Inter and intra-tumoral heterogeneity as a platform for personalized therapies in medulloblastoma

Medulloblastoma is the most common malignant CNS tumor of childhood, affecting-350 patients/year in the USA. In 2020, most children are cured of their disease, however, survivors are left with life-long late-effects as a consequence of intensive surgery, and application of chemo-and radio-therapy to the developing brain. A major contributor to improvements in patient survival has been the development of risk-stratified treatments derived from a better understanding of the prognostic value of disease biomarkers. The characterization and validation of these biomarkers has engendered a comprehensive understanding of the extensive heterogeneity that exists within the disease, which can occur both between and within tumors (inter-and intra-tumoral heterogeneity, respectively). In this review, we discuss inter-tumoral heterogeneity, describing the early characterization of clinical and histopathological disease heterogeneity, the more recent elucidation of molecular disease subgroups, and the potential for novel therapies based on specific molecular defects. We reflect on the limitations of current approaches when applied to a rare disease. We then review early investigations of intra-tumoral heterogeneity using FISH and immunohistochemical approaches, and focus on the application of next generation sequencing on bulk tumors to elucidate intra-tumoral heterogeneity. Finally, we critically appraise the applications of single-cell sequencing approaches and discuss their potential to drive next biological insights, and for routine clinical application. (c) 2021 Published by Elsevier Inc.

Automated summary

Medulloblastoma is the most common malignant CNS tumor in children, with survivors facing lifelong late-effects from intensive treatments. Risk-stratified treatments based on better understanding of biomarkers have improved patient survival. Comprehensive understanding of disease heterogeneity within and between tumors has potential for novel therapies.