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

Overview of attention for article published in Genome Medicine, October 2016
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  • In the top 5% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (93rd percentile)
  • High Attention Score compared to outputs of the same age and source (85th percentile)

Mentioned by

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3 news outlets
blogs
1 blog
twitter
12 X users
facebook
2 Facebook pages
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2 Google+ users

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49 Mendeley
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Title
Genome-wide methylation profiling of ovarian cancer patient-derived xenografts treated with the demethylating agent decitabine identifies novel epigenetically regulated genes and pathways
Published in
Genome Medicine, October 2016
DOI 10.1186/s13073-016-0361-5
Pubmed ID
Authors

Tushar Tomar, Steven de Jong, Nicolette G. Alkema, Rieks L. Hoekman, Gert Jan Meersma, Harry G. Klip, Ate GJ van der Zee, G. Bea A. Wisman

Abstract

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. 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. Only 0.6-1.0 % of all analyzed CpGs (388,696 CpGs) changed significantly (p < 0.01) during propagation, showing that HGSOC PDXs were epigenetically stable. Treatment of F3 PDXs with decitabine caused a significant reduction in methylation in 10.6 % of CpG sites in comparison to untreated PDXs (p < 0.01, false discovery rate <10 %). Cisplatin treatment had a marginal effect on the PDX methylome. Pathway analysis of decitabine-treated PDX tumors revealed several putative epigenetically regulated pathways (e.g., the Src family kinase pathway). In particular, the C-terminal Src kinase (CSK) gene was successfully validated for epigenetic regulation in different PDX models and ovarian cancer cell lines. Low CSK methylation and high CSK expression were both significantly associated (p < 0.05) with improved progression-free survival and overall survival in HGSOC patients. HGSOC PDXs resemble the global epigenome of patients over many generations and can be modulated by epigenetic drugs. Novel epigenetically regulated genes such as CSK and related pathways were identified in HGSOC. Our observations encourage future application of PDXs for cancer epigenome studies.

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X Demographics

X Demographics

The data shown below were collected from the profiles of 12 X users who shared this research output. Click here to find out more about how the information was compiled.
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Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 49 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Netherlands 1 2%
Unknown 48 98%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 12 24%
Researcher 7 14%
Student > Master 5 10%
Student > Doctoral Student 4 8%
Student > Bachelor 2 4%
Other 5 10%
Unknown 14 29%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 17 35%
Medicine and Dentistry 7 14%
Agricultural and Biological Sciences 4 8%
Engineering 4 8%
Computer Science 1 2%
Other 1 2%
Unknown 15 31%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 38. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 30 November 2016.
All research outputs
#1,142,719
of 26,458,381 outputs
Outputs from Genome Medicine
#222
of 1,648 outputs
Outputs of similar age
#20,102
of 326,291 outputs
Outputs of similar age from Genome Medicine
#5
of 34 outputs
Altmetric has tracked 26,458,381 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 95th percentile: it's in the top 5% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 1,648 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 26.6. This one has done well, scoring higher than 86% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 326,291 tracked outputs that were published within six weeks on either side of this one in any source. This one has done particularly well, scoring higher than 93% of its contemporaries.
We're also able to compare this research output to 34 others from the same source and published within six weeks on either side of this one. This one has done well, scoring higher than 85% of its contemporaries.