Tracing Evolution History of 100 Whole Genome Sequences of Diffuse Stem Brain Tumor

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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.


We thank members of Children’s Brain Tumor Tissue Consortium (CBTTC) ( for their support of open access, biospecimen driven research.