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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 (94th percentile)
  • High Attention Score compared to outputs of the same age and source (84th percentile)

Mentioned by

news
3 news outlets
blogs
1 blog
twitter
13 tweeters
facebook
2 Facebook pages
googleplus
2 Google+ users

Citations

dimensions_citation
29 Dimensions

Readers on

mendeley
50 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.

Twitter Demographics

Twitter Demographics

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Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 50 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Netherlands 1 2%
Unknown 49 98%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 12 24%
Researcher 9 18%
Student > Master 5 10%
Student > Doctoral Student 4 8%
Student > Bachelor 2 4%
Other 5 10%
Unknown 13 26%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 18 36%
Medicine and Dentistry 7 14%
Agricultural and Biological Sciences 4 8%
Engineering 4 8%
Computer Science 1 2%
Other 2 4%
Unknown 14 28%
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
#989,937
of 24,138,997 outputs
Outputs from Genome Medicine
#192
of 1,494 outputs
Outputs of similar age
#19,119
of 320,529 outputs
Outputs of similar age from Genome Medicine
#6
of 32 outputs
Altmetric has tracked 24,138,997 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 1,494 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 87% 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 320,529 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 94% of its contemporaries.
We're also able to compare this research output to 32 others from the same source and published within six weeks on either side of this one. This one has done well, scoring higher than 84% of its contemporaries.