|Year : 2021 | Volume
| Issue : 4 | Page : 92-99
Molecular and clinical correlates of medulloblastoma subgroups: A narrative review
Hallie Coltin1, Vijay Ramaswamy2
1 Division of Hematology/Oncology, Hospital for Sick Children; Programme in Developmental and Stem Cell Biology, Arthur and Sonia Labatt Brain Tumor Research Center, Hospital for Sick Children, Toronto, ON, Canada
2 Division of Hematology/Oncology, Hospital for Sick Children; Programme in Developmental and Stem Cell Biology, Arthur and Sonia Labatt Brain Tumor Research Center, Hospital for Sick Children; Departments of Medical Biophysics and Pediatrics, University of Toronto, Toronto, ON, Canada
|Date of Submission||02-Nov-2021|
|Date of Decision||20-Nov-2021|
|Date of Acceptance||01-Dec-2021|
|Date of Web Publication||13-Jan-2022|
Dr. Vijay Ramaswamy
686 Bay St., 17-9705 PGCRL, Hospital for Sick Children, Toronto, ON
Source of Support: None, Conflict of Interest: None
Medulloblastoma is a major cause of cancer-related morbidity and mortality in children, as a significant proportion of patients succumb to their disease and most survivors are left with life-long sequelae of therapy. Prior medulloblastoma classification systems relied heavily on histology and failed to account for tumor biology. The upcoming 2021 WHO classification of central nervous system tumors now firmly establishes that medulloblastoma actually comprises at least four distinct molecular entities, with considerable substructure within each group. For the first time, the study design of contemporary clinical trials has now recognized the molecular heterogeneity of medulloblastoma. The incorporation of routine molecular subgrouping into upcoming clinical trials has the potential to significantly improve survival and quality of life for children and adults diagnosed with medulloblastoma. This review was conducted to summarize these recent advances in the genomics of medulloblastoma and to summarize the timely results of molecularly-informed published clinical trials. Specifically, English language literature will be reviewed in addition to the results of SJMB03, ACNS0331, and ACNS0332.
Keywords: Genomics, medulloblastoma, sonic hedgehog, subgroup, wingless
|How to cite this article:|
Coltin H, Ramaswamy V. Molecular and clinical correlates of medulloblastoma subgroups: A narrative review. Glioma 2021;4:92-9
| Introduction|| |
Medulloblastoma is a malignant embryonal tumor of the cerebellum originally described by Cushing and Bailey in 1925. It is common among children and becomes less prevalent with increasing age; the incidence is 0.48/100,000 in the 0–14-year age group and 0.11 and 0.02/100,000 in the 15–39-year-old and over 40-year-old populations, respectively. Historically, ascertaining the incidence of medulloblastoma was difficult as these tumors could not be histologically distinguished from other undifferentiated tumors in the cerebellum, such as atypical teratoid/rhabdoid tumors or embryonal tumors with multilayered rosettes. The integration of molecular profiling techniques has allowed medulloblastoma to be recognized as a distinct entity from other embryonal tumors in the posterior fossa., It is now established that medulloblastoma comprises four disease entities, each with its own distinct transcriptional profile, genetic events, and clinical characteristics: wingless (WNT)-activated, sonic hedgehog (SHH)-activated, Group 3, and Group 4., Even within these subgroups, there is significant heterogeneity, with four molecular subtypes of SHH and 8 subtypes among Group 3 and Group 4 having been identified.,, The identification of these subgroups and subtypes has important risk stratification and prognostic significance and now informs treatment approaches as evidenced by contemporary clinical trials.
Before the recognition of biological heterogeneity within medulloblastoma, no treatment stratification approaches existed. Patients were treated surgically until the 1950s when craniospinal irradiation (CSI) with posterior fossa boost was introduced; this treatment modality led to improved clinical outcomes at the cost of devastating neurocognitive sequelae among younger patients.,, The prevalence of these serious late effects prompted a series of trials focused on delayed radiation for young children or radiation avoidance., Currently, infants with medulloblastoma, defined as children <5 years of age, are treated with radiation-sparing approaches, while those older than 5 years of age are classified as having average-or high-risk disease and are treated with risk-adapted CSI and cisplatin-based chemotherapy.,, Average-risk disease confers a 5-year event-free survival (EFS) of approximately 80%–85%, in contrast to <70% for high-risk disease.,,,,,,,,, Adults with medulloblastoma remain a neglected population, and treatment is controversial. The majority are treated with CSI alone, though adjuvant chemotherapy using the Packer regimen is becoming more common and may improve survival outcomes.,
Importantly, contemporary risk-stratification approaches which reflect the 2021 WHO classification system incorporate not only clinical variables such as patient age, metastatic status, and residual tumor volume but also disease subgroup and cytogenetic characteristics.,, The clinical implications of these subgroups have recently been validated in prospective cooperative group trials by assigning subgroups post hoc to nonmolecularly informed trials, which has led to the identification of subgroup-specific treatment strategies, particularly for high-risk Group 3 patients. The purpose of this review is two-fold. First, we will review the molecular and clinical correlates that are fundamental to our current approaches to treating medulloblastoma. Secondy, we will review and summarize for the first time the findings of three recently published international clinical trials of average-and high-risk medulloblastoma (SJMB03, ACNS 0331, ACNS 0332).,,
| Search Strategy|| |
A search of the English language literature was conducted using the PubMed database between September 1, 2021 and October 1, 2021, using “medulloblastoma,” “pediatric,” “childhood,” “adult,” “treatment,” “risk,” “clinical trial,” “outcome,” “prognosis,” “relapse,” “molecular,” “subgroup,” “WNT,” “SHH,” “Group 3,” “Group 4” as the keywords. Articles were filtered based on relevance in the title and abstract and synthesized into the text where appropriate. The relevance of articles was based on the clinical expertise and knowledge of the authors.
