Journal
CELL
Volume 177, Issue 7, Pages 1842-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2019.05.013
Keywords
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Categories
Funding
- National Human Genome Research Institute (NHGRI) [5U54HG003067]
- Washington University in St. Louis
- NHGRI [U54 HG003079]
- Washington University Cancer Genome Initiative
- Siteman Cancer Center
- Korea Health Technology R&D Project through the Korea Health Industry Development Institute - Ministry of Health & Welfare of Korea [HI16C2387, HI17C1836]
- Suh Kyungbae Foundation [SUHF-18010082]
- National Research Foundation of Korea grant - Korean government (MSIP) [NRF-2014R1A2A2A05003665]
- 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 (Korea) [10067758]
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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 fusiononcogene-driven LADCs had frequent SETD2 mutations. Our study highlights LADC oncogenesis driven by endogenous mutational processes.
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