Recurrent adamantinomatous craniopharyngiomas show MAPK pathway activation, clonal evolution and rare TP53-loss-mediated malignant progression.

in Acta neuropathologica communications by John R Apps, Jose Mario Gonzalez-Meljem, Romain Guiho, Jessica C Pickles, Eric Prince, Edward Schwalbe, Nikhil Joshi, Thomas J Stone, Olumide Ogunbiyi, Jane Chalker, Akang Bassey, Georg Otto, Rosalind Davies, Debbie Hughes, Sebastian Brandner, Enrica Tan, Victoria Lee, Caroline Hayhurst, Cassie Kline, Sergi Castellano, Todd Hankinson, Timo Deutschbein, Thomas S Jacques, Juan Pedro Martinez-Barbera

TLDR

  • The study looked at the biology of a rare tumor called craniopharyngioma in children and adults. The study used different tests to analyze the tumor samples and found that copy number changes and clonal evolution occur in recurrent craniopharyngioma. The study also found that the MAPK/ERK pathway is activated in most cases of recurrent craniopharyngioma, except for one aggressive case with a specific genetic mutation. The study also found differences in the cellular composition and spatial distribution of the tumor immune infiltrate between ACP and PCP craniopharyngioma. The study provides evidence that MAPK pathway inhibitors and immunomodulatory approaches could be used to treat recurrent craniopharyngioma.

Abstract

The two types of craniopharyngioma, adamantinomatous (ACP) and papillary (PCP), are clinically relevant tumours in children and adults. Although the biology of primary craniopharyngioma is starting to be unravelled, little is known about the biology of recurrence. To fill this gap in knowledge, we have analysed through methylation array, RNA sequencing and pERK1/2 immunohistochemistry a cohort of paired primary and recurrent samples (32 samples from 14 cases of ACP and 4 cases of PCP). We show the presence of copy number alterations and clonal evolution across recurrence in 6 cases of ACP, and analysis of additional whole genome sequencing data from the Children's Brain Tumour Network confirms chromosomal arm copy number changes in at least 7/67 ACP cases. The activation of the MAPK/ERK pathway, a feature previously shown in primary ACP, is observed in all but one recurrent cases of ACP. The only ACP without MAPK activation is an aggressive case of recurrent malignant human craniopharyngioma harbouring a CTNNB1 mutation and loss of TP53. Providing support for a functional role of this TP53 mutation, we show that Trp53 loss in a murine model of ACP results in aggressive tumours and reduced mouse survival. Finally, we characterise the tumour immune infiltrate showing differences in the cellular composition and spatial distribution between ACP and PCP. Together, these analyses have revealed novel insights into recurrent craniopharyngioma and provided preclinical evidence supporting the evaluation of MAPK pathway inhibitors and immunomodulatory approaches in clinical trials in against recurrent ACP.

Overview

  • The study aims to analyze the biology of recurrence in craniopharyngioma, a rare tumor in children and adults. The study uses methylation array, RNA sequencing, and pERK1/2 immunohistochemistry to analyze paired primary and recurrent samples from 14 cases of adamantinomatous (ACP) and 4 cases of papillary (PCP) craniopharyngioma. The study aims to identify copy number alterations, clonal evolution, and activation of the MAPK/ERK pathway in recurrent craniopharyngioma. The study also aims to characterize the tumor immune infiltrate in ACP and PCP craniopharyngioma.

Comparative Analysis & Findings

  • The study found the presence of copy number alterations and clonal evolution across recurrence in 6 cases of ACP. The activation of the MAPK/ERK pathway was observed in all but one recurrent case of ACP. The only ACP without MAPK activation was an aggressive case of recurrent malignant human craniopharyngioma harboring a CTNNB1 mutation and loss of TP53. The study also found differences in the cellular composition and spatial distribution between ACP and PCP craniopharyngioma in the tumor immune infiltrate.

Implications and Future Directions

  • The study provides preclinical evidence supporting the evaluation of MAPK pathway inhibitors and immunomodulatory approaches in clinical trials against recurrent ACP. The study also highlights the importance of understanding the biology of recurrence in craniopharyngioma to develop more effective treatments for this rare tumor. Future research should focus on identifying additional genetic and epigenetic alterations that contribute to recurrence and developing targeted therapies based on these alterations.
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