| Molecular-Clinical Correlates|| |
Medulloblastoma risk stratification has significantly evolved over recent years. Historically, tumor histology and clinical variables were the driving factors behind medulloblastoma risk stratification. The correlation of histology with patient outcomes has largely been replaced by molecular characterization of tumors. For example, the finding of desmoplastic histology being associated with excellent clinical outcomes highlights a subset of SHH tumors in infants, although it is now recognized that infants with SHH tumors as a whole represent a group with favorable prognosis even with classic histology.,,, Moreover, the intraobserver reliability of desmoplastic histology in the most recent Children's Oncology Group study (ACNS1221) was low across three expert pediatric neuropathologists, calling into question the utility of the histologically based classification. The limitations of tumor histology were also highlighted by the SJYC07 trial, a multicenter phase II trial of young children with medulloblastoma who received induction chemotherapy, risk-adapted consolidation therapy, and oral maintenance therapy. A post hoc review of SJYC07 also suggests that the association between desmoplasia and SHH activation increases over time, suggesting that pathological interpretation is evolving as molecular correlates are increasingly identified. A similar overlap exists between large-cell/anaplastic tumors on histology with SHH-TP53–mutant tumors or Group 3 tumors with high-risk features such as MYC amplification.,,,, Anaplastic histology remains an exclusion criterion for many average-risk trials as a result of the historical association with poor outcomes., Despite such associations between histological features and medulloblastoma subgroups, contemporary clinical trials have shifted toward molecular classification as their foundation as a way to mitigate the limitations of histologically-based prognostication.
| Contemporary Clinical Trials|| |
The recent publication of the results of three molecularly-informed international clinical trials has prompted this review and the study details will be reviewed here. The first trial, SJMB03, was a risk-adapted Phase III trial of 330 average-and high-risk patients aged 3 years and older. Enrollment risk stratification was based on metastatic status and extent of resection. By correlating the biological features of tumors within subgroups and subtypes with outcomes, the investigators were able to create new molecularly-based risk stratification approaches for SHH as well as Group 3 and Group 4 tumors. The Children's Oncology Group study, ACNS0331, randomized children with average-risk medulloblastoma to receive either posterior fossa radiation therapy or involved field radiation therapy after CSI. Younger children underwent a second randomization between standard-dose and low-dose CSI. Involved field radiation therapy was found to be noninferior to posterior fossa radiation therapy but low-dose CSI resulted in worse outcomes compared to those who received standard-dose CSI. Subgroup-specific analyses were conducted post hoc. The last study to be evaluated was ACNS0332, a Phase III trial of 260 high-risk patients (metastatic disease, residual disease, or diffuse anaplasia) which aimed to determine whether daily carboplatin administered during radiation therapy resulted in improved event-free survival; subgroup-specific analyses were conducted. For the first time, international clinical trials were conducted according to molecular subgroups, providing a tangible application of biological advances to clinical care.
In the following sections, molecular and clinical correlates of each of the subgroups will be reviewed including novel findings from the above clinical trials and summarized in [Figure 1].
|Figure 1: Clinical and molecular correlates of medulloblastoma subgroups and subtypes: A summary of clinical, genomic and prognostic features of medulloblastoma subgroups and subtypes. amp: Amplification, chemo: Chemotherapy, CNV: Copy number variation, PFS: Progression-free survival, SHH: Sonic hedgehog, WNT: Wingless|
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| Wnt|| |
WNT tumors carry favorable outcomes for pediatric patients and are deemed appropriate candidates for the consideration of therapy de-escalation. WNT tumors are characterized by transcriptional activation of the WNT pathway, with approximately 90% having somatic CTNNB1 mutations. Of those lacking CTNNB1 mutations, pathogenic APC germline variants are prevalent and highlight the necessity of performing germline testing for Turcot syndrome for this population.,, Mutations in TP53 are seen in 10%–15% of cases but are not associated with the same prognostic implications, unlike the case for SHH tumors.,, Other genes that are commonly mutated in WNT medulloblastoma include DDX3X, CSNK2B, EPHA7, and subunits of the SWI/SNF nucleosome-remodeling complex (SMARCA4, ARID1A, ARID2)., Approximately 80% of WNT tumors have monosomy 6, which is the most common recurrent somatic copy number aberration. With the application of integrated clustering, two subtypes of WNT have been identified: The WNT α subtype, comprising pediatric-aged patients with monosomy 6, and the WNT β subtype, comprising older patients with only a 40% prevalence of monosomy 6. WNT tumors arise from the lower rhombic lip of the brainstem and have a unique radiological pattern that frequently arises from the lateral recesses.,, Preclinical data have suggested that the blood-brain barrier is compromised in WNT patients thereby facilitating the entry of chemotherapy agents, and potentially influencing their favorable outcome.
