Oncology Scan—Molecular Genotyping of Medulloblastoma: A New Treatment Era

Abstract

Medulloblastoma is the most common malignant central nervous system tumor of childhood. The current classification schemes are based primarily on histopathology, with treatment dependent upon risk stratification incorporating clinical factors of age, extent of surgical resection, and metastatic disease. For children more than 3 years of age, the current mainstay of treatment involves maximal surgical resection followed by adjuvant craniospinal irradiation (CSI) and boost, in combination with concurrent and maintenance chemotherapy. Although the poor prognostic impact of additional histopathological factors, such as large-cell variant and diffuse anaplasia, have been recognized, the incorporation of molecular genetic features into treatment strategies has previously been elusive. With advances in molecular genetics, it has now been recognized that medulloblastoma comprises a heterogeneous group of tumors with distinct genomic signatures and associated prognostic implications ( 1 Northcott P.A. Korshunov A. Witt H. et al. Medulloblastoma comprises four distinct molecular variants. J Clin Oncol. 2011; 29: 1408-1414 Crossref PubMed Scopus (940) Google Scholar , 2 Ellison D.W. Kocak M. Dalton J. et al. Definition of disease-risk stratification groups in childhood medulloblastoma using combined clinical, pathologic, and molecular variables. J Clin Oncol. 2011; 29: 1400-1407 Crossref PubMed Scopus (212) Google Scholar , 3 Tamayo P. Cho Y.J. Tsherniak A. et al. Predicting relapse in patients with medulloblastoma by integrating evidence from clinical and genomic features. J Clin Oncol. 2011; 29: 1415-1423 Crossref PubMed Scopus (57) Google Scholar , 4 Cho Y.J. Tsherniak A. Tamayo P. et al. Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. J Clin Oncol. 2011; 29: 1424-1430 Crossref PubMed Scopus (518) Google Scholar , 5 Schwalbe E.C. Lindsey J.C. Straughton D. et al. Rapid diagnosis of medulloblastoma molecular subgroups. Clin Cancer Res. 2011; 17: 1883-1894 Crossref PubMed Scopus (58) Google Scholar ). Four principal transcriptional subgroups of medulloblastoma are recognized, which include: Wnt, Shh (sonic hedgehog), Group 3, and Group 4 ( 6 Taylor M.D. Northcott P.A. Korshunov A. et al. Molecular subgroups of medulloblastoma: The current consensus. Acta Neuropathol. 2012; 123: 465-472 Crossref PubMed Scopus (1179) Google Scholar ). The Wnt and Shh groups are associated with biomarkers of aberrant signaling pathways that drive tumor initiation, whereas Group 3 and Group 4 are more vaguely defined as the underlying genetic alterations driving clinical outcomes that are less well understood. The identification of underlying biology as a clinical driver provides tremendous opportunities for better therapeutic targeting (eg, Shh inhibitors) and allows re-stratification of prognostic groups beyond the clinical markers in use today.