Spatial tumour heterogeneity and branched evolution in DIPG

From our deep sequencing and immunohistochemical studies of DIPG, we   know that H3F3A and TP53 mutations are heterozygous and are present in all  tumour cells. However,  other genes  are  mutated  with  lower  allelic  frequency,  suggesting  that  they  may  represent  later genetic hits  present  in a clone of the  original  tumour and pointing to the possibility of tumour genetic heterogeneity. In  addition  to these  indications  of genetic heterogeneity, our  histologic  studies demonstrate morphologic and proteomic heterogeneity. Detailed histopathological  studies by  our  group have  revealed  that DIPGs represent  a  diverse  histologic  spectrum,  including multiple  cases in  which different tumour regions are  observed to  contain  a histological  grade unique  to  that  of  the  primary  site. Further,  we  have  shown  that  approximately one  third of  DIPG  patients have leptomeningeal spread of their tumour and that diffuse invasion of the brainstem, spinal cord and thalamus is common, with some cases showing distant spread as far as the frontal lobes. Although  DIPGs are  histologically  heterogeneous, the  degree  of genetic heterogeneity between the  main  mass  in  the  pons and the infiltrative and  metastatic  compartments is not well studied. We are interested in understanding how DIPGs evolve over time, both genetically as well as epigenetically and transcriptionally. This will be  critical  for  clinical  decision  making  and  design  of future therapeutics.