This Work Is Licensed under a Creative Commons Attribution 3.0 Unported License Combined Myc and P53 Defects Emerge at Medulloblastoma Relapse and Define Rapidly Progressive, Therapeutically Targetable Disease

SUMMARY We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC family amplifications and P53 pathway defects commonly emerged at relapse, and all patients in this group died of rapidly progressive disease postrelapse. To study this interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development of Trp53 inactivating mutations. Abrogation of p53 function in this model produced aggressive tumors that mimicked characteristics of relapsed human tumors with combined P53-MYC dysfunction. Restoration of p53 activity and genetic and therapeutic suppression of MYCN all reduced tumor growth and prolonged survival. Our findings identify P53-MYC interactions at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically. Significance There are currently no effective therapies for children with relapsed medulloblastoma. Although clinical and biological features of the disease at diagnosis are increasingly well understood, biopsy is rarely performed at relapse, and few biological data are available to guide more effective treatments. Here, we show that medulloblastomas develop altered biology at relapse, which is predictive of disease course and cannot be detected at diagnosis. We have discovered the emergence of P53-MYC interactions at relapse, as biomarkers of clinically aggressive relapsed disease, which can be modeled and targeted therapeutically in genetically engineered mice. These data support the incorporation of biopsy at relapse into routine clinical practice, to direct palliative care and the development of improved treatment strategies.