Tracing Oncogene Rearrangements in the Mutational History of Lung Adenocarcinoma
Open accessAbstract
Mutational processes giving rise to lung adenocarcinomas (LADCs) in non-smokers remain elusive. We analyzed 138 LADC whole genomes, including 83 cases with minimal contribution of smoking-associated mutational signature. Genomic rearrangements were not correlated with smoking-associated mutations and frequently served as driver events of smoking-signature-low LADCs. Complex genomic rearrangements, including chromothripsis and chromoplexy, generated 74% of known fusion oncogenes, including EML4-ALK, CD74-ROS1, and KIF5B-RET. Unlike other collateral rearrangements, these fusion-oncogene-associated rearrangements were frequently copy-number-balanced, representing a genomic signature of early oncogenesis. Analysis of mutation timing revealed that fusions and point mutations of canonical oncogenes were often acquired in the early decades of life. During a long latency, cancer-related genes were disrupted or amplified by complex rearrangements. The genomic landscape was different between subgroups-EGFR-mutant LADCs had frequent whole-genome duplications with p53 mutations, whereas fusion-oncogene-driven LADCs had frequent SETD2 mutations. Our study highlights LADC oncogenesis driven by endogenous mutational processes.
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ALK-rearranged LUAD are less likely to harbor TP53 alterations (23.8%-26.5%) than other driver subgroups.
“but are less likely to harbor TP53 alterations (23.8%−26.5%) compared with other driver subgroups15, 128.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [128]
CDKN2B alterations are enriched in advanced-stage ALK-rearranged LUAD, at 26.5%.
“and CDKN2B (26.5%)”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [128]
CDKN2A alterations are enriched in advanced-stage LUAD with ALK rearrangement, at 32.5%.
“advanced-stage ALK-rearrangement -positive LUAD are enriched in somatic alterations in CDKN2A (32.5%)”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [128]
TP53 co-mutations promote genomic instability in ALK-rearranged LUAD.
“TP53 co-mutations promote genomic instability”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [128]
TP53 co-mutations are an independent negative prognostic factor in ALK-rearranged LUAD regardless of systemic therapy type.
“are an independent negative prognostic factor in ALK-re-arrangement-positive LUAD, regardless of the type of systemic therapy used128–130.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [128]
Additional co-mutations are rare in ALK-rearranged LUAD.
“The prevalence of additional co-mutations in this group is low,128”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [128]
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- Authors
- Lee, J. J.-K., Park, S., Park, H., Kim, S., Lee, J., Lee, J., Youk, J., Yi, K., An, Y., Park, I. K., Kang, C. H., Chung, D. H., Kim, T. M., Jeon, Y. K., Hong, D., Park, P. J., Ju, Y. S., & Kim, Y. T.
- Affiliations
- Harvard University (US)
- Korea Advanced Institute of Science and Technology (KR)
- Seoul National University (KR)
- National Cancer Center (KR)
- Corresponding author
- Ju, Young Seok
- Kim, Young Tae
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2019-06
- Volume
- 177
- Issue
- 7
- Pages
- 1842-1857.e21
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2947095040
- Cited by
- 233
- References
- 71
- Citations by year
- 2026: 13 · 2025: 19 · 2024: 26 · 2023: 36 · 2022: 38 · 2021: 60 · 2020: 31 · 2019: 9
- FWCI
- 11.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Human Genome Research Institute (5U54HG003067)
- Washington University in St. Louis
- NHGRI (U54 HG003079)
- Washington University Cancer Genome Initiative
- Siteman Cancer Center
- Korea Health Technology R&D Project
- Korea Health Industry Development Institute
- Ministry of Health & Welfare of Korea (HI16C2387, HI17C1836)
- Suh Kyungbae Foundation (SUHF-18010082)
- National Research Foundation of Korea (NRF-2014R1A2A2A05003665)
- Research Program 2016
- Seoul National University College of Medicine Research Foundation (800-20160251)
- Ludwig Center at Harvard
- Korea Institute of Science and Technology Information (K-17-L03-C022)
- Ministry of Trade, Industry, and Energy (10067758)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- lung adenocarcinoma, oncogene rearrangement, mutational signatures, non-smokers, chromothripsis, chromoplexy, fusion oncogenes, EML4-ALK fusion, KIF5B-RET, mutation timing, EGFR mutation, whole-genome duplication, TP53 mutation, SETD2 mutation, carcinogenesis
- MeSH terms
- Adenocarcinoma of Lung, Female, Humans, Lung Neoplasms, Male, Mutation, Gene Rearrangement, Oncogene Proteins, Fusion
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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.
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