Recurrent homozygous deletion of DROSHA and microduplication of PDE4DIP in pineoblastoma

Area of Science:

• Neuro-oncology
• Genomics
• Molecular Biology

Background:

• Pineoblastoma is a rare, aggressive childhood brain tumor within the primitive neuroectodermal tumor (PNET) spectrum.
• Germline DICER1 mutations increase pineoblastoma risk, but genetic drivers of sporadic cases are largely unknown.
• Understanding genetic alterations is crucial for developing targeted therapies for this aggressive malignancy.

Purpose of the Study:

• To investigate the genomic landscape of sporadic pineoblastoma in pediatric and adult patients.
• To identify novel genetic alterations and pathways involved in pineoblastoma pathogenesis.
• To differentiate molecular profiles between pediatric and adult pineoblastoma subtypes.

Main Methods:

• Analysis of 23 pediatric and adult pineoblastoma samples.
• Utilized genome-wide DNA methylation profiling.
• Employed whole-exome sequencing (WES) or whole-genome sequencing (WGS).

Main Results:

• Distinct DNA methylation profiles were observed between pediatric and adult pineoblastomas.
• Adult pineoblastomas clustered molecularly with lower-grade pineal tumors and normal pineal tissue.
• Identified recurrent variants in PKA, NF-κB signaling, and chromatin remodeling genes.
• Discovered homozygous deletions of DROSHA (upstream of DICER1) and a microduplication at 1q21 involving PDE4DIP (myomegalin) with DUF1220 domains.
• PDE4DIP and DUF1220 protein expression were specific to pineoblastomas with PDE4DIP gain.

Conclusions:

• Pineoblastomas exhibit distinct molecular signatures based on age, suggesting different developmental origins.
• Recurrent genetic alterations in microRNA processing (DROSHA) and signaling pathways (PKA, NF-κB) are implicated in sporadic pineoblastoma.
• The novel 1q21 microduplication involving PDE4DIP represents a potential oncogenic driver in a subset of pineoblastomas.