Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Acta Neuropathologica
Published in: Acta Neuropathologica 2/2011

01-02-2011 | Original Paper

Preponderance of sonic hedgehog pathway activation characterizes adult medulloblastoma

Authors: Hani Al-Halabi, Andre Nantel, Almos Klekner, Marie-Christine Guiot, Steffen Albrecht, Peter Hauser, Miklos Garami, Laszlo Bognar, Peter Kavan, Noha Gerges, Margret Shirinian, David Roberge, Thierry Muanza, Nada Jabado

Published in: Acta Neuropathologica | Issue 2/2011

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
Ang C, Hauerstock D, Guiot MC, Kasymjanova G, Roberge D, Kavan P, Muanza T (2008) Characteristics and outcomes of medulloblastoma in adults. Pediatr Blood Cancer 51:603–607CrossRefPubMed
2.
Brandes AA, Palmisano V, Monfardini S (1999) Medulloblastoma in adults: clinical characteristics and treatment. Cancer Treat Rev 25:3–12CrossRefPubMed
3.
Chargari C, Feuvret L, Levy A, Lamproglou I, Assouline A, Hemery C, Ghorbal L, Lopez S, Tep B, GB G, Lang P, Laigle-Donadey F, Cornu P, Mazeron JJ, Simon JM (2010) Reappraisal of clinical outcome in adult medulloblastomas with emphasis on patterns of relapse. Br J Neurosurg 24:460–467CrossRefPubMed
4.
Clifford SC, Lusher ME, Lindsey JC, Langdon JA, Gilbertson RJ, Straughton D, Ellison DW (2006) Wnt/Wingless pathway activation and chromosome 6 loss characterize a distinct molecular sub-group of medulloblastomas associated with a favorable prognosis. Cell Cycle 5:2666–2670CrossRefPubMed
5.
de Haas T, Hasselt N, Troost D, Caron H, Popovic M, Zadravec-Zaletel L, Grajkowska W, Perek M, Osterheld MC, Ellison D, Baas F, Versteeg R, Kool M (2008) Molecular risk stratification of medulloblastoma patients based on immunohistochemical analysis of MYC, LDHB, and CCNB1 expression. Clin Cancer Res 14:4154–4160CrossRefPubMed
6.
Ellison DW, Clifford SC, Gajjar A, Gilbertson RJ (2003) What’s new in neuro-oncology? Recent advances in medulloblastoma. Eur J Paediatr Neurol 7:53–66CrossRefPubMed
7.
Ellison DW, Onilude OE, Lindsey JC, Lusher ME, Weston CL, Taylor RE, Pearson AD, Clifford SC (2005) beta-Catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children’s Cancer Study Group Brain Tumour Committee. J Clin Oncol 23:7951–7957CrossRefPubMed
8.
Ellison DW (2010) Childhood medulloblastoma: novel approaches to the classification of a heterogeneous disease. Acta Neuropathol 120:305–316CrossRefPubMed
9.
Faury D, Nantel A, Dunn SE, Guiot MC, Haque T, Hauser P, Garami M, Bognar L, Hanzely Z, Liberski PP, Lopez-Aguilar E, Valera ET, Tone LG, Carret AS, Del Maestro RF, Gleave M, Montes JL, Pietsch T, Albrecht S, Jabado N (2007) Molecular profiling identifies prognostic subgroups of pediatric glioblastoma and shows increased YB-1 expression in tumors. J Clin Oncol 25:1196–1208CrossRefPubMed
10.
Gajjar A, Hernan R, Kocak M, Fuller C, Lee Y, McKinnon PJ, Wallace D, Lau C, Chintagumpala M, Ashley DM, Kellie SJ, Kun L, Gilbertson RJ (2004) Clinical, histopathologic, and molecular markers of prognosis: toward a new disease risk stratification system for medulloblastoma. J Clin Oncol 22:984–993CrossRefPubMed
11.
Gajjar A, Chintagumpala M, Ashley D, Kellie S, Kun LE, Merchant TE, Woo S, Wheeler G, Ahern V, Krasin MJ, Fouladi M, Broniscer A, Krance R, Hale GA, Stewart CF, Dauser R, Sanford RA, Fuller C, Lau C, Boyett JM, Wallace D, Gilbertson RJ (2006) Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial. Lancet Oncol 7:813–820CrossRefPubMed
12.
Grotzer MA, Janss AJ, Fung K, Biegel JA, Sutton LN, Rorke LB, Zhao H, Cnaan A, Phillips PC, Lee VM, Trojanowski JQ (2000) TrkC expression predicts good clinical outcome in primitive neuroectodermal brain tumors. J Clin Oncol 18:1027–1035PubMed
13.
Grotzer MA, Hogarty MD, Janss AJ, Liu X, Zhao H, Eggert A, Sutton LN, Rorke LB, Brodeur GM, Phillips PC (2001) MYC messenger RNA expression predicts survival outcome in childhood primitive neuroectodermal tumor/medulloblastoma. Clin Cancer Res 7:2425–2433PubMed
