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공공누리This item is licensed Korea Open Government License

Title
Tracing Oncogene Rearrangements in the Mutational History of Lung Adenocarcinoma
Author(s)
이준구주영석이준학
Publisher
Cell Press
Publication Year
2019-06-13
Abstract
Summary 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. Highlights Driver fusion oncogenes in LADCs are generated from complex genomic rearrangements These rearrangements are frequently copy-number balanced, resembling germline events Fusions often arise in early decades of life, leaving long latency to diagnosis SETD2 inactivation is cooperative with fusion oncogenes in TP53-wild-type LADCs Graphical Abstract [DISPLAY OMISSION]
Keyword
Fusion oncogene; Chromothripsis; Chromoplexy; Complex genomic rearrangement; Balanced rearrangement; p53; Whole-genome duplication; SETD2; Lung adenocarcinoma; Tumor initiation
Journal Title
Cell;
Citation Volume
177
ISSN
0092-8674
DOI
10.1016/j.cell.2019.05.013
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Appears in Collections:
7. KISTI 연구성과 > 학술지 발표논문
URI
https://repository.kisti.re.kr/handle/10580/16063
Fulltext
 https://scienceon.kisti.re.kr/srch/selectPORSrchArticle.do?cn=NART100317867
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