EPIG-09GENETIC AND EPIGENETIC TUMOR EVOLUTION IN GLIOMATOSIS CEREBRI

Abstract

Gliomatosis cerebri (GC) is a rare and aggressive cancer (fewer than 100 cases diagnosed in the United States each year). GC is an extensively infiltrating high-grade glial tumor to at least three lobes in the brain (median length of survival is 9.5 months). Accumulating evidence suggests that epigenetic dysregulation may play an important role in tumor progression, and epigenetic modulators have begun to show promise as therapeutic options in other pediatric and adult malignancies. However, the evolution of GC tumor genetics and epigenetic dynamics have not been well studied. Here we describe the GC somatic mutation spectrum of 12 patients and an intra-tumor evolution pattern between lower and higher grade areas in three patients. We performed exome-capture sequencing, and reduced representation bisulfite sequencing to examine the genetic and epigenetic dynamics for the GC samples. Recurrent mutations were found in genes related to Cell cycle, p53 signaling, Wnt signaling, and MAPK signaling pathways. Furthermore, we found increased epigenetic heterogeneity in tumor samples with enhancement compared to the normal brain samples, which suggests that epigenetic dynamics permits a superior evolutionary trajectory leading to GC progression. These findings may help explain tumor evolution and target mechanism for therapeutic diversification. By understanding the driver events, one may eventually provide more accurate diagnosis of the disease and define clinical targets for improvement of the treatment and survival rate of GC patients.