Tracing evolution history of 100 whole genome sequences of diffuse stem brain tumor

Abstract

Diffuse intrinsic pontine glioma (DIPG) is a deadly disease among young children. The evolution path and mutational processes giving rise to DIPG remain elusive. We analyzed 100 whole genome sequences (WGS) from 60 DIPG patients. This revealed 25% DIPGs acquired whole-genome duplications (WGD) early during tumor evolution. WGD samples are associated with loss of TP53 and poorer survival. In addition, almost all WGD samplers harbor complex structural variations (SVs) and show characteristic short microhomology at SV breakpoints. Mutation analysis revealed that H3K27M driver mutation is acquired early during tumor clonal evolution. Mutation signature analysis identified a unique mutational process at a late stage of tumor evolution. This study revealed that tumor evolution of DIPG is characterized by chromosomal instability shaped by DNA repair defects and dynamic mutational processes. Our work shed new insights on the disease pathogenesis of DIPG and provided rationale for designing novel therapy for this deadly disease.