WNT tumors rarely occur in patients <5 years of age, and the outcomes of pediatric patients <16 years of age are excellent; the role of therapy de-escalation, specifically CSI doses of 15–18 Gy, is actively being investigated in open clinical trials (NCT: NCT01878617, NCT: NCT02724579, NCT: NCT02066220).,,,,,, The excellent prognosis conferred to younger patients with WNT tumors has not been extended to older adolescents and adults; whether this finding is related to lower rates of chemotherapy use for older populations is undetermined.,, Among patients with average-risk WNT tumors, EFS was not impacted by a smaller tumor boost volume or a lower CSI dose in the ACNS0331 trial. The receipt of high-dose cyclophosphamide chemotherapy after radiotherapy may be associated with improved survival compared to regimens with no or intermediate doses of cyclophosphamide and/or CCNU based maintenance. Relapses can occur metastatically or in the surgical cavity,, although a unique pattern of relapses occurring in the lateral ventricles was reported in one recent study by our group. Clinical variables such as metastatic disease and extent of resection have not been shown to predict relapse in WNT medulloblastoma.,,, In three molecularly informed studies of high-risk medulloblastoma, specifically the SJMB03 and ACNS0332 trials and the HIT-GPOH high-risk study, the high-risk features of WNT tumors, such as residual disease >1.5 cm2 and metastatic disease, were not associated with a poor prognosis, suggesting that this infrequent but important group may be candidates for therapy de-escalation.,, WNT tumors, even in the setting of high-risk features, are associated with favorable prognoses among pediatric patients. Future studies are required to determine the etiology of the worse outcome of adult patients with WNT tumors, including if treatment differences from the omission of chemotherapy account for the relatively poorer prognosis of adult patients with WNT medulloblastoma.
| Shh|| |
SHH tumors are characterized by activation of the SHH signaling pathway through mutations or copy number aberrations. SHH tumors arise from the external granule layer, as evidenced by their near-ubiquitous cerebellar location, usually in the cerebellar hemispheres.,,, Such alterations include loss-of-function mutations or deletions in Patched (PTCH) and in Suppressor of Fused (SUFU) and activating mutations in Smoothened (SMO).,,,, SMO inhibitors are being investigated as maintenance therapy in the SJMB12 trial but only in patients who have obtained skeletal maturity due to premature osseous fusion.,,,, TERT promoter mutations are found in almost all adults but are present in only 10%–20% of pediatric tumors.,,, Amplifications of GLI2 and MYCN often occur with somatic or germline TP53 mutations in older children, conferring a very poor prognosis.,,, SHH-TP53 mutant tumors are considered a distinct entity in the WHO classification given their uniformly poor prognosis. Classic somatic copy number alterations in SHH include losses of chromosomes 9q, 10q, and 17p, leading to loss of heterozygosity for PTCH1, SUFU, and TP53, respectively.,,,,, Chromosome 2 gain occurs in some infants.,, Poor prognostic markers include 10q loss, 14q loss, and chromothripsis., SHH tumors occur in all age groups but most commonly in infants <3 years of age and adults over 16 years of age, with 4 molecular subtypes having been identified: SHH-α (adolescents), SHH-β (infants with poor prognosis), SHH-γ (infants with good prognosis), and SHH-δ (adults). In general, the prognosis for infants is favorable compared to that of older children with TP53 mutations (somatic or germline) and/or MYCN amplification, which is dismal.,,,, Among adults with SHH tumors, the prognosis is intermediate, with 5-year progression-free survival rates of approximately 60%–70%; late relapses are common.,,, SHH tumors are uncommonly metastatic at diagnosis (approximately 20%) with a mixed pattern of relapse, with 40%–60% of relapses being in the initial surgical cavity.,,
All children with SHH tumors require evaluation for cancer predisposition syndromes since germline predisposition occurs in 14% of patients. Infants require screening for germline PTCH and SUFU mutations causing Gorlin's syndrome, whereas older children should have their tumors sequenced for TP53 and subsequently undergo germline testing for Li-Fraumeni syndrome should somatic mutations be found.,,,, Other considerations should include testing for mutations in BRCA1 and PALB2 in cases where homologous recombination repair deficiency is suspected., In the recently published ACNS0331 trial for average-risk patients, involved field radiation therapy versus posterior fossa radiation therapy was associated with improved