Cited by 233Cancer Genomics and DiagnosticsLung Cancer Treatments and MutationsChromatin Remodeling and Cancer

Tracing Oncogene Rearrangements in the Mutational History of Lung Adenocarcinoma

Open access
Lee, Jake June-Koo, Park, Seongyeol, Park, Hansol, Kim, Sehui, Lee, Jongkeun, Lee, Junehawk, Youk, Jeonghwan, Yi, Kijong +10 more·2019·Cell

Abstract

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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Crossref · 10.1016/j.cell.2019.05.013

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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
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
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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