Preponderance of sonic hedgehog pathway activation characterizes adult medulloblastoma.
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.
Department of Radiation Oncology, Montreal General Hospital, McGill University Health Centre, Canada.
Hani
H
Al-Halabi
Andre
A
Nantel
Almos
A
Klekner
Marie-Christine
MC
Guiot
Steffen
S
Albrecht
Peter
P
Hauser
Miklos
M
Garami
Laszlo
L
Bognar
Peter
P
Kavan
Noha
N
Gerges
Margret
M
Shirinian
David
D
Roberge
Thierry
T
Muanza
Nada
N
Jabado
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D016019:Survival Analysis; D014157:Transcription Factors / Q000378:metabolism; D055815:Young Adult; D000071676:Zinc Finger Protein GLI1; D051176:beta Catenin / Q000378:metabolism; D000094742:Secreted Frizzled-Related Proteins
D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D051176:beta Catenin; C400551:GLI1 protein, human; C000606236:PTCH1 protein, human; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins; C509239:SHH protein, human