Gene expression based profiling of pleomorphic xanthoastrocytoma highlights two prognostic subgroups

Area of Science:

• Neuro-oncology
• Molecular pathology
• Genomics

Background:

• Pleomorphic xanthoastrocytomas (PXA) are rare astrocytomas, predominantly WHO grade II, with a subset progressing to anaplastic (APXA) grade III.
• Limited molecular data exists for PXA and APXA, hindering understanding of their pathogenesis and progression.

Purpose of the Study:

• To investigate the molecular heterogeneity of PXA and APXA using genome-wide expression profiling.
• To identify molecular markers associated with tumor behavior and recurrence.

Main Methods:

• Genome-wide expression profiling via microarray on 14 PXA and 6 APXA samples.
• Validation of differentially expressed genes, including CDK14 and MTFP1, using qRT-PCR.
• Unsupervised hierarchical clustering to identify molecular subgroups.

Main Results:

• Two distinct molecular clusters were identified, with both grade II and III tumors distributed across clusters, indicating molecular heterogeneity.
• Cluster 2 showed significantly worse progression-free survival (P=0.003).
• mRNA profiling predicted recurrence independently of histological grade, BRAF mutation, or CDKN2A deletion status.

Conclusions:

• This study reveals distinct molecular subgroups within PXA, challenging traditional classification.
• Differentially expressed genes may serve as novel biomarkers for prognostication and potential therapeutic targets.
• Findings pave the way for histology-independent classification and targeted therapies for PXA patients.