Patterns and impacts of genomic rearrangements in lung tumorigenesis폐선암에 존재하는 구조 변이의 양상 및 암 발생과정에서의 역할에 대한 유전체학적 연구

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Lung adenocarcinomas (LADCs) are the most frequent type of lung cancer and also the major cancer type of high mortality worldwide. However, genomic rearrangements in LADCs have not studied well. Whole-genome sequencing enabled us to detect complex genomic rearrangements such as chromothripsis and chromoplexy. I analyzed 138 LADC whole-genome sequences and found various types of somatic mutations including genomic rearrangements. Using the amount and number of mutational signature 4, which is associated with smoking, I classified LADCs into smoking-related and –unrelated ones. I found the much higher number of point mutations in smoking-related LADCs (24.0/Mbp vs. 1.9/Mbp, p < 0.0001), but the number of genomic rearrangements were not significantly higher in smoking-related LADCs than smoking-unrelated LADCs (171 vs. 145, p = 0.2665). The most genomic rearrangements were the part of complex genomic rearrangements (16,585 out of 21,420, 77%). The majority of fusion oncogenes, including EML4-ALK, CD74-ROS1, and KIF5B-RET, were also made by complex genomic rearrangements (29 out of 39, 74%). At least 48% of fusion oncogenes by complex rearrangements had shown a balanced pattern of copy number variations, and that was a distinct feature of fusion oncogene-generating rearrangements compared to collateral rearrangements. Using the information of point mutations and copy number variations, I assumed the timing of occurrence of fusion oncogenes. More than half of fusion oncogenes were generated decades earlier than diagnosis (median age 27 vs. 55). It implies the long latency of oncogenic events during tumorigenesis. I also found amplification of oncogene and loss of tumor suppressor gene by genomic rearrangements in many samples. The most frequently amplified oncogenes were TERT (n = 21) and MDM2 (n = 11). I compared mutational profiles among driver groups of LADCs and found distinct features of fusion oncogene-positive LADCs: intact TP53 (odds ratio = 0.17, p = 0.0001) and frequent SETD2 inactivation (odds ratio = 21.44, p = 0.0049). Our study highlights the pattern and impact of genomic rearrangements in LADC oncogenesis.
Advisors
Ju, Young Seokresearcher주영석researcher
Description
한국과학기술원 :의과학대학원,
Publisher
한국과학기술원
Issue Date
2020
Identifier
325007
Language
eng
Description

학위논문(박사) - 한국과학기술원 : 의과학대학원, 2020.2,[iv, 105 p. :]

Keywords

Lung adenocarcinoma▼aGenomic rearrangement▼aChromothripsis▼aChromoplexy▼aFusion oncogene▼aTiming of amplification▼aTP53▼aSETD2; 전장 유전체 염기서열▼a폐선암▼a구조 변이▼a융합 종양유전자▼a증폭 발생 시점▼aTP53▼aSETD2

URI
http://hdl.handle.net/10203/283570
Link
http://library.kaist.ac.kr/search/detail/view.do?bibCtrlNo=907107&flag=dissertation
Appears in Collection
MSE-Theses_Ph.D.(박사논문)
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