Desmoplastic Infantile Ganglioglioma/Astrocytoma (DIG/DIA) Are Distinct Entities with Frequent BRAFV600 Mutations

Abstract

Desmoplastic infantile ganglioglioma (DIG) and desmoplastic infantile astrocytoma (DIA) are extremely rare tumors that typically arise in infancy; however, these entities have not been well characterized in terms of genetic alterations or clinical outcomes. Here, through a multi-institutional collaboration, the largest cohort of DIG/DIA to date is examined using advanced laboratory and data processing techniques. Targeted DNA exome sequencing and DNA methylation profiling were performed on tumor specimens obtained from different patients (<i>n</i> = 8) diagnosed histologically as DIG/DIGA. Two of these cases clustered with other tumor entities, and were excluded from analysis. The remaining 16 cases were confirmed to be DIG/DIA by histology and by DNA methylation profiling. Somatic <i>BRAF</i> gene mutations were discovered in 7 instances (43.8%); 4 were <i>BRAF^V600E</i> mutations, and 3 were <i>BRAF^V600D</i> mutations. Three instances of malignant transformation were found, and sequencing of the recurrence demonstrated a new <i>TP53</i> mutation in one case, new <i>ATRX</i> deletion in one case, and in the third case, the original tumor harbored an <i>EML4-ALK</i> fusion, also present at recurrence. DIG/DIA are distinct pathologic entities that frequently harbor <i>BRAF^V600</i> mutations. Complete surgical resection is the ideal treatment, and overall prognosis is excellent. While, the small sample size and incomplete surgical records limit a definitive conclusion about the risk of tumor recurrence, the risk appears quite low. In rare cases with wild-type <i>BRAF</i>, malignant progression can be observed, frequently with the acquisition of other genetic alterations.<b>Implications:</b> DIG/DIA are a distinct molecular entity, with a subset frequently harboring either <i>BRAF</i> ^V600E or <i>BRAF</i> ^V600D mutations. <i>Mol Cancer Res; 16(10); 1491-8. ©2018 AACR</i>.