MPTH-13ADULT MEDULLOBLASTOMAS: MOLECULAR SUBGROUPING AND CORRELATION WITH CLINICOPATHOLOGICAL CHARACTERISTICS, AND EXPRESSION OF miR-379/miR-656 CLUSTER (C14MC)

Abstract

Medulloblastoma(MB) is a childhood tumor comprising of four molecular subgroups, viz. Wnt, Shh, group3 and group4, with therapeutic and prognostic connotations. Very few studies are available regarding molecular subgrouping of adult MBs. Recently, loss of chromosome 14q has been reported in ∼25% of Shh MBs with downregulation of some of the miRNAs of miR-379/miR-656 cluster (C14MC) located on 14q32.31 in pediatric Shh MBs. Hence, the present study was undertaken to (i)study the molecular subgrouping and clinicopathological characteristics of adult MBs (ii)analyze the expression of C14MC and its positive transcriptional regulator, MEF2 in Shh subgroup. Sixty adult (>18 years) MBs were analyzed. Immunohistochemistry for beta-catenin(Wnt), GAB-1(Shh) and YAP-1(both Wnt and Shh) was performed. In non-Wnt/Shh, c-Myc amplification was evaluated by FISH. Expression profiling of 47 miRNAs from C14MC was performed using customized Taqman low-density array microfluidic assay in 10 Shh MBs. Expression of MEF-2, was examined using RT-PCR. Wnt tumors constituted 3.3%, Shh 65%, and Non-Wnt/Shh 31.7%. C-Myc amplification was identified in 20% cases. As compared to paediatric tumors, adult MBs had male predominance and majority were located laterally(52%). Although classic was the commonest histological type(50%), a significant proportion were Desmoplastic/Nodular(35%), unlike in children, and MBEN was not seen. Shh was the predominant subgroup(65%) in contrast to NonWnt/Shh in children. Patient outcome was worse in adults(median PFS-1.5years). Significant downregulation of C14MC was observed in Shh MBs and MEF-2 expression was also downregulated. Thus, compared to childhood MBs, adult MBs are distinct in terms of tumor location, histopathology, distribution of molecular subgroups and clinical outcome. Silencing of C14MC in adult Shh MBs, similar to pediatric MBs, suggests its role as a tumor suppressor locus in Shh MB tumorigenesis. Deregulation of C14MC in Shh MBs can possibly be attributed to repression of transcription factor MEF2 and/or LOH of 14q.