14.
Haque T, Faury D, Albrecht S, Lopez-Aguilar E, Hauser P, Garami M, Hanzely Z, Bognar L, Del Maestro RF, Atkinson J, Nantel A, Jabado N (2007) Gene expression profiling from formalin-fixed paraffin-embedded tumors of pediatric glioblastoma. Clin Cancer Res 13:6284–6292CrossRefPubMed
15.
Hubbard JL, Scheithauer BW, Kispert DB, Carpenter SM, Wick MR, Laws ER Jr (1989) Adult cerebellar medulloblastomas: the pathological, radiographic, and clinical disease spectrum. J Neurosurg 70:536–544CrossRefPubMed
16.
Kool M, Koster J, Bunt J, Hasselt NE, Lakeman A, van Sluis P, Troost D, Meeteren NS, Caron HN, Cloos J, Mrsic A, Ylstra B, Grajkowska W, Hartmann W, Pietsch T, Ellison D, Clifford SC, Versteeg R (2008) Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PLoS One 3:e3088CrossRefPubMed
17.
Korshunov A, Remke M, Werft W, Benner A, Ryzhova M, Witt H, Sturm D, Wittmann A, Schottler A, Felsberg J, Reifenberger G, Rutkowski S, Scheurlen W, Kulozik AE, von Deimling A, Lichter P, Pfister SM (2010) Adult and pediatric medulloblastomas are genetically distinct and require different algorithms for molecular risk stratification. J Clin Oncol 28:3054–3060CrossRefPubMed
18.
Lal P, Nagar YS, Kumar S, Singh S, Maria Das KJ, Narayan SL, Kumar R, Jain VK, Ayyagari S (2002) Medulloblastomas: clinical profile, treatment techniques and outcome—an institutional experience. Indian J Cancer 39:97–105PubMed
19.
Maleci A, Cervoni L, Delfini R (1992) Medulloblastoma in children and in adults: a comparative study. Acta Neurochir (Wien) 119:62–67CrossRef
20.
McManamy CS, Pears J, Weston CL, Hanzely Z, Ironside JW, Taylor RE, Grundy RG, Clifford SC, Ellison DW (2007) Nodule formation and desmoplasia in medulloblastomas-defining the nodular/desmoplastic variant and its biological behavior. Brain Pathol 17:151–164CrossRefPubMed
21.
Merchant TE, Kiehna EN, Li C, Shukla H, Sengupta S, Xiong X, Gajjar A, Mulhern RK (2006) Modeling radiation dosimetry to predict cognitive outcomes in pediatric patients with CNS embryonal tumors including medulloblastoma. Int J Radiat Oncol Biol Phys 65:210–221CrossRefPubMed
22.
Northcott PA, Korshunov A, Witt H, Hielscher T, Eberhart CG, Mack S, Bouffet E, Clifford SC, Hawkins CE, French P, Rutka JT, Pfister S, Taylor MD (2010) Medulloblastoma Comprises Four Distinct Molecular Variants. J Clin Oncol
23.
Packer RJ, Finlay JL (1988) Medulloblastoma: presentation, diagnosis and management. Oncology (Williston Park) 2:35–45, 48–39
24.
Packer RJ, Gajjar A, Vezina G, Rorke-Adams L, Burger PC, Robertson PL, Bayer L, LaFond D, Donahue BR, Marymont MH, Muraszko K, Langston J, Sposto R (2006) Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol 24:4202–4208CrossRefPubMed
25.
Padovani L, Sunyach MP, Perol D, Mercier C, Alapetite C, Haie-Meder C, Hoffstetter S, Muracciole X, Kerr C, Wagner JP, Lagrange JL, Maire JP, Cowen D, Frappaz D, Carrie C (2007) Common strategy for adult and pediatric medulloblastoma: a multicenter series of 253 adults. Int J Radiat Oncol Biol Phys 68:433–440CrossRefPubMed
26.
Pfister S, Remke M, Benner A, Mendrzyk F, Toedt G, Felsberg J, Wittmann A, Devens F, Gerber NU, Joos S, Kulozik A, Reifenberger G, Rutkowski S, Wiestler OD, Radlwimmer B, Scheurlen W, Lichter P, Korshunov A (2009) Outcome prediction in pediatric medulloblastoma based on DNA copy-number aberrations of chromosomes 6q and 17q and the MYC and MYCN loci. J Clin Oncol 27:1627–1636CrossRefPubMed
27.
Pfister SM, Korshunov A, Kool M, Hasselblatt M, Eberhart C, Taylor MD (2010) Molecular diagnostics of CNS embryonal tumors. Acta Neuropathol 120:553–566CrossRefPubMed
28.
Pomeroy SL, Tamayo P, Gaasenbeek M, Sturla LM, Angelo M, McLaughlin ME, Kim JY, Goumnerova LC, Black PM, Lau C, Allen JC, Zagzag D, Olson JM, Curran T, Wetmore C, Biegel JA, Poggio T, Mukherjee S, Rifkin R, Califano A, Stolovitzky G, Louis DN, Mesirov JP, Lander ES, Golub TR (2002) Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 415:436–442CrossRefPubMed
