zhao, Liuda Ziaugra, Michael C. Zody, Thomas Giordano, Mark B. Orringer, Jack A. Roth, Margaret R. Spitz, Ignacio I. Wistuba, Bradley Ozenberger, Peter J. Good, Andrew C. Chang, David G. Beer, Mark A. Watson, Marc Ladanyi, Stephen Broderick, Akihiko Yoshizawa, William D. Travis, William Pao, Michael A. Province, George M. Weinstock, Harold E. Varmus, Stacey B. Gabriel, Eric S. Lander, Richard A. Gibbs, Matthew Meyerson, Richard K. Wilson

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Abstract

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.

Original language	English (US)
Pages (from-to)	1069-1075
Number of pages	7
Journal	Nature
Volume	455
Issue number	7216
DOIs	https://doi.org/10.1038/nature07423
State	Published - Oct 23 2008

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Ding, L., Getz, G., Wheeler, D. A., Mardis, E. R., McLellan, M. D., Cibulskis, K., Sougnez, C., Greulich, H., Muzny, D. M., Morgan, M. B., Fulton, L., Fulton, R. S., Zhang, Q., Wendl, M. C., Lawrence, M. S., Larson, D. E., Chen, K., Dooling, D. J., Sabo, A., ... Wilson, R. K. (2008). Somatic mutations affect key pathways in lung adenocarcinoma. Nature, 455(7216), 1069-1075. https://doi.org/10.1038/nature07423

Ding, L, Getz, G, Wheeler, DA, Mardis, ER, McLellan, MD, Cibulskis, K, Sougnez, C, Greulich, H, Muzny, DM, Morgan, MB, Fulton, L, Fulton, RS, Zhang, Q, Wendl, MC, Lawrence, MS, Larson, DE, Chen, K, Dooling, DJ, Sabo, A, Hawes, AC, Shen, H, Jhangiani, SN, Lewis, LR, Hall, O, Zhu, Y, Mathew, T, Ren, Y, Yao, J, Scherer, SE, Clerc, K, Metcalf, GA, Ng, B, Milosavljevic, A, Gonzalez-Garay, ML, Osborne, JR, Meyer, R, Shi, X, Tang, Y, Koboldt, DC, Lin, L, Abbott, R, Miner, TL, Pohl, C, Fewell, G, Haipek, C, Schmidt, H, Dunford-Shore, BH, Kraja, A, Crosby, SD, Sawyer, CS, Vickery, T, Sander, S, Robinson, J, Winckler, W, Baldwin, J, Chirieac, LR, Dutt, A, Fennell, T, Hanna, M, Johnson, BE, Onofrio, RC, Thomas, RK, Tonon, G, Weir, BA, Zhao, X, Ziaugra, L, Zody, MC, Giordano, T, Orringer, MB, Roth, JA, Spitz, MR, Wistuba, II, Ozenberger, B, Good, PJ, Chang, AC, Beer, DG, Watson, MA, Ladanyi, M, Broderick, S, Yoshizawa, A, Travis, WD, Pao, W, Province, MA, Weinstock, GM, Varmus, HE, Gabriel, SB, Lander, ES, Gibbs, RA, Meyerson, M & Wilson, RK 2008, 'Somatic mutations affect key pathways in lung adenocarcinoma', Nature, vol. 455, no. 7216, pp. 1069-1075. https://doi.org/10.1038/nature07423

@article{de3d6dd369e04a1fb1aa6317e389bca9,

title = "Somatic mutations affect key pathways in lung adenocarcinoma",

abstract = "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.",

author = "Li Ding and Gad Getz and Wheeler, {David A.} and Mardis, {Elaine R.} and McLellan, {Michael D.} and Kristian Cibulskis and Carrie Sougnez and Heidi Greulich and Muzny, {Donna M.} and Morgan, {Margaret B.} and Lucinda Fulton and Fulton, {Robert S.} and Qunyuan Zhang and Wendl, {Michael C.} and Lawrence, {Michael S.} and Larson, {David E.} and Ken Chen and Dooling, {David J.} and Aniko Sabo and Hawes, {Alicia C.} and Hua Shen and Jhangiani, {Shalini N.} and Lewis, {Lora R.} and Otis Hall and Yiming Zhu and Tittu Mathew and Yanru Ren and Jiqiang Yao and Scherer, {Steven E.} and Kerstin Clerc and Metcalf, {Ginger A.} and Brian Ng and Aleksandar Milosavljevic and Gonzalez-Garay, {Manuel L.} and Osborne, {John R.} and Rick Meyer and Xiaoqi Shi and Yuzhu Tang and Koboldt, {Daniel C.} and Ling Lin and Rachel Abbott and Miner, {Tracie L.} and Craig Pohl and Ginger Fewell and Carrie Haipek and Heather Schmidt and Dunford-Shore, {Brian H.} and Aldi Kraja and Crosby, {Seth D.} and Sawyer, {Christopher S.} and Tammi Vickery and Sacha Sander and Jody Robinson and Wendy Winckler and Jennifer Baldwin and Chirieac, {Lucian R.} and Amit Dutt and Tim Fennell and Megan Hanna and Johnson, {Bruce E.} and Onofrio, {Robert C.} and Thomas, {Roman K.} and Giovanni Tonon and Weir, {Barbara A.} and Xiaojun Zhao and Liuda Ziaugra and Zody, {Michael C.} and Thomas Giordano and Orringer, {Mark B.} and Roth, {Jack A.} and Spitz, {Margaret R.} and Wistuba, {Ignacio I.} and Bradley Ozenberger and Good, {Peter J.} and Chang, {Andrew C.} and Beer, {David G.} and Watson, {Mark A.} and Marc Ladanyi and Stephen Broderick and Akihiko Yoshizawa and Travis, {William D.} and William Pao and Province, {Michael A.} and Weinstock, {George M.} and Varmus, {Harold E.} and Gabriel, {Stacey B.} and Lander, {Eric S.} and Gibbs, {Richard A.} and Matthew Meyerson and Wilson, {Richard K.}",

