Patient-specific identification of genome-wide DNA-methylation differences between intracranial and extracranial melanoma metastases

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung


Melanomas frequently metastasize to distant organs and especially intracranial metastases still represent a major clinical challenge. Epigenetic reprogramming of intracranial metastases is thought to be involved in therapy failure, but so far only little is known about patient-specific DNA-methylation differences between intra- and extracranial melanoma metastases. Hierarchical clustering of the methylomes of 24 patient-matched intra- and extracranial melanoma metastases pairs revealed that intra- and extracranial metastases of individual patients were more similar to each other than to metastases in the same tissue from other patients. Therefore, a personalized analysis of each metastases pair was done by a Hidden Markov Model to classify methylation levels of individual CpGs as decreased, unchanged or increased in the intra- compared to the extracranial metastasis. The predicted DNA-methylation alterations were highly patient-specific differing in the number and methylation states of altered CpGs. Nevertheless, four important general observations were made: (i) intracranial metastases of most patients mainly showed a reduction of DNA-methylation, (ii) cytokine signaling was most frequently affected by differential methylation in individual metastases pairs, but also MAPK, PI3K/Akt and ECM signaling were often altered, (iii) frequently affected genes were mainly involved in signaling, growth, adhesion or apoptosis, and (iv) an enrichment of functional terms related to channel and transporter activities supports previous findings for a brain-like phenotype. In addition, the derived set of 17 signaling pathway genes that distinguished intra- from extracranial metastases in more than 50% of patients included well-known oncogenes (e.g. PRKCA, DUSP6, BMP4) and several other genes known from neuronal disorders (e.g. EIF4B, SGK1, CACNG8). Moreover, associations of gene body methylation alterations with corresponding gene expression changes revealed that especially the three signaling pathway genes JAK3, MECOM, and TNXB differ strongly in their expression between patient-matched intra- and extracranial metastases. Our analysis contributes to an in-depth characterization of DNA-methylation differences between patient-matched intra- and extracranial melanoma metastases and may provide a basis for future experimental studies to identify targets for new therapeutic approaches.


FachzeitschriftScientific reports
PublikationsstatusVeröffentlicht - 9 Jan. 2023

Externe IDs

PubMed 36624125
ORCID /0000-0003-4340-0402/work/145223806
ORCID /0000-0003-4340-9706/work/145224722
WOS 000915457700004
PubMedCentral PMC9829750
ORCID /0000-0002-2844-053X/work/153110483


Ziele für nachhaltige Entwicklung

ASJC Scopus Sachgebiete


  • Brain metastases, Expression, Gastric-cancer, Hypermethylation, Inhibition, Multicenter, Mutations, Open-label, Pi3k pathway, Survival, Melanoma/pathology, Humans, Calcium Channels/genetics, DNA Methylation, DNA/therapeutic use, Phosphatidylinositol 3-Kinases/genetics, Brain Neoplasms/drug therapy