EFS, which may in part be explained by the higher incidence of second malignant neoplasms in the posterior fossa radiation therapy group as a result of cancer predisposition. The ACNS0332 and SJMB03 trials suggested an overall poor prognosis for high-risk SHH medulloblastoma, suggesting that new approaches are required for this group, especially as this group is enriched for patients with TP53 mutations. In SJMB03, high-risk SHH tumors were those with any of the following features: metastatic disease, large cell/anaplastic histology, TP53 single nucleotide variants or loss, MYCN amplification, GLI2 amplification, or chromosome 17p deletion. Several approaches, including omission of alkylator therapy for germline TP53 patients and the introduction of novel agents, identified preclinically in bona fide SHH models into upfront therapy, such as CDK4/6 inhibition, MEK inhibitors, and CK2 inhibitors, are being explored.,,,
Molecularly stratified treatment of SHH medulloblastoma varies by age. In infants, trials of de-escalation of therapy for those with desmoplastic histology were considered a failure, but applying post hoc molecular correlates suggested that SHH-γ disease has significantly better survival than SHH-β. Interestingly, in those studies with intensified therapy, such as HIT-SKK with intraventricular methotrexate, there was no difference in outcome between infants with either SHH-γ or SHH-β medulloblastoma, suggesting that SHH-β disease requires additional therapy. The Headstart-3 study, a prospective trial of intensive induction chemotherapy followed by myeloablative chemotherapy and stem cell rescue for young patients with medulloblastoma, was not subgrouped but showed 5-year event-free and overall survivals of 93% across all desmoplastic histologies. These histologies are known to be highly enriched, where they are likely to be exclusively comprising SHH, suggesting that a single cycle of autologous transplant may be sufficient for this group. SMO inhibitors are limited in their use due to premature osseous fusion in prepubertal children and their lack of efficacy in tumors with SHH activation downstream of SMO, which constitute the majority of failures. In adults, there is a potential role for SMO inhibitors; however, clinical trials are still ongoing.,,,,
Group 3 tumors occur in infants and young children, have a 3:1 male-to-female sex ratio and are metastatic in approximately half of cases.,, Group 3 tumors have a poor prognosis, especially among metastatic cases and tumors with MYC amplification, which comprises 15%–20% of these tumors.,,,,, OTX2 amplification, GFI1 and GFI1b activation, somatic nucleotide variants in SMARCA4, KBTBD4, and CTDNEP1 are other focal alterations that occur in Group 3 tumors.,, Common broad copy number events include isochromosome 17, gains of 1q and 7, and losses of chromosomes 8, 10q, and 16q., Cancer predisposition is rare in Group 3 and Group 4, but consideration should be made for testing for PALB2 and BRCA2 germline mutations in those with concerning family histories and/or homologous recombination repair deficiency. The precise cell of origin of Group 3 is not clear but appears to arise from early cerebellar precursor cells., Overall, the biology of non-MYC amplified Group 3 tumors is complex and poorly understood.
Patients with metastatic disease have survival rates of approximately 40%, and survival is rare among patients with metastatic, MYC/MYCN amplified tumors.,,,,,, Survivors with nonmetastatic disease and MYC amplification have been reported.,, In ACNS0332, the addition of daily carboplatin to weekly vincristine during radiation therapy resulted in improved EFS for patients with Group 3 tumors exclusively, with a higher magnitude of improvement when restricted to patients with metastatic disease. Infants with metastatic Group 3 tumors are rarely cured without the addition of CSI, although there appears to be a role for high-dose methotrexate during induction chemotherapy as part of intensive high-dose thiotepa consolidation chemotherapy.,,, Infants treated with radiation-sparing approaches as well as irradiated children generally experience disseminated relapses with the leptomeningeal disease over short time frames.,, Group 3 disease recurs almost exclusively with metastatic dissemination, irrespective of therapy, suggesting that additional treatment to the metastatic compartment is necessary, particularly in young children treated with a radiation-sparing approach., The availability of several preclinical models of MYC-amplified Group 3, including many patient-derived xenograft models, has led to many therapies proposed for this group, including conventional chemotherapies such as actinomycin-D, which have not previously been considered.
