Download Implications of Tumor Location on Subtypes of Medulloblastoma

Pediatr Blood Cancer 2013;60:1408–1410
PRIORITY REPORT
Implications of Tumor Location on Subtypes of Medulloblastoma
Wan-Yee Teo, MBBS,1 Jianhe Shen, MS,1 Jack Meng Fen Su, MD,1,2 Alexander Yu, BS,1 Jian Wang, PhD,1
Wing-Yuk Chow, PhD,1 Xiaonan Li, MD, PhD,1,2 Jeremy Jones, MD,3 Robert Dauser, MD,2,4 William Whitehead, MD,2,4
Adekunle M. Adesina, MD, PhD,2,5 Murali Chintagumpala, MD,1,2 Tsz-Kwong Man, PhD,1,2 and Ching C. Lau, MD, PhD1,2*
Background. Medulloblastoma (MB) comprises of four molecular
subtypes, Sonic hedgehog (SHH), Wingless (WNT), Groups 3 and 4.
WNT-subtype MBs were found to arise from midline of the brainstem
occupying the fourth ventricle while SHH-subtype occupied the
cerebellar hemisphere in a small subset of patients. Procedure. We
tested this hypothesis in a large cohort of pediatric MBs comprising of
all four molecular subtypes. Results. We validated in the first
comprehensive analysis of tumor location of 60 human MBs
representative of the four molecular subtypes, that hemispheric
tumors are significantly associated with SHH-subtype MBs while
midline tumors with WNT-subtype, Group 3 and 4 MBs (P < 0.001).
Nearly half of SHH-subtype MBs were midline. Conclusions. Tumor
location should not be generalized to MB subtypes. SHH-subtype
MBs are not exclusively hemispheric and hemispheric MBs are not
always SHH-activated. It is imperative to identify subtypes in
conjunction with tumor location when exploring currently available
targeted therapy. Pediatr Blood Cancer 2013;60:1408–1410.
# 2013 Wiley Periodicals, Inc.
Key words: medulloblastoma; molecular subtypes; pediatric; tumor location
INTRODUCTION
Medulloblastoma (MB) is the most common malignant brain
tumor in children. Multimodality treatment regimens involving
surgery, chemotherapy and radiotherapy have improved survival
rates. However, approximately one third of patients with MBs
remain incurable. MB is recently recognized as comprising of four
molecular subtypes through global genomic profiling [1–5]. Two of
these groups are characterized by activation of either Sonic
hedgehog (SHH, 25% of cases [1–14]) or Wingless (WNT, 10–15%
of cases [1–5,15–21]) pathways. The mechanisms driving the
remaining two subgroups (Group 3 and 4) remain unknown.
Specifically, Group 3 and 4 MBs exhibited worse prognosis
compared to the SHH- and WNT-subtypes.
Gibson et al. [22] reported using a xenograft mouse model that
WNT-subtype MBs arise from outside the cerebellum of the dorsal
brainstem and showed that 6/6 WNT-subtype human MBs were
located within the fourth ventricle and infiltrated the dorsal
brainstem, whereas 6/6 SHH-subtype human tumors were
distributed away from the brainstem within the cerebellar hemispheres. The latter observation is consistent with previous reports
that SHH-subtype MBs arise from external granule layer (EGL)
precursors of the cerebellum in mouse models [11–12,23–25].
These results also suggest that WNT- and SHH- subtypes of MBs
have distinct cellular origins. We therefore sought to test this
hypothesis in a large cohort of pediatric MBs comprising of all four
molecular subtypes.
PROCEDURES
We performed a blinded review of the diagnostic MRIs of 60
pediatric MBs, classified the tumor location and correlated to the
molecular subtype. One case had a tumor location which was not
classifiable and was excluded from the analysis. All tumor
specimens were obtained through an IRB-approved protocol
from patients at the Texas Children’s Hospital (Houston, TX) after
informed consents were signed. A total of 60 primary pediatric MBs
collected between 1996 and 2008, and 10 controls (normal
cerebellar tissues) were used in this study. Our cohort of MBs
was representative of all four molecular subtypes of the disease
based on global expression profiling (Supplementary Fig. 1, using a
C 2013 Wiley Periodicals, Inc.
