Combined p53 and MYC Alterations Are Common in Relapsed Medulloblastoma

Although the 5-year survival rate for patients with medulloblastoma is over 60%, over 95% of patients who relapse following standard treatment die. Because biopsies are rarely performed at relapse in this disease, the clinical, pathologic, and molecular characteristics of relapsed medulloblastoma are largely unknown, and clinical management is generally limited to palliative strategies. Hill, Kuijper, Lindsey, Petrie, and colleagues analyzed a cohort of 29 relapsed medulloblastomas and their paired diagnostic samples and found that although the molecular subgroup did not change, combined defects in the p53 pathway and amplification of MYC family genes were significantly more frequent in relapsed tumors than at diagnosis regardless of molecular subgroup, with specific combinations of alterations only observed at relapse and not at diagnosis. Moreover, these combined defects defined a population of patients with locally aggressive tumors who had a significantly shorter time to death than other patients with relapsed disease. To determine whether p53 and MYC alterations interact to drive medulloblastoma progression, the authors investigated Trp53 status in spontaneous tumors in a transgenic medulloblastoma model driven by MYCN expression and found that 10 of 12 tumors (83%) had acquired somatic Trp53 mutations. Additionally, targeted disruption of endogenous p53 in this MYCN-driven model dramatically increased tumor penetrance and decreased overall survival, generating tumors with clinical and pathologic features of locally aggressive disease. Given that MYCN stability is regulated by Aurora kinase A (AURKA), the authors treated the p53-deficient, MYCN-driven model of relapsed medulloblastoma with the AURKA inhibitor alisertib and observed blood–brain barrier penetration and significantly prolonged survival, suggesting that indirectly targeting MYCN may be effective in relapsed medulloblastoma with combined p53 and MYC defects. These findings reveal that relapsed medulloblastoma is biologically unique and provide support for routine biopsies of medulloblastoma at relapse to help guide patient management and development of therapeutic strategies.

Hill RM, Kuijper S, Lindsey JC, Petrie K, Schwalbe EC, Barker K, et al. Combined MYC and P53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease. Cancer Cell 2014 Dec 18 [Epub ahead of print].