Transcriptomics,Genomics

Dataset Information

172

Genomic signatures of platinum re-sensitization in ovarian cancer [RNA-Seq]


ABSTRACT: Epigenetic changes, particularly DNA methylation aberrations have been implicated in acquired resistance to platinum in ovarian cancer. A multi-institutional randomized clinical trial compared a regimen of a DNA methyl transferase (DNMT) inhibitor guadecitabine and carboplatin to physician’s choice chemotherapy for patients with recurrent platinum resistant ovarian cancer. Tumor biopsies or malignant ascites were collected at day 1 of cycle 1 (pre-guadecitabine) and after two cycles of treatment (post-decitabine). The goal of the current study was to analyze guadecitabine-induced DNA methylation and gene expression changes and correlate pretreatment levels with clinical outcomes. Epigenomic and transcriptomic profiling using the Infinium HumanMethylation450 BeadChip (HM450) and RNA sequencing revealed extensive methylation and gene expression changes induced by guadecitabine in ovarian tumors. Ninety-four gene promoters were significantly hypomethylated after treatment with guadecitabine and 949 genes were differentially expressed in pre vs. post-treatment tumors. Pathways associated with immune reactivation and DNA repair were significantly altered by guadecitabine treatment. Expression levels of 1155 genes involved in 25 networks on day 1 of cycle 1 correlated with progression free survival. Increased expression of selected genes (e.g. DOK2, miR193a) silenced through promoter methylation restored platinum sensitivity in ovarian cancer cells. Together, these results support that guadecitabine altered DNA methylation and expression of genes and gene networks correlate with re-sensitization to carboplatin in ovarian cancer patients. Overall design: 93 samples are analyzed, including tumor samples collected from patients with platinum resistant ovarian cancer before treated by guadecitabine and after treated by guadecitabine.

INSTRUMENT(S): Illumina HiSeq 2000 (Homo sapiens)

SUBMITTER: Kenneth Nephew  

PROVIDER: GSE102118 | GEO | 2018-06-05

REPOSITORIES: GEO

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Publications

Genomic and Epigenomic Signatures in Ovarian Cancer Associated with Resensitization to Platinum Drugs.

Fang Fang F   Cardenas Horacio H   Huang Hao H   Jiang Guanglong G   Perkins Susan M SM   Zhang Chi C   Keer Harold N HN   Liu Yunlong Y   Nephew Kenneth P KP   Matei Daniela D  

Cancer research 20171211 3


DNA methylation aberrations have been implicated in acquired resistance to platinum drugs in ovarian cancer. In this study, we elucidated an epigenetic signature associated with platinum drug resensitization that may offer utility in predicting the outcomes of patients who are coadministered a DNA methyltransferase inhibitor. The ovarian cancer specimens we analyzed were derived from a recent clinical trial that compared the responses of patients with recurrent platinum-resistant ovarian cancer  ...[more]

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