As with Group 3 tumors, the understanding of the biology of Group 4 tumors is limited., The cells of origin of Group 4 appear to be unipolar brush cells and are radiologically characterized by a higher propensity for focal metastasis and nonenhancing lesions.,, Loss-of-function mutations in KDM6A, ZMYM3, and KMT2C are common and result in disrupted chromatin modifiers, which may influence the DNA damage response and tumorigenesis.,,,,,, Isochromosome 17q occurs in over 80% of Group 4 tumors, with other common copy number alterations being 7q gain and 8p loss. Amplifications of CDK6 and MYCN occur in up to 10% of cases, although unlike for SHH and Group 3 medulloblastoma, the poor prognostic significance of MYCN does not exist for Group 4 tumors.,,,
Group 4 tumors represent the most frequent subgroup of tumors (40% of cases), occur in older children and less commonly adults, and have a male predominance., Approximately 30%–40% are metastatic at diagnosis and characteristically have longer prediagnostic and relapse latency phases.,,, Furthermore characteristically, Group 4 tumors are not enhanced on diagnostic magnetic resonance imaging and are located in the fourth ventricle.,,, Patients who receive radiation have intermediate survival outcomes, with 5-year progression-free survival rates of 80%–90% and 60%–70% for average-and high-risk patients, respectively., In the ACNS0331 trial, average-risk patients with Group 4 medulloblastoma who received low-dose CSI had inferior EFS to that of patients who received standard-dose CSI; this trend was not observed for those with Group 3 tumors. Infants treated with radiation-sparing approaches have poor survival., Positive cytogenetic markers in children include whole chromosome 11 loss and chromosome 17 gain.,, In adults, these markers do not appear to have any prognostic value, although chromosome 8 loss is associated with favorable survival. Similar to Group 3 tumors, previously irradiated Group 4 medulloblastoma recur almost exclusively with metastatic dissemination, highlighting the importance of treatment of the metastatic compartment. There is a paucity of patient-derived models of Group 4 medulloblastoma, which are limited to a subset of orthotopic xenograft models that require 4–8 months to propagate in the hindbrain of immunocompromised mice. Transgenic models and in vitro cell lines currently do not exist for this group.
| Molecular Subgroups of Group 3 and Group 4 Medulloblastoma|| |
A number of subtypes within Group 3 and Group 4 subgroups have been identified and reflect the heterogeneity within these tumors.,, Subtype I is known for a balanced genomic structure, subtype II for striking chromosome 8 gain, subtype III for chromosome 10q loss, subtype IV for losses of chromosome 8, chromosome 10, and chromosome 11, subtype V for isochromosome 17q and chromosome 16q loss, subtypes VI and VII for the gain of chromosome 7 and loss of chromosome 8, and subtype VIII for isochromosome 17q.,,, Based on the results of SJMB03, the authors proposed a new risk classification approach to Group 3 and Group 4 tumors consisting of low-risk (nonmetastatic subtype VII), intermediate-risk (nonmetastatic disease and not within III or VII subtypes), and high-risk (metastatic disease, subtype III, or MYC amplification) disease. However, the role of these subtypes in relation to clinical trial design and treatment approaches is in its infancy.
This review is limited by the inclusion of English-language literature only, potential gaps in the literature search process, and the potential omission of relevant work.
| Conclusions|| |
In this review, we have summarized the new developments in the understanding of molecular-clinical correlates within the medulloblastoma subgroups and subtypes. The incorporation of molecular correlates into the stratification of medulloblastoma has significantly improved our ability to classify patients into appropriate risk groups [Figure 1]. The identification of the four core subgroups is now considered the first step after the morphological diagnosis of medulloblastoma and is a crucial part of tailoring therapy. The recent publication of subgroup-informed international clinical trials has highlighted the feasibility and importance of incorporating tumor biology into the trial methodology. Most ongoing or upcoming clinical trials are incorporating molecular-based stratification of patients, and although specific targeted therapies have thus far been elusive, the post hoc subgrouping of closed clinical trials has shown a far more precise risk stratification than the use of clinical variables alone and has identified potential tailored therapies such as daily carboplatin for high-risk Group 3 patients. Through the routine application of biological risk stratification in future clinical trials worldwide, we have the unique opportunity to improve the quality of life for children with low-risk diseases and introduce new therapies to those patients facing treatment failure with current therapies.
Financial support and sponsorship
This work was supported by Garron Family Cancer Centre Fellowship to HC, and operating funds from the Canadian Institutes for Health Research, Brain Canada, and Canadian Cancer Society Research Institute to VR.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Bailey P, Cushing H. Medulloblastoma cerebelli: A common type of midcerebellar glioma of childhood. Arch Neurol Psychiatr 1925;14:192-224.
Ostrom QT, Cioffi G, Gittleman H, Patil N, Waite K, Kruchko C, et al
. CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2012-2016. Neuro Oncol 2019;21:v1-100.
Ellison DW, Dalton J, Kocak M, Nicholson SL, Fraga C, Neale G, et al
. Medulloblastoma: Clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups. Acta Neuropathol 2011;121:381-96.
Pomeroy SL, Tamayo P, Gaasenbeek M, Sturla LM, Angelo M, McLaughlin ME, et al
. Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 2002;415:436-42.
Sturm D, Orr BA, Toprak UH, Hovestadt V, Jones DT, Capper D, et al
. New brain tumor entities emerge from molecular classification of CNS-PNETs. Cell 2016;164:1060-72.
Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al
. The 2016 World Health Organization classification of tumors of the central nervous system: A summary. Acta Neuropathol 2016;131:803-20.
Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, et al
. Molecular subgroups of medulloblastoma: The current consensus. Acta Neuropathol 2012;123:465-72.
Skowron P, Farooq H, Cavalli FM, Morrissy AS, Ly M, Hendrikse LD, et al
. The transcriptional landscape of Shh medulloblastoma. Nat Commun 2021;12:1749.
