Abstract Details

Adult pilocytic astrocytoma (PA) represents approximately 25% of all PAs and is associated with inferior survival outcomes compared to pediatric PA. The most common genomic alterations in PA result in aberrant MAPK pathway signaling. Systematic characterization of adult PA phenotypes in the context of individual molecular alterations will be an essential component of delivering emerging targeted therapies.

To characterize the prevalence of MAPK pathway alterations and their association with aggressive features among adult PA cases in the literature.

273 cases of adult PA with 336 reported molecular alterations were found. 88.3% of the cases had alterations associated with MAPK pathway dysregulation, the most frequent of which were fusions of BRAF (54.5%), FGFR alterations (19.1%), NF1 mutations (12.8%), and BRAF mutations (9.7%). The majority of MAPK alterations arose in the posterior fossa (63.8%), 55.0% of which were KIAA1549-BRAF fusions. We analyzed the frequency of MAPK alterations co-occurring with extra-pathway markers known to predict aggressive PA behavior. MAPK alterations were present in 67.8% of cases with ATRX loss and/or alternative lengthening of telomeres (ALT), 64.6% of cases with CDKN2A/B deletion, and 62.1% of cases with anaplastic histology.

These preliminary findings support that adult PA is largely a single-hit disease resulting from MAPK pathway dysfunction and preferentially arises in the posterior fossa. Further study is needed to define the relationship of specific MAPK alterations with tumor aggressiveness, which thus far is best informed by extra-pathway characteristics including anaplasia, ATRX loss/ALT, and CDKN2A/B deletion. Coordinated clinical research efforts are needed to further define the role of MAPK pathway inhibitors in treatment of adult PA.