Genome-wide methylation profiling of ovarian cancer patient-derived xenografts treated with the demethylating agent decitabine identifies novel epigenetically regulated genes and pathways

Autor: Steven de Jong, Tushar Tomar, Gert Jan Meersma, Ate Gj van der Zee, G. Bea A. Wisman, Nicolette G. Alkema, Rieks L Hoekman, Harry G. Klip
Přispěvatelé: Guided Treatment in Optimal Selected Cancer Patients (GUTS), Targeted Gynaecologic Oncology (TARGON)
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
lcsh:Medicine
Mice
SCID
Epigenesis
Genetic
chemistry.chemical_compound
Mice
Mice
Inbred NOD
Tumor Cells
Cultured
Genetics(clinical)
DNA METHYLATION
Genetics (clinical)
IN-VIVO
Ovarian Neoplasms
PLATINUM
Reverse Transcriptase Polymerase Chain Reaction
TUMOR XENOGRAFTS
SRC-KINASE CSK
Gene Expression Regulation
Neoplastic
DNA methylation
Azacitidine
Molecular Medicine
Female
CPG SITES
Epigenetic therapy
medicine.drug
Signal Transduction
EXPRESSION
Antimetabolites
Antineoplastic
lcsh:QH426-470
CARCINOMA
Decitabine
Biology
Real-Time Polymerase Chain Reaction
VALIDATION
03 medical and health sciences
MICROARRAY
Genetics
medicine
Animals
Humans
Epigenetics
RNA
Messenger
Molecular Biology
Gene Expression Profiling
Research
lcsh:R
Cancer
Epigenome
medicine.disease
Xenograft Model Antitumor Assays
Demethylating agent
lcsh:Genetics
030104 developmental biology
chemistry
Cancer research
Zdroj: Genome Medicine, Vol 8, Iss 1, Pp 1-15 (2016)
Genome Medicine
Genome medicine, 8(107). BMC
ISSN: 1756-994X
DOI: 10.1186/s13073-016-0361-5
Popis: Background In high-grade serous ovarian cancer (HGSOC), intrinsic and/or acquired resistance against platinum-containing chemotherapy is a major obstacle for successful treatment. A low frequency of somatic mutations but frequent epigenetic alterations, including DNA methylation in HGSOC tumors, presents the cancer epigenome as a relevant target for innovative therapy. Patient-derived xenografts (PDXs) supposedly are good preclinical models for identifying novel drug targets. However, the representativeness of global methylation status of HGSOC PDXs compared to their original tumors has not been evaluated so far. Aims of this study were to explore how representative HGSOC PDXs are of their corresponding patient tumor methylome and to evaluate the effect of epigenetic therapy and cisplatin on putative epigenetically regulated genes and their related pathways in PDXs. Methods Genome-wide analysis of the DNA methylome of HGSOC patients with their corresponding PDXs, from different generations, was performed using Infinium 450 K methylation arrays. Furthermore, we analyzed global methylome changes after treatment of HGSOC PDXs with the FDA approved demethylating agent decitabine and cisplatin. Findings were validated by bisulfite pyrosequencing with subsequent pathway analysis. Publicly available datasets comprising HGSOC patients were used to analyze the prognostic value of the identified genes. Results Only 0.6–1.0 % of all analyzed CpGs (388,696 CpGs) changed significantly (p
Databáze: OpenAIRE
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