Tracing Oncogene Rearrangements in the Mutational History of Lung Adenocarcinoma

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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.
Publisher
CELL PRESS
Issue Date
2019-06
Language
English
Article Type
Article
Citation

CELL, v.177, no.7, pp.1842 - +

ISSN
0092-8674
DOI
10.1016/j.cell.2019.05.013
URI
http://hdl.handle.net/10203/263092
Appears in Collection
MSE-Journal Papers(저널논문)
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