DOI 10.1002/pbc.24511
Published online 19 March 2013 in Wiley Online Library
(wileyonlinelibrary.com).
class discovery method by unsupervised hierarchical clustering),
consistent with reports from other groups [1–5]. To confirm the
classification of SHH- and WNT-MBs, we used gene expression
signatures of SHH (41 genes) and WNT (193 genes) activation
obtained from MSigDB [26] and literature and performed
unsupervised hierarchical clustering separately (Supplementary
Figs. 2 and 3). Patients with WNT-subtype disease (n ¼ 5) were
characterized by WNT signature genes and monosomy 6q [1–5,15–
21], while SHH-subtype cases (n ¼ 17) were identified by their
characteristic transcriptional profile marked by SHH signature
genes [1–14] and exclusively high expression of ATOH1 [11,27–
31], a transcription factor which is highly expressed in early EGL
precursors and modulates the signal transduction of SHH pathway
in SHH-subtype MBs (validated by qRT-PCR, Supplementary
Fig. 4). The remaining tumors formed the less well-defined
subtypes, Group 3 (n ¼ 10) and Group 4 (n ¼ 25). Group 4 tumors
Additional Supporting information may be found in the online version
of this article.
1
Department of Pediatrics, Division of Hematology-Oncology, Texas
Children’s Cancer Center, Baylor College of Medicine, Houston, Texas;
2
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston,
Texas; 3Department of Neuroradiology, Texas Children’s Hospital,
Baylor College of Medicine, Houston, Texas; 4Department of
Neurosurgery, Texas Children’s Hospital, Baylor College of Medicine,
Houston, Texas; 5Department of Pathology and Immunology, Texas
Children’s Hospital, Baylor College of Medicine, Houston, Texas
Grant sponsor: National Institutes of Health; Grant number: CA109467;
Grant sponsor: The Gillson Longenbaugh Foundation; Grant sponsor:
John S. Dunn Research Foundation and the Robert J. Kleberg, Jr. and
Helen C. Kleberg Foundation; Grant sponsor: Association for Research
of Childhood Cancer (to C.C.L.); Grant sponsor: The National Medical
Research Council (Singapore) Research Fellowship Award (to W.Y.T.);
Grant sponsor: The Pediatric Brain Tumor Foundation of the United
States Fellowship and ASCO Young Investigator Award (to J.M.S.)
Correspondence to: Ching C. Lau, Texas Children’s Hospital, Feigin
Center, Room 1030.11, 1102 Bates Street, Houston, TX 77030.
E-mail: [email protected]
Received 2 October 2012; Accepted 31 January 2013
Tumor Location in Medulloblastoma Subtypes
were particularly enriched for isochromosome 17q, which is in
agreement with findings reported by other groups [1–5].
RESULTS AND DISCUSSION
Strikingly, cerebellar hemispheric tumors are significantly
associated with SHH-subtype MBs while midline tumors with
WNT-subtype, Group 3 and 4 MBs (P < 0.001, Fig. 1, Table I). In
agreement with the recently published WNT-subtype MB mouse
model which demonstrated that WNT-subtype MBs tend to occur in
the midline and arise from progenitor cells in the brainstem [22], we
found that all the WNT-subtype MBs in our cohort are midline in
location. A surprising observation was that 8 out of 17 SHH-subtype
MBs were midline in location (Table I), indicating that SHHsubtype MBs are not exclusively hemispheric. There was no
unifying characteristics within the midline SHH tumors versus
hemispheric SHH tumors. There was a range of pathology in both
groups. The median age of patients with midline SHH tumors was
1409
3.9 years (range: 0.5–18.1 years), not different from the median age
of patients with hemispheric SHH tumors which was 3.8 years
(range: 1–11.5 years). However, it is intriguing that of seven SHH
infant cases (<3 years old), only 1 of 4 midline cases survived, at
1.2 years post-diagnosis, whereas 1 of 3 hemispheric cases
survived, 10.2 years from diagnosis. These findings within a
homogenous clinical population of a well-defined SHH-subtype of
MB is interesting because it is currently not known if there are
differences in tumor behavior with respect to tumor location. All
infantile SHH MBs in our cohort received a gross total resection. Of
seven SHH infant MBs, three tumors were classic in histology, three
were nodular desmoplastic, one was nodular desmoplastic with
anaplastic large cell features. Of the two infant SHH MB survivors,
the midline tumor had nodular desmoplastic with anaplastic large
cell features and the hemispheric tumor had classic histology.
We found two Group 4 MBs located in the cerebellar
hemispheres (Table I), indicating that hemispheric MBs are not
exclusively SHH-subtype, as previously suggested by other
Fig. 1. MRI showing differences in tumor location of human MBs among subgroups.Panels A, D, G, J, M in axial view, Panels B, E, H, K, N in coronal
views, Panels C, F, I, L, O in saggital views.
Pediatr Blood Cancer DOI 10.1002/pbc
1410
Teo et al.