note = "Funding Information: Acknowledgements We thank A. Lash, M. F. Zakowski, M. G. Kris and V. Rusch for intellectual contributions, and many members of the Baylor Human Genome Sequencing Center, the Broad Institute of Harvard and MIT, and the Genome Center at Washington University for support. This work was funded by grants from the National Human Genome Research Institute to E.S.L., R.A.G. and R.K.W.",

year = "2008",

month = oct,

day = "23",

doi = "10.1038/nature07423",

language = "English (US)",

volume = "455",

pages = "1069--1075",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7216",

}

TY - JOUR

T1 - Somatic mutations affect key pathways in lung adenocarcinoma

AU - Ding, Li

AU - Getz, Gad

AU - Wheeler, David A.

AU - Mardis, Elaine R.

AU - McLellan, Michael D.

AU - Cibulskis, Kristian

AU - Sougnez, Carrie

AU - Greulich, Heidi

AU - Muzny, Donna M.

AU - Morgan, Margaret B.

AU - Fulton, Lucinda

AU - Fulton, Robert S.

AU - Zhang, Qunyuan

AU - Wendl, Michael C.

AU - Lawrence, Michael S.

AU - Larson, David E.

AU - Chen, Ken

AU - Dooling, David J.

AU - Sabo, Aniko

AU - Hawes, Alicia C.

AU - Shen, Hua

AU - Jhangiani, Shalini N.

AU - Lewis, Lora R.

AU - Hall, Otis

AU - Zhu, Yiming

AU - Mathew, Tittu

AU - Ren, Yanru

AU - Yao, Jiqiang

AU - Scherer, Steven E.

AU - Clerc, Kerstin

AU - Metcalf, Ginger A.

AU - Ng, Brian

AU - Milosavljevic, Aleksandar

AU - Gonzalez-Garay, Manuel L.

AU - Osborne, John R.

AU - Meyer, Rick

AU - Shi, Xiaoqi

AU - Tang, Yuzhu

AU - Koboldt, Daniel C.

AU - Lin, Ling

AU - Abbott, Rachel

AU - Miner, Tracie L.

AU - Pohl, Craig

AU - Fewell, Ginger

AU - Haipek, Carrie

AU - Schmidt, Heather

AU - Dunford-Shore, Brian H.

AU - Kraja, Aldi

AU - Crosby, Seth D.

AU - Sawyer, Christopher S.

AU - Vickery, Tammi

AU - Sander, Sacha

AU - Robinson, Jody

AU - Winckler, Wendy

AU - Baldwin, Jennifer

AU - Chirieac, Lucian R.

AU - Dutt, Amit

AU - Fennell, Tim

AU - Hanna, Megan

AU - Johnson, Bruce E.

AU - Onofrio, Robert C.

AU - Thomas, Roman K.

AU - Tonon, Giovanni

AU - Weir, Barbara A.

AU - Zhao, Xiaojun

AU - Ziaugra, Liuda

AU - Zody, Michael C.

AU - Giordano, Thomas

AU - Orringer, Mark B.

AU - Roth, Jack A.

AU - Spitz, Margaret R.

AU - Wistuba, Ignacio I.

AU - Ozenberger, Bradley

AU - Good, Peter J.

AU - Chang, Andrew C.

AU - Beer, David G.

AU - Watson, Mark A.

AU - Ladanyi, Marc

AU - Broderick, Stephen

AU - Yoshizawa, Akihiko

AU - Travis, William D.

AU - Pao, William

AU - Province, Michael A.

AU - Weinstock, George M.

AU - Varmus, Harold E.

AU - Gabriel, Stacey B.

AU - Lander, Eric S.

AU - Gibbs, Richard A.

AU - Meyerson, Matthew

AU - Wilson, Richard K.

N1 - Funding Information: Acknowledgements We thank A. Lash, M. F. Zakowski, M. G. Kris and V. Rusch for intellectual contributions, and many members of the Baylor Human Genome Sequencing Center, the Broad Institute of Harvard and MIT, and the Genome Center at Washington University for support. This work was funded by grants from the National Human Genome Research Institute to E.S.L., R.A.G. and R.K.W.

PY - 2008/10/23

Y1 - 2008/10/23

N2 - 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.

AB - 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.

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UR - http://www.scopus.com/inward/citedby.url?scp=54549094903&partnerID=8YFLogxK

U2 - 10.1038/nature07423

DO - 10.1038/nature07423

M3 - Article

C2 - 18948947

AN - SCOPUS:54549094903

SN - 0028-0836

VL - 455

SP - 1069

EP - 1075

JO - Nature

JF - Nature

IS - 7216

ER -

Somatic mutations affect key pathways in lung adenocarcinoma

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