Update on molecular and genetic alterations in adult medulloblastoma

Abstract

Medulloblastoma encompasses a group of aggressively growing cancers that arise either in the cerebellum or brain stem. They present primarily in children, with 80-85 % of medulloblastomas being diagnosed in patients of 16 years and younger. In adults, medulloblastomas are rare and account for less than 1 % of intracranial malignancies. Due to the low incidence of medulloblastoma in adults, the biology and genetics of adult medulloblastomas have long been poorly understood. Many centers therefore still treat adults either by radiotherapy only or by using glioblastoma protocols (both often noncurative), or with standard pediatric medulloblastoma regimes (often associated with dose-limiting toxicity).Current clinical staging systems discriminate between standard-risk or high-risk patients based on clinical and histological parameters. However, clinico-pathological features often fail to accurately predict treatment response. In children, molecularly defined risk assessment has become important to improve survival of high-risk patients and to decrease treatment-related toxicity and long-term sequelae in standard-risk patients. However, several recent studies have shown that adult and pediatric medulloblastomas are genetically distinct and may require different algorithms for molecular risk stratification. Moreover, four subtypes of medulloblastoma have been identified that appear at different frequencies in children and adults and that have a different prognostic impact depending on age. Molecular markers such as chromosome 10q and chromosome 17 statuses can be used for molecular risk stratification of adult medulloblastoma, but only in a subgroup-specific context. Here we present an overview of the current knowledge of the genomics of adult medulloblastoma and how these tumors differ from their pediatric counterparts.

Keywords: Adults; Medulloblastoma; Molecular stratification.

Fig. 1

Overall survival (OS) analyses of molecular and histological subgroups within adult medulloblastomas using Kaplan–Meier plots and log-rank tests. Tumor data are combined from gene expression studies and tissue microarray (TMA) analyses as described in [6] plus 17 new adult cases that were recently added to our MB TMAs. a OS analysis of molecular subgroups among all adult medulloblastoma patients (n = 158). b OS analysis of classic, desmoplastic, and LCA histological subgroups among all adult medulloblastoma patients. c OS analysis of MYC or MYCN amplified adult medulloblastomas versus nonamplified adult medulloblastomas. d, g, j OS analyses of patients harboring 10q loss versus patients with a balanced 10q, either in all adult medulloblastoma patients (d), in SHH medulloblastomas only (g), or in Group 4 medulloblastomas only (j). e, h, k OS analyses of patients harboring 17p loss versus patients with a balanced 17p, either in all adult medulloblastoma patients (e), in SHH medulloblastomas only (h), or in Group 4 medulloblastomas only (k). f, i, l OS analyses of patients harboring 17q gain versus patients with a balanced 17q, either in all adult medulloblastoma patients (f), in SHH medulloblastomas only (I), or in Group 4 medulloblastomas only (l). Numbers on the Y axis indicate the fraction of surviving patients. Numbers on the X axis indicate the follow-up time in months. Numbers next to the Kaplan Meier plots indicate the total number of patients per subgroup and the number of events in that subgroup. NS not significant