Anaplastic pleomorphic xanthoastrocytomas (PXAs) account for less than 1% of all brain tumors. Anaplastic PXAs can be diagnosed de novo or at the time of progression from lower grade tumors. The rate of malignant transformation of grade II to grade III PXAs is between 10% and 25%. The prognosis of patients with anaplastic PXAs is worse than those with grade II tumors but better than those with glioblastoma. The treatment of patients with anaplastic PXA consists of the combination of maximum safe resection, radiation therapy, and chemotherapy. The molecular characteristics of anaplastic PXAs are poorly understood. The largest study to date performed targeted sequencing of approximately 500 genes in tumor samples from 15 patients with anaplastic PXAs. The most common molecular abnormalities reported in these tumors are BRAF V600E mutations (between 17% and 100% of cases), CDKN2A loss (between 57% and 95%), and amplification or hotspot mutations in the promoter region of TERT (approximately 50%). The DNA methylation profiling in 202 histologically-confirmed pediatric glioblastomas identified a molecular subgroup of PXA-like tumors that molecularly resembled WHO grade II PXAs. PXA-like glioblastomas accounted for 13% of cases and were associated with a younger age, increased incidence of BRAF V600E mutations and a better outcome. The use of BRAF inhibitors has shown promising activity in patients with BRAF V600E-mutated tumors, including anaplastic PXAs, but tumor progression invariably occurs. There remains a big void in understanding the molecular characteristics of anaplastic PXAs and the bases for their refractoriness to therapy and predisposition to malignant transformation.
What are the goals of this project?
The goal of this project is to review the clinical and radiologic characteristics of anaplastic PXAs and to perform detailed molecular analyses including DNA methylation profiling, and whole exome and RNA sequencing.
What is the impact of this project?
By assembling a large patient cohort in this multi-institutional study, and by performing detailed analyses of clinical, radiologic, and molecular characteristics associated with anaplastic PXAs, we hope that our research will unveil new molecular targets and markers that may improve the care for patients with these rare and deadly cancers.
The Children's Brain Tumor Network contributed to this project by providing access to the Pediatric Brain Tumor Atlas.
PI: Alberto Broniscer
Baoli Hu, PhD
Oncobiology of glioma and medulloblastoma; cancer stem cells; functional cancer genomics; mechanisms of tumor initiation, progression, treatment resistance, and recurrence; translational research in druggable targets and biomarkers discovery
UPMC Children's Hospital of Pittsburgh