Cavalli FM, Remke M, Rampasek L, Peacock J, Shih DJ, Luu B, et al
. Intertumoral heterogeneity within medulloblastoma subgroups. Cancer Cell 2017;31:737-54.e6.
Northcott PA, Buchhalter I, Morrissy AS, Hovestadt V, Weischenfeldt J, Ehrenberger T, et al
. The whole-genome landscape of medulloblastoma subtypes. Nature 2017;547:311-7.
Paterson E, Farr RF. Cerebellar medulloblastoma: Treatment by irradiation of the whole central nervous system. Acta radiol 1953;39:323-36.
Ramaswamy V, Taylor MD. Medulloblastoma: From myth to molecular. J Clin Oncol 2017;35:2355-63.
Mulhern RK, Merchant TE, Gajjar A, Reddick WE, Kun LE. Late neurocognitive sequelae in survivors of brain tumours in childhood. Lancet Oncol 2004;5:399-408.
Duffner PK, Horowitz ME, Krischer JP, Friedman HS, Burger PC, Cohen ME, et al
. Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 1993;328:1725-31.
Rutkowski S, Bode U, Deinlein F, Ottensmeier H, Warmuth-Metz M, Soerensen N, et al
. Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 2005;352:978-86.
Ramaswamy V, Remke M, Bouffet E, Bailey S, Clifford SC, Doz F, et al
. Risk stratification of childhood medulloblastoma in the molecular era: The current consensus. Acta Neuropathol 2016;131:821-31.
Ramaswamy V, Remke M, Adamski J, Bartels U, Tabori U, Wang X, et al
. Medulloblastoma subgroup-specific outcomes in irradiated children: Who are the true high-risk patients? Neuro Oncol 2016;18:291-7.
Packer RJ, Gajjar A, Vezina G, Rorke-Adams L, Burger PC, Robertson PL, et al
. Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol 2006;24:4202-8.
Michalski JM, Janss AJ, Vezina LG, Smith KS, Billups CA, Burger PC, et al
. Children's Oncology Group phase III trial of reduced-dose and reduced-volume radiotherapy with chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol 2021;39:2685-97.
Gajjar A, Robinson GW, Smith KS, Lin T, Merchant TE, Chintagumpala M, et al
. Outcomes by clinical and molecular features in children with medulloblastoma treated with risk-adapted therapy: Results of an International Phase III Trial (SJMB03). J Clin Oncol 2021;39:822-35.
Gajjar A, Chintagumpala M, Ashley D, Kellie S, Kun LE, Merchant TE, et al
. 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 2006;7:813-20.
Lannering B, Rutkowski S, Doz F, Pizer B, Gustafsson G, Navajas A, et al
. Hyperfractionated versus conventional radiotherapy followed by chemotherapy in standard-risk medulloblastoma: Results from the randomized multicenter HIT-SIOP PNET 4 trial. J Clin Oncol 2012;30:3187-93.
Tarbell NJ, Friedman H, Polkinghorn WR, Yock T, Zhou T, Chen Z, et al
. High-risk medulloblastoma: A pediatric oncology group randomized trial of chemotherapy before or after radiation therapy (POG 9031). J Clin Oncol 2013;31:2936-41.
Taylor RE, Bailey CC, Robinson KJ, Weston CL, Walker DA, Ellison D, et al
. Outcome for patients with metastatic (M2-3) medulloblastoma treated with SIOP/UKCCSG PNET-3 chemotherapy. Eur J Cancer 2005;41:727-34.
Gandola L, Massimino M, Cefalo G, Solero C, Spreafico F, Pecori E, et al
. Hyperfractionated accelerated radiotherapy in the Milan strategy for metastatic medulloblastoma. J Clin Oncol 2009;27:566-71.
von Bueren AO, Kortmann RD, von Hoff K, Friedrich C, Mynarek M, Müller K, et al
. Treatment of children and adolescents with metastatic medulloblastoma and prognostic relevance of clinical and biologic parameters. J Clin Oncol 2016;34:4151-60.
Leary SE, Packer RJ, Li Y, Billups CA, Smith KS, Jaju A, et al
. Efficacy of carboplatin and isotretinoin in children with high-risk medulloblastoma: A randomized clinical trial from the Children's Oncology Group. JAMA Oncol 2021;7:1313-21.
Lassaletta A, Ramaswamy V. Medulloblastoma in adults: They're not just big kids. Neuro Oncol 2016;18:895-7.
Packer RJ, Goldwein J, Nicholson HS, Vezina LG, Allen JC, Ris MD, et al
. Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: A Children's Cancer Group Study. J Clin Oncol 1999;17:2127-36.
Franceschi E, Hofer S, Brandes AA, Frappaz D, Kortmann RD, Bromberg J, et al
. EANO-EURACAN clinical practice guideline for diagnosis, treatment, and follow-up of post-pubertal and adult patients with medulloblastoma. Lancet Oncol 2019;20:e715-28.
Franceschi E, Minichillo S, Mura A, Tosoni A, Mascarin M, Tomasello C, et al
. Adjuvant chemotherapy in average-risk adult medulloblastoma patients improves survival: A long term study. BMC Cancer 2020;20:755.
