Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct

Abstract

Recent integrative genomic approaches have defined molecular subgroups of medulloblastoma that are genetically and clinically distinct. Sonic hedgehog (Shh) medulloblastomas account for one-third of all cases and comprise the majority of infant and adult medulloblastomas. To discern molecular heterogeneity among Shh-medulloblastomas, we analyzed transcriptional profiles from four independent Shh-medulloblastoma expression datasets (n = 66). Unsupervised clustering analyses demonstrated a clear distinction between infant and adult Shh-medulloblastomas, which was reliably replicated across datasets. Comparison of transcriptomes from infant and adult Shh-medulloblastomas revealed deregulation of multiple gene families, including genes implicated in cellular development, synaptogenesis, and extracellular matrix maintenance. Furthermore, metastatic dissemination is a marker of poor prognosis in adult, but not in pediatric Shh-medulloblastomas. Children with desmoplastic Shh-medulloblastomas have a better prognosis than those with Shh-medulloblastomas and classic histology. Desmoplasia is not prognostic for adult Shh-medulloblastoma. Cytogenetic analysis of a large, non-overlapping cohort of Shh-medulloblastomas (n = 151) revealed significant over-representation of chromosome 10q deletion (P < 0.001) and MYCN amplification (P < 0.05) in pediatric Shh cases compared with adults. Adult Shh-medulloblastomas harboring chromosome 10q deletion, 2 gain, 17p deletion, 17q gain, and/or GLI2 amplification have a much worse prognosis as compared to pediatric cases exhibiting the same aberrations. Collectively, our data demonstrate that pediatric and adult Shh-medulloblastomas are clinically, transcriptionally, genetically, and prognostically distinct.

Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics

“…Alternatively, the Shh mouse models may only represent a specific subtype of human SHH-MBs (Northcott et al 2011a). Consistent with our findings, previously published mouse microarray results showed up-regulation of Eag2 in 50% (three of six) of Shh-MB mouse models (expressing Shh pathway markers including Hhip, Sfrp1, and Mycn) and only 33% (one of three) of Wnt-MB mice (expressing Wnt pathway markers including Wif1, Dkk1, and Dkk2) ( Fig.…”

Sox2 Requirement in Sonic Hedgehog-Associated Medulloblastoma

“…This is in line with the observation that most, if not all, desmoplastic medulloblastomas molecularly belong to the SHH group (6). It is further known that SHH medulloblastomas themselves divide into diverse clinically and molecularly distinct subpopulations, namely infantile, childhood, and adult cases (29). When dividing our cohort into these 3 age groups, we found that SOX2 is expressed in an age-dependent manner.…”

“…By examining both, human medulloblastoma tissue sections and mRNA expression data, we found that SOX2 expression also coincides with both classification systems of medulloblastoma. SHH-associated and desmoplastic medulloblastoma show a biphasic distribution concerning patient age (29). Keeping this in mind, the particularly high expression of SOX2 in adult cases of SHH-associated medulloblastoma may indicate a distinct role for the formation of adult medulloblastoma.…”

Foretinib Is Effective Therapy for Metastatic Sonic Hedgehog Medulloblastoma

“…In pediatric patients with SHH tumors, activation of cMET is correlated with an increased rate of relapse and a shorter progression-free survival. Notably, this association is not seen in adult SHH patients confirming the previously reported clinical and molecular distinction between adult and pediatric SHH medulloblastomas (44). Furthermore, p-cMET status does not correlate with the presence of metastases or TP53 mutations, two known markers of poor prognosis across medulloblastoma subgroups (45) and within the SHH subgroup (46), respectively.…”