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

Abstract

<jats:p>The recent genomic and transcriptomic characterization of human craniopharyngiomas has provided important insights into the pathogenesis of these tumors and supports that these tumor types are distinct entities. Critically, the insights provided by these data offer the potential for the introduction of novel therapies and surgical treatment paradigms for these tumors, which are associated with high morbidity rates and morbid conditions. Mutations in the <jats:italic>CTNNB1</jats:italic> gene are primary drivers of adamantinomatous craniopharyngioma (ACP) and lead to the accumulation of β-catenin protein in a subset of the nuclei within the neoplastic epithelium of these tumors. Dysregulation of epidermal growth factor receptor (EGFR) and of sonic hedgehog (SHH) signaling in ACP suggest that paracrine oncogenic mechanisms may underlie ACP growth and implicate these signaling pathways as potential targets for therapeutic intervention using directed therapies. Recent work shows that ACP cells have primary cilia, further supporting the potential importance of SHH signaling in the pathogenesis of these tumors. While further preclinical data are needed, directed therapies could defer, or replace, the need for radiation therapy and/or allow for less aggressive surgical interventions. Furthermore, the prospect for reliable control of cystic disease without the need for surgery now exists. Studies of papillary craniopharyngioma (PCP) are more clinically advanced than those for ACP. The vast majority of PCPs harbor the <jats:italic>BRAF</jats:italic><jats:sup>v600e</jats:sup> mutation. There are now 2 reports of patients with PCP that had dramatic therapeutic responses to targeted agents. Ongoing clinical and research studies promise to not only advance our understanding of these challenging tumors but to offer new approaches for patient management.</jats:p>

High‐resolution melting and immunohistochemical analysis efficiently detects mutually exclusive genetic alterations of adamantinomatous and papillary craniopharyngiomas

“…In this study, the CTNNB1 mutation was identified in 78.6% of the aCP cases, as analyzed by DNA‐based detection. The reported frequency of CTNNB1 mutations in aCP range from 63% to 100%, which is consistent with our results. Due to the relative inaccessibility of frozen tissues in the clinical setting, many of these previous studies analyzed DNA extracted from formalin‐fixed paraffin embedded (FFPE) tissues.…”

“…Recently, genetic analyses have revealed subtype‐specific genetic alterations in craniopharyngioma, which are consistent with clinicopathological differences between the two types . aCP is characterized by frequent β‐catenin gene ( CTNNB1 ) mutations.…”

“…Recently, genetic analyses have revealed subtypespecific genetic alterations in craniopharyngioma, which are consistent with clinicopathological differences between the two types. [4][5][6][7][8][9][10][11] aCP is characterized by frequent β-catenin gene (CTNNB1) mutations. CTNNB1 is an adherens junction protein and a downstream signaling molecule of the Wnt pathway.…”

Pediatric Craniopharyngiomas: A Primer for the Skull Base Surgeon

“…[18][19][20][21][22][23] Looking more closely at other prominent pathologic molecular markers, although the discovery of BRAF V600E mutations in papillary tumors generated considerable interest in the use of BRAF inhibitors such as vemurafenib for adults, the identification of candidate genes in pediatric adamantinomatous craniopharyngioma has been more frustrating. 24,25 The most widely observed mutation, CTNNB1, occurs in more than 90% of adamantinomatous craniopharyngiomas, and results in abnormal accumulation of β-catenin, an important player in canonical Wnt signaling pathway and therefore cell differentiation and proliferation. 25,26 This may provide a useful disease marker-inroads are currently being made toward serum-based cell free deoxyribonucleic acid (DNA) assays, which may lead to biopsy-free diagnostic testing-however, β-catenin is a nearly universal player in cellular homeostasis, and the development of specific Wnt pathway inhibitors has been challenging.…”

“…24,25 The most widely observed mutation, CTNNB1, occurs in more than 90% of adamantinomatous craniopharyngiomas, and results in abnormal accumulation of β-catenin, an important player in canonical Wnt signaling pathway and therefore cell differentiation and proliferation. 25,26 This may provide a useful disease marker-inroads are currently being made toward serum-based cell free deoxyribonucleic acid (DNA) assays, which may lead to biopsy-free diagnostic testing-however, β-catenin is a nearly universal player in cellular homeostasis, and the development of specific Wnt pathway inhibitors has been challenging. 24,26 Other studies have demonstrated increased expression of both sonic hedgehog (SHH) and its receptor PTCH1 in adamantinomatous craniopharyngioma, often in patterns correlating with epithelial palisades and co-localizing with β-catenin, indicating a potential autocrine-paracrine mechanism.…”