Stratification of infant patients with medulloblastoma: Genomics and biology complement histological classification

Abstract

Desmoplastic/nodular histology is a favourable prognostic marker in medulloblastoma (MB) of infancy that allows the reduction of therapy to decrease side-effects. In a cohort of 168 infant MB (< 5 years) we analysed the histology, hedgehog pathway activation (immunostaining for YAP-1 and p75-NGFR) and genomic landscape by molecular inversion profiling. Desmoplastic/nodular histology (MB with extensive nodularity (MBEN) and desmoplastic MB (DMB)) showed a high concordance (> 98%) with hedgehog activation. The frequency of chromosomal copy number aberrations was significantly lower in the desmoplastic/nodular subtypes. MBEN and DMB were characterized by LOH of chromosomal arms 9q or 10q (MBEN, 77%; DMB, 76%), whereas classic MB (CMB) and large cell or anaplastic MB (LCA-MB) showed 17q gains (CMB, 67%; LCA-MB, 79%) or an isochromosome 17q (CMB, 30%; LCA-MB, 57%), and gains of OTX2 (CMB, 73%; LCA-MB, 79%). Moreover, 71% of LCA-MB carried MYCC or MYCN amplifications. In summary, hedgehog activation and specific genetic features are strongly associated with distinct histological subtypes of infant MB and therefore represent useful diagnostic tools to correctly classify these tumors.