TABLE I. Distinct Differences in Tumor Location and Age Characteristics Among Human MB Subgroups
Age, years
Median
Range
SHH-subtype MBs
WNT-subtype MBs
Non-SHH/WNT-subtype MBs
Clearly vermis-midline
tumors (n¼48)
Clearly hemispheric-lateral
tumors or hemispheric tumors
touching midline (n¼11)
6.6
0.5–18.2
8
5
35
5.1
1–11.5
9
0
2
groups [22]. Both patients with Group 4 MBs occupying the
cerebellar hemisphere aged 9.8 and 5.4 years old at diagnosis, are
alive at 6.2 and 1.9 years, respectively, and relapse-free. Histology
was classic with focal desmoplasia in the first case and nodular
desmoplastic in the other case. Both patients had M0 disease and
were treated according to the A9961 protocol.
MB occurs primarily in children [32], with 85% of MBs
diagnosed in patients younger than 18 years of age, and is rare in
adults [33–35]. Distinct differences in the genetic and molecular
profiles of adult versus pediatric MBs have been identified [36]. We
discovered that hemispheric MBs (n ¼ 11) frequently occur in
infants and children less than 9 years old (9/11, 82% of hemispheric
MBs) and are rare among older children and adolescents (9 years,
2/11, 18% of hemispheric MBs). On the contrary, adolescent
patients frequently have midline MBs (16/18, 89% of adolescents).
These findings may suggest different pathogenesis and/or cells of
origin between infants and younger children versus adolescents
with MB.
This study represents a comprehensive analysis of tumor
location of MBs in relation to the molecular subtypes. Differences
in tumor locations between and within the four molecular MB
subtypes are biologically and clinically relevant. In contrast to
previous reports, which drew conclusions from limited subsets of
MB subtypes in patients [22], we conclude that tumor location
should not be generalized to specific MB subtypes, but should
instead be interpreted in conjunction with the molecular subtype of
the disease when exploring currently available targeted therapy.
Further biological studies will be needed to determine if midline
SHH tumors are biologically distinct from hemispheric SHH
tumors. Particularly, in the context of preclinical testing,
understanding the tumor location, and perhaps the cells of origin,
may facilitate the development of genetic mouse models of Group 3
and 4 MBs, for which currently there are none.
REFERENCES
1. Thompson MC, Fuller C, Hogg TL, et al. Genomics identifies medulloblastoma subgroups that are
enriched for specific genetic alterations. JCO 2006;24:1924–1931.
2. Kool M, Koster J, Bunt J, et al. Integrated genomics identifies five medulloblastoma subtypes with distinct
genetic profiles, pathway signatures and clinicopathological features. PLoS ONE 2008;3:e3088.
3. Northcott PA, Korshunov A, Witt H, et al. Medulloblastoma comprises of four distinct variants. JCO
2011;29:1408–1414.
4. Cho YJ, Tshemiak A, Tamayo P, et al. Integrative genomic analysis of medulloblastoma identifies a
molecular subgroup that drives poor clinical outcome. JCO 2011;29:1424–1430.
5. Taylor MD, Northcott PA, Korshunov A, et al. Molecular subgroups of medulloblastoma: The current
consensus. Acta Neuropathol 2012;123:465–472.
Pediatr Blood Cancer DOI 10.1002/pbc
P-value
0.13
<0.001
6. Taylor MD, Liu L, Raffel C, et al. Mutations in SUFU predispose to medulloblastoma. Nat Genet
2002;31:306–310.
7. Wolter M, Reifenberger J, Sommer C, et al. Mutations in the human homologue of the Drosophila
segment polarity gene patched (PTCH) in sporadic basal cell carcinomas of the skin and primitive
neuroectodermal tumors of the central nervous system. Cancer Res 1997;57:2581–2585.
8. Hallahan AR, Pritchard JI, Hansen S, et al. The SmoA1 mouse model reveals that notch signaling is
critical for the growth and survival of sonic hedgehog-induced medulloblastomas. Cancer Res
2004;64:7794–7800.
9. Romer JT, Kimura H, Magdaleno S, et al. Suppression of the SHH pathway using a small molecule
inhibitor eliminates medulloblastoma in Ptc1(þ/)p53(/) mice. Cancer Cell 2004;6:229–240.
10. Oliver TG, Read TA, Kessler JD, et al. Loss of patched and disruption of granule cell development in a
pre-neoplastic stage of medulloblastoma. Development 2005;132:2425–2439.
11. Yang ZJ, Ellis T, Markant SL, et al. Medulloblastoma can be initiated by deletion of patched in lineagerestricted progenitors or stem cells. Cancer Cell 2008;14:135–145.
12. Schüller U, Heine VM, Mao J, et al. Acquisition of granule neuron precursor identity is a critical
determinant of progenitor cell competence to form Shh-induced medulloblastoma. Cancer Cell
2008;14:123–134.
