Adamantinomatous and papillary craniopharyngiomas are characterized by distinct epigenomic as well as mutational and transcriptomic profiles

Abstract

Introduction: Craniopharyngiomas (CP) are rare epithelial tumors of the sellar region. Two subtypes, adamantinomatous (adaCP) and papillary CP (papCP), were previously identified based on histomorphological and epidemiological aspects. Recent data indicates that both variants are defined by specific genetic alterations, and influenced by distinct molecular pathways and particular origins. The fact that CP is an uncommon tumor entity renders studies on large cohorts difficult and exceptional. In order to achieve further insights distinguishing CP variants, we conducted whole genome methylation (450 k array) and microarray-based gene expression studies in addition to CTNNB1 and BRAF mutation analysis using a comprehensive cohort of 80 adaCP and 35 papCP. Results: BRAFV600E mutations were solely found in the papCP subgroup and were not detectable in adaCP samples. In contrast, CTNNB1 mutations were exclusively detected in adaCP. The methylome fingerprints assigned DNA specimens to entity-specific groups (papCP (n = 18); adaCP (n = 25)) matching perfectly with histology-based diagnosis, suggesting that they represent truly distinct biological entities. However, we were not able to detect within the adaCP group (including 11 pediatric and 14 adult cases) a significant difference in methylation signature by age. Integrative comparison of the papCP with the adaCP group based on differential gene expression and methylation revealed a distinct upregulation of Wnt-and SHH signaling pathway genes in adaCP. Conclusions: AdaCP and papCP thus represent distinct tumor subtypes that harbor mutually exclusive gene mutations and methylation patterns, further reflected in differences in gene expression. This study demonstrates that DNA methylation analyses are an additional method to classify CP into subtypes, and implicates a role of epigenetic mechanisms in the genesis of the respective CP variants. Detection of tumor-specific signaling pathway activation enables the possibility of target-oriented intervention.

Molecular pathology of adamantinomatous craniopharyngioma: review and opportunities for practice

“…19 An additional 18 ACP samples underwent expression array analysis and were compared with 10 PCP samples by Holsken et al in 2016. 23 This study also highlighted the activation of the WNT and SHH pathways in ACP. In this paper, the methylation profiles of 25 ACPs and 18 PCPs were assessed, revealing distinct patterns between tumor types.…”

“…23,31 With respect to genomic copy number alterations, previous studies using G banding or comparative genomic hybridization have given variable, often controversial, results. While the majority showed normal karyotype, cases with copy number variants were described in some cohorts.…”

“…While the majority showed normal karyotype, cases with copy number variants were described in some cohorts. 23,44,58 Clearly, a better molecular characterization of more ACP tumors is required to determine and refine the mutational landscape of these tumors. …”

Potential evolution of neurosurgical treatment paradigms for craniopharyngioma based on genomic and transcriptomic characteristics

“…Hölsken and colleagues 25 demonstrated a much higher expression of SHH pathway genes in the transcriptomes of ACP compared with PCP. These findings correlated with distinct methylation patterns between the 2 tumor types.…”

TREM-1 expression in craniopharyngioma and Rathke's cleft cyst: its possible implication for controversial pathology

“…Genetic and molecular pathologic features support a distinct pathogenesis of aCP and pCP [12–17]. It was reported that pCPs present BRAF p.V600E mutations in 95% of cases and CTNNB1 mutations are exclusive and specific to aCPs [16].…”