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Mapping the Hallmarks of Lung Adenocarcinoma with Massively Parallel Sequencing
Open accessAbstract
Lung adenocarcinoma, the most common subtype of non-small cell lung cancer, is responsible for more than 500,000 deaths per year worldwide. Here, we report exome and genome sequences of 183 lung adenocarcinoma tumor/normal DNA pairs. These analyses revealed a mean exonic somatic mutation rate of 12.0 events/megabase and identified the majority of genes previously reported as significantly mutated in lung adenocarcinoma. In addition, we identified statistically recurrent somatic mutations in the splicing factor gene U2AF1 and truncating mutations affecting RBM10 and ARID1A. Analysis of nucleotide context-specific mutation signatures grouped the sample set into distinct clusters that correlated with smoking history and alterations of reported lung adenocarcinoma genes. Whole-genome sequence analysis revealed frequent structural rearrangements, including in-frame exonic alterations within EGFR and SIK2 kinases. The candidate genes identified in this study are attractive targets for biological characterization and therapeutic targeting of lung adenocarcinoma.
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“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 [23]
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 [62]
In the citing paper
“Landmark large scale sequencing studies have established a census of major KRAS co-mutations in both early-stage and advanced LUAD15, 34, 59, 62.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [62]
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“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 [62]
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Self-citation
Metadata
- Authors
- Imielinski, M., Berger, A. H., Hammerman, P. S., Hernandez, B., Pugh, T. J., Hodis, E., Cho, J., Suh, J., Capelletti, M., Sivachenko, A., Sougnez, C., Auclair, D., Lawrence, M. S., Stojanov, P., Cibulskis, K., Choi, K., de Waal, L., Sharifnia, T., Brooks, A., Greulich, H., Banerji, S., Zander, T., Seidel, D., Leenders, F., Ansén, S., Ludwig, C., Engel-Riedel, W., Stoelben, E., Wolf, J., Goparju, C., Thompson, K., Winckler, W., Kwiatkowski, D., Johnson, B. E., Jänne, P. A., Miller, V. A., Pao, W., Travis, W. D., Pass, H. I., Gabriel, S. B., Lander, E. S., Thomas, R. K., Garraway, L. A., Getz, G., & Meyerson, M.
- Affiliations
- Broad Institute (US)
- Samsung Medical Center (KR)
- NYU Langone Health (US)
- Dana-Farber Cancer Institute (US)
- University of Cologne (DE)
- Memorial Sloan Kettering Cancer Center (US)
- Vanderbilt University (US)
- Corresponding author
- Meyerson, Matthew
- ORCID
- Imielinski, Marcin
- Berger, Alice H.
- Hammerman, Peter S.
- Hernandez, Bryan
- Pugh, Trevor J.
- Hodis, Eran
- Cho, Jeonghee
- Suh, James
- Capelletti, Marzia
- Sivachenko, Andrey
- Auclair, Daniel
- Lawrence, Michael S.
- Cibulskis, Kristian
- Sharifnia, Tanaz
- Brooks, Angela
- Greulich, Heidi
- Banerji, Shantanu
- Zander, Thomas
- Seidel, Danila
- Stoelben, Erich
- Wolf, Jürgen
- Winckler, Wendy
- Kwiatkowski, David
- Johnson, Bruce E.
- Miller, Vincent A.
- Pao, William
- Travis, William D.
- Pass, Harvey I.
- Gabriel, Stacey B.
- Lander, Eric S.
- Thomas, Roman K.
- Garraway, Levi A.
- Getz, Gad
- Meyerson, Matthew
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-09
- Volume
- 150
- Issue
- 6
- Pages
- 1107-1120
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3557932
- OpenAlex
- W2042386784
- Cited by
- 1,789
- References
- 79
- Citations by year
- 2026: 38 · 2025: 66 · 2024: 81 · 2023: 94 · 2022: 124 · 2021: 128 · 2020: 155 · 2019: 131 · 2018: 138 · 2017: 138 · 2016: 145 · 2015: 187 · 2014: 199 · 2013: 148 · 2012: 14
- FWCI
- 141.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 380 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Max Planck Institute for Plasma Physics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Broad Institute
- Canadian Institutes of Health Research
- National Human Genome Research Institute (U54HG003067)
- National Cancer Institute (R01CA109038, R01CA116020, T32 CA9216, P50CA090578, T32CA009216)
- National Institute of General Medical Sciences (T32 GM07753, T32GM007753)
- 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, mutational signatures, U2AF1, RBM10, ARID1A, structural rearrangement, EGFR, SIK2, smoking history, cancer genomics, therapeutic target
- MeSH terms
- Adenocarcinoma of Lung, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Cohort Studies, Genes, Neoplasm, Genome-Wide Association Study, High-Throughput Nucleotide Sequencing, Exome, Mutation Rate
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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