Preponderance of sonic hedgehog pathway activation characterizes adult medulloblastoma

Abstract

Medulloblastoma (MB) represents approximately 4% of adult brain tumours, and as such is a poorly studied disease. Although many adult MB are treated using paediatric MB protocols, the reported outcomes are inferior to those observed in children. It remains unclear whether biologic differences underlie these clinical observations. We investigated the molecular characteristics of 31 adult MB. Twelve and 19 adult MB were respectively examined using Affymetrix-HG-U133-plus-2.0-genechips and immunohistochemical analyses. 26/31 (84%) of adult MB examined by gene expression and/or immunohistochemical analysis showed evidence of sonic hedgehog (SHH) pathway activation. A comparison of adult and paediatric MB showed that most adult tumours cluster within the SHH-active subgroup of paediatric MB. The preponderance of SHH activity in adult MB tumours was also shown by positive SFRP1 immunostaining in 16/19 adult paraffin-embedded adult MB tumour blocks. A smaller proportion of adult tumours exhibited evidence of WNT pathway activation, as confirmed by nuclear β-catenin staining (9.7%; 3/31). Notably, we found PTCH1 gene mutation in 4/8 samples tested. Similar to children, adult MB has abnormalities in developmental signalling pathways including SHH and WNT. Importantly, we found a preponderance of SHH pathway activation amongst MB tumours in adults. This SHH signature does not appear to correlate with a long-term favourable outcome. Differences in molecular profiles exist between adult and paediatric SHH-driven MB and further investigations are needed to better characterize age-related molecular profiles in this subgroup.

Molecular subgroups of medulloblastoma

“…WNT pathway genes SFRP1 , SFRP4 and SFRP5 are also highly expressed in SHH tumors, as are members of the SOX gene family including SOX2 , SOX9 and SOX13 . Comparing the transcriptomes of pediatric SHH tumors to their adult counterparts, we [23] and others [48] recently noted very distinct expression patterns between these age groups, with adult SHH tumors expressing elevated levels of HOX family genes (i.e., HOXA5 , HOXA9 and HOXA2 ) and genes involved in tissue development, whereas pediatric SHH tumors showed an enrichment of gene sets related to extracellular matrix function. The disparate transcriptional profiles observed between these two age groups of SHH medulloblastoma suggest they have distinct underlying biologies, and as a result may respond differently to current targeted therapies designed to abrogate SHH pathway activation [49,50].…”

“…Additional over-represented copy number changes that have been reported in SHH tumors include gain of chromosomes 2 and 3, and losses of chromosomes 10q and 20p. Importantly, 9q and 10q deletions are generally mutually exclusive events, suggesting genetic heterogeneity within the SHH subgroup, some of which may be explained by underlying molecular differences between pediatric and adult SHH tumors [23,48], including a reduced frequency of 10q loss in adult cases [23]. These results, in conjunction with age-dependent prognostic markers, demonstrate that pediatric and adult cases of SHH medulloblastoma are biologically and clinically distinct [23].…”

Complete and sustained response of adult medulloblastoma to first-line sonic hedgehog inhibition with vismodegib

“…19 Interestingly, WNT pathway activation is less frequent in adult medulloblastomas. 20 Further studies have substantiated these differences in pathway activation as compared to pediatric cases. Evidence to date suggests that SHH pathway activation in adults does not correlate with a favorable prognosis.…”

“…19 As many as 84% of adult medulloblastoma tumors may show evidence of activation of the SHH pathway. 20 When considering both pediatric and adult cases, most studies report a prevalence of approximately 28%. 19 Notably, more than half of medulloblastoma cases are driven by the SHH pathway in the infant population as well as adults.…”

“…Evidence to date suggests that SHH pathway activation in adults does not correlate with a favorable prognosis. 20 In a meta-analysis of 550 cases, Kool et al reported an approximately 70% overall survival rate of adults with SHH medulloblastomas by 5 years, but with significant subsequent rise in mortality, evidenced by a 30% overall survival rate by 150 months (12.5 years). 19 Agents targeting the sonic hedgehog (SHH) pathway have been investigated in recurrent adult and pediatric medulloblastomas because a significant subgroup of this disease is driven by this molecular pathway.…”