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

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)1069-1075
Number of pages7
JournalNature
Volume455
Issue number7216
DOIs
StatePublished - Oct 23 2008
Externally publishedYes

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Mutation
Genes
Neoplasms
Eph Family Receptors
Vascular Endothelial Growth Factor Receptor
Tumor Suppressor Genes
DNA Sequence Analysis
DNA Repair
Protein-Tyrosine Kinases
Single Nucleotide Polymorphism
Adenocarcinoma of lung
Carcinogenesis
Smoking
Gene Expression

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Ding, L., Getz, G., Wheeler, D. A., Mardis, E. R., McLellan, M. D., Cibulskis, K., ... Wilson, R. K. (2008). Somatic mutations affect key pathways in lung adenocarcinoma. Nature, 455(7216), 1069-1075. https://doi.org/10.1038/nature07423

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

In: Nature, Vol. 455, No. 7216, 23.10.2008, p. 1069-1075.

Research output: Contribution to journalArticle

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
Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature. 2008 Oct 23;455(7216):1069-1075. https://doi.org/10.1038/nature07423
Ding, Li ; Getz, Gad ; Wheeler, David A. ; Mardis, Elaine R. ; McLellan, Michael D. ; Cibulskis, Kristian ; Sougnez, Carrie ; Greulich, Heidi ; Muzny, Donna M. ; Morgan, Margaret B. ; Fulton, Lucinda ; Fulton, Robert S. ; Zhang, Qunyuan ; Wendl, Michael C. ; Lawrence, Michael S. ; Larson, David E. ; Chen, Ken ; Dooling, David J. ; Sabo, Aniko ; Hawes, Alicia C. ; Shen, Hua ; Jhangiani, Shalini N. ; Lewis, Lora R. ; Hall, Otis ; Zhu, Yiming ; Mathew, Tittu ; Ren, Yanru ; Yao, Jiqiang ; Scherer, Steven E. ; Clerc, Kerstin ; Metcalf, Ginger A. ; Ng, Brian ; Milosavljevic, Aleksandar ; Gonzalez-Garay, Manuel L. ; Osborne, John R. ; Meyer, Rick ; Shi, Xiaoqi ; Tang, Yuzhu ; Koboldt, Daniel C. ; Lin, Ling ; Abbott, Rachel ; Miner, Tracie L. ; Pohl, Craig ; Fewell, Ginger ; Haipek, Carrie ; Schmidt, Heather ; Dunford-Shore, Brian H. ; Kraja, Aldi ; Crosby, Seth D. ; Sawyer, Christopher S. ; Vickery, Tammi ; Sander, Sacha ; Robinson, Jody ; Winckler, Wendy ; Baldwin, Jennifer ; Chirieac, Lucian R. ; Dutt, Amit ; Fennell, Tim ; Hanna, Megan ; Johnson, Bruce E. ; Onofrio, Robert C. ; Thomas, Roman K. ; Tonon, Giovanni ; Weir, Barbara A. ; Zhao, Xiaojun ; Ziaugra, Liuda ; Zody, Michael C. ; Giordano, Thomas ; Orringer, Mark B. ; Roth, Jack A. ; Spitz, Margaret R. ; Wistuba, Ignacio I. ; Ozenberger, Bradley ; Good, Peter J. ; Chang, Andrew C. ; Beer, David G. ; Watson, Mark A. ; Ladanyi, Marc ; Broderick, Stephen ; Yoshizawa, Akihiko ; Travis, William D. ; Pao, William ; Province, Michael A. ; Weinstock, George M. ; Varmus, Harold E. ; Gabriel, Stacey B. ; Lander, Eric S. ; Gibbs, Richard A. ; Meyerson, Matthew ; Wilson, Richard K. / Somatic mutations affect key pathways in lung adenocarcinoma. In: Nature. 2008 ; Vol. 455, No. 7216. pp. 1069-1075.
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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.

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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