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Molecular characterization of DICER1-mutated pituitary blastoma

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Abstract

Pituitary blastoma (PitB) has recently been identified as a rare and potentially lethal pediatric intracranial tumor. All cases that have been studied molecularly possess at least one DICER1 pathogenic variant. Here, we characterized nine pituitary samples, including three fresh frozen PitBs, three normal fetal pituitary glands and three normal postnatal pituitary glands using small-RNA-Seq, RNA-Seq, methylation profiling, whole genome sequencing and Nanostring® miRNA analyses; an extended series of 21 pituitary samples was used for validation purposes. These analyses demonstrated that DICER1 RNase IIIb hotspot mutations in PitBs induced improper processing of miRNA precursors, resulting in aberrant 5p-derived miRNA products and a skewed distribution of miRNAs favoring mature 3p over 5p miRNAs. This led to dysregulation of hundreds of 5p and 3p miRNAs and concomitant dysregulation of numerous mRNA targets. Gene expression analysis revealed PRAME as the most significantly upregulated gene (500-fold increase). PRAME is a member of the Retinoic Acid Receptor (RAR) signaling pathway and in PitBs, the RAR, WNT and NOTCH pathways are dysregulated. Cancer Hallmarks analysis showed that PI3K pathway is activated in the tumors. Whole genome sequencing demonstrated a quiet genome with very few somatic alterations. The comparison of methylation profiles to publicly available data from ~ 3000 other central nervous system tumors revealed that PitBs have a distinct methylation profile compared to all other tumors, including pituitary adenomas. In conclusion, this comprehensive characterization of DICER1-related PitB revealed key molecular underpinnings of PitB and identified pathways that could potentially be exploited in the treatment of this tumor.

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adapted from ref [23]. Consistent with activation of WNT and NOTCH pathways in PitB and normal fetal pituitary (NFP) samples, these samples show higher level of undifferentiated cells compared to normal postnatal pituitary (NPP) samples. PitB samples have lower level of differentiated cells compared to both NPP and NFP samples (see Online Resource 11 for a full list of the genes which were selected from the list of mouse genes listed in ref [10])

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Funding

This project was supported by the Canadian Cancer Society Research Institute Innovation grant #702071 and the Canadian Institutes for Health Research grant FDN-148390 awarded to WDF and was partially supported by C17 funded by the Childhood Cancer Canada Foundation. LdK was a recipient of a Vanier Canada Graduate Scholarship and Delta Kappa Gamma World Fellowship. We thank Alan Spatz MD PhD, Andreas Papadakis PhD and the Georges & Olga Minarik Research Pathology Facility for technical support.

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Nadaf, J., de Kock, L., Chong, AS. et al. Molecular characterization of DICER1-mutated pituitary blastoma. Acta Neuropathol 141, 929–944 (2021). https://doi.org/10.1007/s00401-021-02283-6

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