DNA methylation analysis reveals two patient clusters in adamantinomatous craniopharyngioma

medwireNews: Patients with adamantinomatous craniopharyngioma (ACP) can be grouped into two distinct clusters based on their DNA methylation profile, Brazilian researchers report.

The two clusters, identified using machine learning methods and termed ACP-1 and ACP-2, differed in tumour volume, mutation rates in the known ACP oncogenic driver gene CTNNB1 and the level of hypomethylation, report Margaret de Castro (University of São Paulo, Brazil) and co-authors in The Journal of Clinical Endocrinology & Metabolism.

They measured DNA methylation levels at more than 850,000 CpG sites in tumoural DNA samples from 35 patients with ACP (mean age 18.1 years, 54% male). Of these, 66% were diagnosed before 18 years of age.

Three different analysis methods consistently revealed two methylation clusters: 18 patients fell into ACP-1 and 17 were in ACP-2.

Just over half (56%) of tumours collected from patients in ACP-1 carried mutations in CTNNB1, with the remainder carrying the wild-type. By comparison, all tumours from patients in ACP-2 carried somatic CTNNB1 mutations.

In addition, among the probes that were differentially methylated between the two clusters, median methylation levels were significantly higher in ACP-1 than in ACP-2 in both CpG island (CGI) and non-CGI sites. The overall hypomethylation in the ACP-2 cluster may suggest “a more aggressive phenotype, as observed in other cancers”, the researchers remark.

In line with this, tumours from the ACP-2 cluster were significantly larger in volume than those from the ACP-1 cluster, at a median of 24.1 cm3 versus 9.5 cm3. However, there were no other significant associations between ACP cluster and clinical features or survival outcomes. At the time of follow-up (median 57 months), all patients in the ACP-1 cluster and 88% in the ACP-2 cluster were alive.

When de Castro and team further explored the differences in the methylation profiles between the two groups, they identified several genes with differential median methylation levels. The majority were involved in signalling transduction, cell adhesion, cytoskeleton organization and development of the epidermis, which the investigators say confirms “several pathways already described to be involved in the pathogenesis of ACPs.”

They also revealed associations with biological processes more specifically linked to the tumoural microenvironment of the ACPs, including regulation of oligodendrocytes, leukocytes, dendritic and mast cells, the development of the epidermis, differentiation of epithelial cells and keratinocyte differentiation.

“These findings suggest that the methylation profile of the ACP-2 cluster controls the expression of genes involved in tumoral growth and invasiveness”, say de Castro et al.

They conclude: “Our work provides new insights into the importance of common (epi-) genetic alterations found in human ACP and shape the path for a future possible incorporation of DNA methylation signatures, especially in conjunction with machine learning methods, into diagnostic and prognostic algorithms for ACPs.”

By Laura Cowen

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group

J Clin Endocrinol Metab 2024; doi:10.1210/clinem/dgae006
Martin Savage
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