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Genetic Profiles Associated with Chemoresistance in Patient-Derived Xenograft Models of Ovarian Cancer

Authors
 Lan Ying Li  ;  Hee Jung Kim  ;  Sun Ae Park  ;  So Hyun Lee  ;  Lee Kyung Kim  ;  Jung Yun Lee  ;  Sunghoon Kim  ;  Young Tae Kim  ;  Sang Wun Kim  ;  Eun Ji Nam 
Citation
 Cancer Research and Treatment, Vol.51(3) : 1117-1127, 2019 
Journal Title
 Cancer Research and Treatment 
ISSN
 1598-2998 
Issue Date
2019
Keywords
Chemoresistance ; Ovarian neoplasms ; Patient-derived xenografts ; RNA sequence analysis ; Whole exome sequencing
Abstract
PURPOSE: Recurrence and chemoresistance (CR) are the leading causes of death in patients with high-grade serous carcinoma (HGSC) of the ovary. The aim of this study was to identify genetic changes associated with CR mechanisms using a patient-derived xenograft (PDX) mouse model and genetic sequencing. MATERIALS AND METHODS: To generate a CR HGSC PDX tumor, mice bearing subcutaneously implanted HGSC PDX tumors were treated with paclitaxel and carboplatin. We compared gene expression and mutations between chemosensitive (CS) and CR PDX tumors with whole exome and RNA sequencing and selected candidate genes. Correlations between candidate gene expression and clinicopathological variables were explored using the Cancer Genome Atlas (TCGA) database and the Human Protein Atlas (THPA). RESULTS: Three CR and four CS HGSC PDX tumor models were successfully established. RNA sequencing analysis of the PDX tumors revealed that 146 genes were significantly up-regulated and 54 genes down-regulated in the CR group compared with the CS group. Whole exome sequencing analysis showed 39 mutation sites were identified which only occurred in CR group. Differential expression of SAP25, HLA-DPA1, AKT3, and PIK3R5 genes and mutation of TMEM205 and POLR2A may have important functions in the progression of ovarian cancer chemoresistance. According to TCGA data analysis, patients with high HLA-DPA1 expression were more resistant to initial chemotherapy (p=0.030; odds ratio, 1.845). CONCLUSION: We successfully established CR ovarian cancer PDX mouse models. PDX-based genetic profiling study could be used to select some candidate genes that could be targeted to overcome chemoresistance of ovarian cancer.
Files in This Item:
T201903039.pdf Download
DOI
10.4143/crt.2018.405
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Obstetrics and Gynecology (산부인과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Kim, Sang Wun(김상운) ORCID logo https://orcid.org/0000-0002-8342-8701
Kim, Sung Hoon(김성훈) ORCID logo https://orcid.org/0000-0002-1645-7473
Kim, Young Tae(김영태) ORCID logo https://orcid.org/0000-0002-7347-1052
Nam, Eun Ji(남은지)
Li, Lan Ying(리란영)
Lee, Jung-Yun(이정윤) ORCID logo https://orcid.org/0000-0001-7948-1350
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/171175
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