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Somatic mutations affect key pathways in lung adenocarcinoma
Open accessAbstract
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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In the citing paper
“While gain of 7p and loss of 8p have been previously reported to occur specifically in EGFR mutated adenocarcinomas16, 17, gain of 16p was a novel association.”
From Integrative Genomic Analyses Identifies GGA2 as a Cooperative Driver of EGFR-Mediated Lung Tumorigenesis (2019) · cites this paper as [17]
Experimental — accuracy not yet measuredIn the citing paper
“KRAS mutations predominate in NSCLCs, accounting for ~78% of all RAS mutations found in such tumours17. The activating missense KRAS mutations that occur in ~25% of NSCLCs19–23 are typically mutually exclusive with other clinically actionable driver mutations, such as those in EGFR, BRAF and ALK24.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [22]
In the citing paper
“Importantly, large-scale profiling studies utilizing either whole exome sequencing or broad targeted sequencing panels in NSCLC tumors have revealed multiple non-random patterns of co-occurring or mutually exclusive mutations, which typically vary depending on the particular oncogenic driver mutation15, 34, 58–62.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [60]
In the citing paper
“Activating mutations in KRAS are the most prevalent oncogenic driver event in both early-stage and metastatic LUAD, occurring in 25–32% of tumors34, 59, 60, 62, 67.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [60]
In the citing paper
“Similarly, mutations in ERBB4 were identified in cancer, particularly melanoma (Prickett et al., 2009), lung adenocarcinoma (Ding et al., 2008), and medulloblastoma (Gilbertson et al., 2001).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Ding et al., 2008
In the citing paper
“Gain/amplification of the mutant EGFR allele has previously been reported to frequently occur in LAC and is known to drive tumor progression17.”
From Integrative Genomic Analyses Identifies GGA2 as a Cooperative Driver of EGFR-Mediated Lung Tumorigenesis (2019) · cites this paper as [17]
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Citations
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Cited by
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Nishimura, R., Osako, T., Nishiyama, Y., Tashima, R., Nakano, M., Fujisue, M., Toyozumi, Y., & Arima, N. (2013) · Oncology · doi:10.1159/000353099 · Cited by 13,239
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Inferring tumour purity and stromal and immune cell admixture from expression data
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Self-citationSignatures of mutational processes in human cancer
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Self-citation
Metadata
- Authors
- 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., Hawes, A. C., Shen, H., Jhangiani, S. N., Lewis, L. R., Hall, O., Zhu, Y., Mathew, T., Ren, Y., Yao, J., Scherer, S. E., Clerc, K., Metcalf, G. A., Ng, B., Milosavljevic, A., Gonzalez-Garay, M. L., Osborne, J. R., Meyer, R., Shi, X., Tang, Y., Koboldt, D. C., Lin, L., Abbott, R., Miner, T. L., Pohl, C., Fewell, G., Haipek, C., Schmidt, H., Dunford-Shore, B. H., Kraja, A., Crosby, S. D., Sawyer, C. S., Vickery, T., Sander, S., Robinson, J., Winckler, W., Baldwin, J., Chirieac, L. R., Dutt, A., Fennell, T., Hanna, M., Johnson, B. E., Onofrio, R. C., Thomas, R. K., Tonon, G., Weir, B. A., Zhao, X., Ziaugra, L., Zody, M. C., Giordano, T., Orringer, M. B., Roth, J. A., Spitz, M. R., Wistuba, I. I., Ozenberger, B., Good, P. J., Chang, A. C., Beer, D. G., Watson, M. A., Ladanyi, M., Broderick, S., Yoshizawa, A., Travis, W. D., Pao, W., Province, M. A., Weinstock, G. M., Varmus, H. E., Gabriel, S. B., Lander, E. S., Gibbs, R. A., Meyerson, M., & Wilson, R. K.
- Affiliations
- Washington University in St. Louis (US)
- Broad Institute (US)
- Baylor College of Medicine (US)
- Brigham and Women's Hospital (US)
- Dana-Farber Cancer Institute (US)
- Max Planck Society (DE)
- University of Michigan (US)
- The University of Texas MD Anderson Cancer Center (US)
- National Institutes of Health (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Meyerson, Matthew
- Wilson, Richard K.
- ORCID
- Ding, Li
- Getz, Gad
- Wheeler, David A.
- Mardis, Elaine R.
- McLellan, Michael D.
- Cibulskis, Kristian
- Greulich, Heidi
- Muzny, Donna M.
- Morgan, Margaret B.
- Fulton, Lucinda
- Fulton, Robert S.
- Wendl, Michael C.
- Lawrence, Michael S.
- Larson, David E.
- Chen, Ken
- Sabo, Aniko
- Shen, Hua
- Jhangiani, Shalini N.
- Zhu, Yiming
- Ren, Yanru
- Yao, Jiqiang
- Scherer, Steven E.
- Metcalf, Ginger A.
- Ng, Brian
- Milosavljevic, Aleksandar
- Tang, Yuzhu
- Koboldt, Daniel C.
- Lin, Ling
- Pohl, Craig
- Crosby, Seth D.
- Vickery, Tammi
- Winckler, Wendy
- Chirieac, Lucian R.
- Dutt, Amit
- Fennell, Tim
- Johnson, Bruce E.
- Thomas, Roman K.
- Tonon, Giovanni
- Zody, Michael C.
- Giordano, Thomas
- Roth, Jack A.
- Wistuba, Ignacio I.
- Ozenberger, Bradley
- 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.
- Venue
- Nature
- Published
- 2008-10
- Volume
- 455
- Issue
- 7216
- Pages
- 1069-1075
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2694412
- OpenAlex
- W2163798887
- Cited by
- 2,681
- References
- 54
- Citations by year
- 2026: 21 · 2025: 48 · 2024: 53 · 2023: 122 · 2022: 124 · 2021: 149 · 2020: 147 · 2019: 145 · 2018: 121 · 2017: 141 · 2016: 158 · 2015: 206 · 2014: 254 · 2013: 213 · 2012: 227
- FWCI
- 167.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Deep Blue (University of Michigan) (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Broad Institute
- National Human Genome Research Institute (U54HG003067)
- National Cancer Institute (U19CA084953, P50CA070907, R01CA154365)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- lung adenocarcinoma, somatic mutations, carcinogenesis, tyrosine kinase, EphA3, Eph receptors, KDR, NTRK, tumor suppressor, neurofibromatosis type 1, APC, RB1, ATM, PTPRD, LRP1B, smoking, DNA repair deficiency, signaling pathways, molecular targets, mutational landscape
- MeSH terms
- Adenocarcinoma, Bronchiolo-Alveolar, Female, Humans, Lung Neoplasms, Male, Mutation, Proto-Oncogenes, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Gene Dosage
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