29.
Qu HQ, Jacob K, Fatet S, Ge B, Barnett D, Delattre O, Faury D, Montpetit A, Solomon L, Hauser P, Garami M, Bognar L, Hansely Z, Mio R, Farmer JP, Albrecht S, Polychronakos C, Hawkins C, Jabado N (2010) Genome-wide profiling using single-nucleotide polymorphism arrays identifies novel chromosomal imbalances in pediatric glioblastomas. Neuro Oncol 12:153–163PubMed
30.
Roberts RO, Lynch CF, Jones MP, Hart MN (1991) Medulloblastoma: a population-based study of 532 cases. J Neuropathol Exp Neurol 50:134–144CrossRefPubMed
31.
Rodriguez FJ, Eberhart C, O’Neill BP, Slezak J, Burger PC, Goldthwaite P, Wu W, Giannini C (2007) Histopathologic grading of adult medulloblastomas. Cancer 109:2557–2565CrossRefPubMed
32.
Rudin CM, Hann CL, Laterra J, Yauch RL, Callahan CA, Fu L, Holcomb T, Stinson J, Gould SE, Coleman B, LoRusso PM, Von Hoff DD, de Sauvage FJ, Low JA (2009) Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med 361:1173–1178CrossRefPubMed
33.
Sarkar C, Pramanik P, Karak AK, Mukhopadhyay P, Sharma MC, Singh VP, Mehta VS (2002) Are childhood and adult medulloblastomas different? A comparative study of clinicopathological features, proliferation index and apoptotic index. J Neurooncol 59:49–61CrossRefPubMed
34.
Tabori U, Sung L, Hukin J, Laperriere N, Crooks B, Carret AS, Silva M, Odame I, Mpofu C, Strother D, Wilson B, Samson Y, Bouffet E (2005) Medulloblastoma in the second decade of life: a specific group with respect to toxicity and management: a Canadian Pediatric Brain Tumor Consortium Study. Cancer 103:1874–1880CrossRefPubMed
35.
Tabori U, Sung L, Hukin J, Laperriere N, Crooks B, Carret AS, Silva M, Odame I, Mpofu C, Strother D, Wilson B, Samson Y, Bouffet E (2006) Distinctive clinical course and pattern of relapse in adolescents with medulloblastoma. Int J Radiat Oncol Biol Phys 64:402–407CrossRefPubMed
36.
Tabori U, Baskin B, Shago M, Alon N, Taylor MD, Ray PN, Bouffet E, Malkin D, Hawkins C (2010) Universal poor survival in children with medulloblastoma harboring somatic TP53 mutations. J Clin Oncol 28:1345–1350CrossRefPubMed
37.
Thompson MC, Fuller C, Hogg TL, Dalton J, Finkelstein D, Lau CC, Chintagumpala M, Adesina A, Ashley DM, Kellie SJ, Taylor MD, Curran T, Gajjar A, Gilbertson RJ (2006) Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol 24:1924–1931CrossRefPubMed
Metadata
Title
Preponderance of sonic hedgehog pathway activation characterizes adult medulloblastoma
Authors
Hani Al-Halabi
Andre Nantel
Almos Klekner
Marie-Christine Guiot
Steffen Albrecht
Peter Hauser
Miklos Garami
Laszlo Bognar
Peter Kavan
Noha Gerges
Margret Shirinian
David Roberge
Thierry Muanza
Nada Jabado
Publication date
01-02-2011
Publisher
Springer-Verlag
Published in
Acta Neuropathologica / Issue 2/2011
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-010-0780-0

Other articles of this Issue 2/2011

Acta Neuropathologica 2/2011 Go to the issue

Original Paper

Patterns of microRNA expression in normal and early Alzheimer’s disease human temporal cortex: white matter versus gray matter

Editorial

Tau pathology in children and young adults: can you still be unconditionally baptist?

Correspondence

Absence of chromosome 19q13.41 amplification in a case of atypical teratoid/rhabdoid tumor with ependymoblastic differentiation

Original Paper

Brain aging and Aβ1–42 neurotoxicity converge via deterioration in autophagy–lysosomal system: a conditional Drosophila model linking Alzheimer’s neurodegeneration with aging

Original Paper

The spectrum and severity of FUS-immunoreactive inclusions in the frontal and temporal lobes of ten cases of neuronal intermediate filament inclusion disease

Correspondence

Parallel fiber counts and parallel fiber integrated density are similar in essential tremor cases and controls