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Cited by 28Epigenetics and DNA MethylationTesticular diseases and treatmentsCancer-related gene regulation

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Differential methylation EPIC analysis discloses cisplatin-resistance related hypermethylation and tumor-specific heterogeneity within matched primary and metastatic testicular germ cell tumor patient tissue samples

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Lobo, João, Constâncio, Vera, Leite-Silva, Pedro, Guimarães, Rita, Cantante, Mariana, Braga, Isaac, Maurício, Joaquina, Looijenga, Leendert H. J., Henrique, Rui, Jerónimo, Carmen·2021·Clinical Epigenetics
DOI 10.1186/s13148-021-01048-yPMC PMC8025580
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Abstract

Testicular germ cell tumors (TGCTs) are among the most common solid malignancies in young-adult men, and currently most mortality is due to metastatic disease and emergence of resistance to cisplatin. There is some evidence that increased methylation is one mechanism behind this resistance, stemming from individual studies, but approaches based on matched primary and metastatic patient samples are lacking. Herein, we provide an EPIC array-based study of matched primary and metastatic TGCT samples. Histology was the major determinant of overall methylation pattern, but some clustering of samples related to response to cisplatin was observed. Further differential analysis of patients with the same histological subtype (embryonal carcinoma) disclosed a remarkable increase in net methylation levels (at both promoter and CpG site level) in the patient with cisplatin-resistant disease and poor outcome compared to the patient with complete response to chemotherapy. This further confirms the recent results of another study performed on isogenic clones of sensitive and resistant TGCT cell lines. Differentially methylated promoters among groups of samples were mostly not shared, disclosing heterogeneity in patient tissue samples. Finally, gene ontology analysis of cisplatin-resistant samples indicated enrichment of differentially hypermethylated promoters on pathways related to regulation of immune microenvironment, and enrichment of differentially hypomethylated promoters on pathways related to DNA/chromatin binding and regulation. This data supports not only the use of hypomethylating agents for targeting cisplatin-resistant disease, but also their use in combination with immunotherapies and chromatin remodelers.

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  • Epigenetic reprogramming is a major pathway of resistance in various tumor types, including TGCTs, particularly in the cisplatin-resistant setting, which is characterized by enrichment of differentially hypermethylated promoters on pathways related to regulation of the immune microenvironment.

    “Epigenetic reprogramming consists of a major pathway of resistance in various tumor types, including TGCTs, particularly in the cisplatin-resistant setting which is characterized by the enrichment of differentially hypermethylated promoters on pathways related to the regulation of the immune microenvironment [77].”

    From The Immune Landscape and Immunotherapeutic Strategies in Platinum-Refractory Testicular Germ Cell Tumors (2024) · cites this paper as [77]

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Metadata

Authors
Lobo, J., Constâncio, V., Leite-Silva, P., Guimarães, R., Cantante, M., Braga, I., Maurício, J., Looijenga, L. H. J., Henrique, R., & Jerónimo, C.
Affiliations
  • Universidade do Porto (PT)
  • IPO Porto (PT)
  • Princess Máxima Center (NL)
Corresponding author
Henrique, Rui
ORCID
Venue
Clinical Epigenetics
Publisher
Springer Science and Business Media LLC
Published
2021-04-06
Volume
13
Issue
1
Pages
70-70
ISSN
  • 1868-7075 (ISSN-L)
  • 1868-7083
DOI
10.1186/s13148-021-01048-y
PMC
PMC8025580
OpenAlex
W3148328959
Cited by
28
References
2
Citations by year
2026: 4 · 2025: 6 · 2024: 5 · 2023: 5 · 2022: 3 · 2021: 5
FWCI
1.41
Type
journal article
Language
en
Open access
Licence
Locations
  • Clinical Epigenetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Fundação para a Ciência e a Tecnologia (PTDC/MECONC/ 29043/2017, SFRH/BD/132751/2017)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Surgery › Testicular diseases and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
Keywords
testicular germ cell tumors, cisplatin resistance, DNA methylation, promoter hypermethylation, metastatic cancer, embryonal carcinoma, tumor heterogeneity, immune microenvironment, hypomethylating agents, combination immunotherapy, chromatin remodeling, histological subtypes
MeSH terms
Adult, Antineoplastic Agents, Cisplatin, Humans, Male, Neoplasm Metastasis, Neoplasms, Germ Cell and Embryonal, Testicular Neoplasms, Gene Expression Regulation, Neoplastic, Treatment Outcome, Drug Resistance, Neoplasm, DNA Methylation, Cell Line, Tumor, Young Adult

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