Zeltzer PM, Boyett JM, Finlay JL, Albright AL, Rorke LB, Milstein JM, et al
. Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: Conclusions from the Children's Cancer Group 921 randomized phase III study. J Clin Oncol 1999;17:832-45.
Northcott PA, Hielscher T, Dubuc A, Mack S, Shih D, Remke M, et al
. Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct. Acta Neuropathol 2011;122:231-40.
Lafay-Cousin L, Bouffet E, Strother D, Rudneva V, Hawkins C, Eberhart C, et al
. Phase II study of nonmetastatic desmoplastic medulloblastoma in children younger than 4 years of age: A report of the Children's Oncology Group (ACNS1221). J Clin Oncol 2020;38:223-31.
Nör C, Ramaswamy V. Clinical and pre-clinical utility of genomics in medulloblastoma. Expert Rev Neurother 2018;18:633-47.
Robinson GW, Rudneva VA, Buchhalter I, Billups CA, Waszak SM, Smith KS, et al
. Risk-adapted therapy for young children with medulloblastoma (SJYC07): Therapeutic and molecular outcomes from a multicentre, phase 2 trial. Lancet Oncol 2018;19:768-84.
Giangaspero F, Rigobello L, Badiali M, Loda M, Andreini L, Basso G, et al
. Large-cell medulloblastomas. A distinct variant with highly aggressive behavior. Am J Surg Pathol 1992;16:687-93.
von Hoff K, Hartmann W, von Bueren AO, Gerber NU, Grotzer MA, Pietsch T, et al
. Large cell/anaplastic medulloblastoma: Outcome according to myc status, histopathological, and clinical risk factors. Pediatr Blood Cancer 2010;54:369-76.
Mori T, Nagase H, Horii A, Miyoshi Y, Shimano T, Nakatsuru S, et al
. Germ-line and somatic mutations of the APC gene in patients with Turcot syndrome and analysis of APC mutations in brain tumors. Genes Chromosomes Cancer 1994;9:168-72.
Waszak SM, Northcott PA, Buchhalter I, Robinson GW, Sutter C, Groebner S, et al
. Spectrum and prevalence of genetic predisposition in medulloblastoma: A retrospective genetic study and prospective validation in a clinical trial cohort. Lancet Oncol 2018;19:785-98.
Nobre L, Zapotocky M, Khan S, Fukuoka K, Fonseca A, McKeown T, et al
. Pattern of relapse and treatment response in WNT-activated medulloblastoma. Cell Rep Med 2020;1:100038.
Zhukova N, Ramaswamy V, Remke M, Pfaff E, Shih DJ, Martin DC, et al
. Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. J Clin Oncol 2013;31:2927-35.
Perreault S, Ramaswamy V, Achrol AS, Chao K, Liu TT, Shih D, et al
. MRI surrogates for molecular subgroups of medulloblastoma. AJNR Am J Neuroradiol 2014;35:1263-9.
Jessa S, Blanchet-Cohen A, Krug B, Vladoiu M, Coutelier M, Faury D, et al
. Stalled developmental programs at the root of pediatric brain tumors. Nat Genet 2019;51:1702-13.
Mata-Mbemba D, Zapotocky M, Laughlin S, Taylor MD, Ramaswamy V, Raybaud C. MRI characteristics of primary tumors and metastatic lesions in molecular subgroups of pediatric medulloblastoma: A single-center study. AJNR Am J Neuroradiol 2018;39:949-55.
Phoenix TN, Patmore DM, Boop S, Boulos N, Jacus MO, Patel YT, et al
. Medulloblastoma genotype dictates blood brain barrier phenotype. Cancer Cell 2016;29:508-22.
Coltin H, Sundaresan L, Smith KS, Skowron P, Massimi L, Eberhart CG, et al
. Subgroup and subtype-specific outcomes in adult medulloblastoma. Acta Neuropathol 2021;142:859-71.
Remke M, Hielscher T, Northcott PA, Witt H, Ryzhova M, Wittmann A, et al
. Adult medulloblastoma comprises three major molecular variants. J Clin Oncol 2011;29:2717-23.
Majd N, Penas-Prado M. Updates on management of adult medulloblastoma. Curr Treat Options Oncol 2019;20:64.
Sabel M, Fleischhack G, Tippelt S, Gustafsson G, Doz F, Kortmann R, et al
. Relapse patterns and outcome after relapse in standard risk medulloblastoma: A report from the HIT-SIOP-PNET4 study. J Neurooncol 2016;129:515-24.
Ellison DW, Kocak M, Dalton J, Megahed H, Lusher ME, Ryan SL, et al
. Definition of disease-risk stratification groups in childhood medulloblastoma using combined clinical, pathologic, and molecular variables. J Clin Oncol 2011;29:1400-7.
Thompson EM, Hielscher T, Bouffet E, Remke M, Luu B, Gururangan S, et al
. Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: A retrospective integrated clinical and molecular analysis. Lancet Oncol 2016;17:484-95.