13. Eberhart CG. Even cancers want commitment. Lineage identity and medulloblastoma formation. Cancer
Cell 2008;14:105–107.
14. Uziel T, Karginovb FV, Xie S, et al. The miR-1792 cluster collaborates with the Sonic Hedgehog pathway
in medulloblastoma. Proc Natl Acad Sci USA 2009;106:2812–2817.
15. Zurawel RH, Chiappa SA, Allen C, et al. Sporadic medulloblastomas contain oncogenic beta-catenin
mutations. Cancer Res 1998;58:896–899.
16. Huang H, Mahler-Araujo BM, Sankila A, et al. APC mutations in sporadic medulloblastomas. Am J
Pathol 2000;156:433–437.
17. Eberhart CG, Tihan T, Burger PC. Nuclear localization and mutation of beta-catenin in medulloblastomas. J Neuropathol Exp Neurol 2000;59:333–337.
18. Clifford SC, Lusher ME, Lindsey JC, et al. Wnt/Wingless pathway activation and chromosome 6 loss
characterize a distinct molecular sub-group of medulloblastomas associated with a favorable prognosis.
Cell Cycle 2006;5:2666–2670.
19. Salaroli R, Tomaso TD, Ronchi A, et al. Radiobiologic response of medulloblastoma cell lines:
Involvement of b-catenin? J Neurooncol 2008;90:243–251.
20. Dakubo GD, Mazerolle CJ, Wallace VA. Expression of Notch and Wnt pathway components and
activation of Notch signaling in medulloblastomas from heterozygous patched mice. J Neuro Oncol
2006;79:221–227.
21. Dahmen RP, Koch A, Denkhaus D, et al. Deletions of AXIN1, a component of the WNT/wingless
pathway, in sporadic medulloblastomas. Cancer Res 2001;61:7039–7043.
22. Gibson P, Tong Y, Robinson G, et al. Subtypes of medulloblastoma have distinct developmental origins.
Nature 2010;468:1095–1099.
23. Borghesani PR, Peyrin JM, Klein R, et al. BDNF stimulates migration of cerebellar granule cells.
Development 2002;129:1435–1442.
24. Abraham H, Tornoczky T, Kosztolanyi G, et al. Cell formation in the cortical layers of the developing
human cerebellum. Int J Dev Neurosci 2001;19:53–62.
25. Wechsler-Reya RJ. Analysis of gene expression in the normal and malignant cerebellum. Recent Prog
Horm Res 2003;58:227–248.
26. Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: A knowledge-based
approach for interpreting genome-wide expression profiles. PNAS 2005;102:15545–15550.
27. Schüller U, Kho AT, Zhao Q, et al. Cerebellar “transcriptome” reveals cell-type and stage-specific
expression during postnatal development and tumorigenesis. Mol Cell Neurosci 2006;33:247–259.
28. Flora A, Klisch TJ, Schuster G, et al. Deletion of Atoh1 disrupts sonic hedgehog signaling in the
developing cerebellum and prevents medulloblastoma. Science 2009;326:1424–1427.
29. Ayrault O, Zhao H, Zindy F, et al. Atoh1 inhibits neuronal differentiation and collaborates with Gli1 to
generate medulloblastoma-initiating cells. Cancer Res 2010;70:5618–5627.
30. Zhao H, Ayrault O, Zindy F, et al. Post-transcriptional down-regulation of ATOH1/Math1 by bone
morphogenic proteins suppresses medulloblastoma development. Genes Dev 2008;22:722–727.
31. Ben-Arie N, Bellen HJ, Armstrong DL, et al. Math1 is essential for genesis of cerebellar granule neurons.
Nature 1997;390:169–172.
32. Polkinghorn WR, Tarbell NJ. Medulloblastoma: Tumorigenesis, current clinical paradigm, and efforts to
improve risk stratification. Nat Clin Pract Oncol 2007;4:295–304.
33. Brandes AA, Franceschi E, Tosoni A, et al. Adult neuroectodermal tumors of posterior fossa
(medulloblastoma) and of supratentorial sites (stPNET). Crit Rev Oncol Hematol 2009;71:165–179.
34. Padovani L, Sunyach MP, Perol D, et al. Common strategy for adult and pediatric medulloblastoma:
A multicenter series of 253 adults. Int J Radiat Oncol Biol Phys 2007;68:433–440.
35. Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of tumours of the central nervous
system. Acta Neuropathol 2007;114:97–109.
36. Korshunov A, Remke M, Werft W, et al. Adult and pediatric medulloblastomas are genetically distinct
and require different algorithms for molecular risk stratification. JCO 2010;28:3054–3060.