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Methylome analysis of extreme chemoresponsive patients identifies novel markers of platinum sensitivity in high-grade serous ovarian cancer

Overview of attention for article published in BMC Medicine, June 2017
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  • In the top 25% of all research outputs scored by Altmetric
  • Good Attention Score compared to outputs of the same age (79th percentile)
  • Average Attention Score compared to outputs of the same age and source

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Title
Methylome analysis of extreme chemoresponsive patients identifies novel markers of platinum sensitivity in high-grade serous ovarian cancer
Published in
BMC Medicine, June 2017
DOI 10.1186/s12916-017-0870-0
Pubmed ID
Authors

Tushar Tomar, Nicolette G. Alkema, Leroy Schreuder, Gert Jan Meersma, Tim de Meyer, Wim van Criekinge, Harry G. Klip, Heidi Fiegl, Els van Nieuwenhuysen, Ignace Vergote, Martin Widschwendter, Ed Schuuring, Ate G. J. van der Zee, Steven de Jong, G. Bea A. Wisman

Abstract

Despite an early response to platinum-based chemotherapy in advanced stage high-grade serous ovarian cancer (HGSOC), the majority of patients will relapse with drug-resistant disease. Aberrant epigenetic alterations like DNA methylation are common in HGSOC. Differences in DNA methylation are associated with chemoresponse in these patients. The objective of this study was to identify and validate novel epigenetic markers of chemoresponse using genome-wide analysis of DNA methylation in extreme chemoresponsive HGSOC patients. Genome-wide next-generation sequencing was performed on methylation-enriched tumor DNA of two HGSOC patient groups with residual disease, extreme responders (≥18 months progression-free survival (PFS), n = 8) and non-responders (≤6 months PFS, n = 10) to platinum-based chemotherapy. DNA methylation and expression data of the same patients were integrated to create a gene list. Genes were validated on an independent cohort of extreme responders (n = 21) and non-responders (n = 31) using pyrosequencing and qRT-PCR. In silico validation was performed using publicly available DNA methylation (n = 91) and expression (n = 208) datasets of unselected advanced stage HGSOC patients. Functional validation of FZD10 on chemosensitivity was carried out in ovarian cancer cell lines using siRNA-mediated silencing. Integrated genome-wide methylome and expression analysis identified 45 significantly differentially methylated and expressed genes between two chemoresponse groups. Four genes FZD10, FAM83A, MYO18B, and MKX were successfully validated in an external set of extreme chemoresponsive HGSOC patients. High FZD10 and MKX methylation were related with extreme responders and high FAM83A and MYO18B methylation with non-responders. In publicly available advanced stage HGSOC datasets, FZD10 and MKX methylation levels were associated with PFS. High FZD10 methylation was strongly associated with improved PFS in univariate analysis (hazard ratio (HR) = 0.43; 95% CI, 0.27-0.71; P = 0.001) and multivariate analysis (HR = 0.39; 95% CI, 0.23-0.65; P = 0.003). Consistently, low FZD10 expression was associated with improved PFS (HR = 1.36; 95% CI, 0.99-1.88; P = 0.058). FZD10 silencing caused significant sensitization towards cisplatin treatment in survival assays and apoptosis assays. By applying genome-wide integrated methylome analysis on extreme chemoresponsive HGSOC patients, we identified novel clinically relevant, epigenetically-regulated markers of platinum-sensitivity in HGSOC patients. The clinical potential of these markers in predictive and therapeutic approaches has to be further validated in prospective studies.

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The data shown below were collected from the profiles of 15 X users who shared this research output. Click here to find out more about how the information was compiled.
Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 65 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 65 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 11 17%
Student > Bachelor 10 15%
Student > Master 8 12%
Researcher 6 9%
Professor 4 6%
Other 9 14%
Unknown 17 26%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 18 28%
Medicine and Dentistry 10 15%
Agricultural and Biological Sciences 6 9%
Nursing and Health Professions 3 5%
Pharmacology, Toxicology and Pharmaceutical Science 1 2%
Other 5 8%
Unknown 22 34%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 9. 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 27 February 2019.
All research outputs
#4,102,938
of 25,473,687 outputs
Outputs from BMC Medicine
#2,194
of 4,026 outputs
Outputs of similar age
#67,509
of 329,576 outputs
Outputs of similar age from BMC Medicine
#29
of 52 outputs
Altmetric has tracked 25,473,687 research outputs across all sources so far. Compared to these this one has done well and is in the 83rd percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 4,026 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 45.8. This one is in the 45th percentile – i.e., 45% of its peers scored the same or lower than it.
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 329,576 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 79% of its contemporaries.
We're also able to compare this research output to 52 others from the same source and published within six weeks on either side of this one. This one is in the 46th percentile – i.e., 46% of its contemporaries scored the same or lower than it.