Vladoiu MC, El-Hamamy I, Donovan LK, Farooq H, Holgado BL, Sundaravadanam Y, et al
. Childhood cerebellar tumours mirror conserved fetal transcriptional programs. Nature 2019;572:67-73.
Hovestadt V, Smith KS, Bihannic L, Filbin MG, Shaw ML, Baumgartner A, et al
. Resolving medulloblastoma cellular architecture by single-cell genomics. Nature 2019;572:74-9.
Kumar R, Liu AP, Northcott PA. Medulloblastoma genomics in the modern molecular era. Brain Pathol 2020;30:679-90.
Kool M, Jones DT, Jäger N, Northcott PA, Pugh TJ, Hovestadt V, et al
. Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell 2014;25:393-405.
Robinson GW, Kaste SC, Chemaitilly W, Bowers DC, Laughton S, Smith A, et al
. Irreversible growth plate fusions in children with medulloblastoma treated with a targeted hedgehog pathway inhibitor. Oncotarget 2017;8:69295-302.
Robinson GW, Orr BA, Wu G, Gururangan S, Lin T, Qaddoumi I, et al
. Vismodegib exerts targeted efficacy against recurrent sonic hedgehog-subgroup medulloblastoma: Results from phase II pediatric brain tumor consortium studies PBTC-025B and PBTC-032. J Clin Oncol 2015;33:2646-54.
Kieran MW, Chisholm J, Casanova M, Brandes AA, Aerts I, Bouffet E, et al
. Phase I study of oral sonidegib (LDE225) in pediatric brain and solid tumors and a phase II study in children and adults with relapsed medulloblastoma. Neuro Oncol 2017;19:1542-52.
Remke M, Ramaswamy V, Peacock J, Shih DJ, Koelsche C, Northcott PA, et al
. TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma. Acta Neuropathol 2013;126:917-29.
Shih DJ, Northcott PA, Remke M, Korshunov A, Ramaswamy V, Kool M, et al
. Cytogenetic prognostication within medulloblastoma subgroups. J Clin Oncol 2014;32:886-96.
Northcott PA, Shih DJ, Peacock J, Garzia L, Morrissy AS, Zichner T, et al
. Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature 2012;488:49-56.
Ramaswamy V, Nör C, Taylor MD. p53 and meduloblastoma. Cold Spring Harb Perspect Med 2015;6:a026278.
Korshunov A, Remke M, Werft W, Benner A, Ryzhova M, Witt H, et al
. Adult and pediatric medulloblastomas are genetically distinct and require different algorithms for molecular risk stratification. J Clin Oncol 2010;28:3054-60.
Ramaswamy V, Remke M, Bouffet E, Faria CC, Perreault S, Cho YJ, et al
. Recurrence patterns across medulloblastoma subgroups: An integrated clinical and molecular analysis. Lancet Oncol 2013;14:1200-7.
Smith MJ, Beetz C, Williams SG, Bhaskar SS, O'Sullivan J, Anderson B, et al
. Germline mutations in SUFU cause Gorlin syndrome-associated childhood medulloblastoma and redefine the risk associated with PTCH1 mutations. J Clin Oncol 2014;32:4155-61.
Korshunov A, Sahm F, Stichel D, Schrimpf D, Ryzhova M, Zheludkova O, et al
. Molecular characterization of medulloblastomas with extensive nodularity (MBEN). Acta Neuropathol 2018;136:303-13.
Guerrini-Rousseau L, Dufour C, Varlet P, Masliah-Planchon J, Bourdeaut F, Guillaud-Bataille M, et al
. Germline SUFU mutation carriers and medulloblastoma: Clinical characteristics, cancer risk, and prognosis. Neuro Oncol 2018;20:1122-32.
Brabetz S, Leary SE, Gröbner SN, Nakamoto MW, Şeker-Cin H, Girard EJ, et al
. A biobank of patient-derived pediatric brain tumor models. Nat Med 2018;24:1752-61.
Rusert JM, Juarez EF, Brabetz S, Jensen J, Garancher A, Chau LQ, et al
. Functional precision medicine identifies new therapeutic candidates for medulloblastoma. Cancer Res 2020;80:5393-407.
Purzner T, Purzner J, Buckstaff T, Cozza G, Gholamin S, Rusert JM, et al
. Developmental phosphoproteomics identifies the kinase CK2 as a driver of Hedgehog signaling and a therapeutic target in medulloblastoma. Sci Signal 2018;11:eaau5147.
Liang L, Coudière-Morrison L, Tatari N, Stromecki M, Fresnoza A, Porter CJ, et al
cells are diagnostic and prognostic and exhibit elevated MAPK activity in SHH medulloblastoma. Cancer Res 2018;78:4745-59.
Dhall G, O'Neil SH, Ji L, Haley K, Whitaker AM, Nelson MD, et al
. Excellent outcome of young children with nodular desmoplastic medulloblastoma treated on “Head Start” III: A multi-institutional, prospective clinical trial. Neuro Oncol 2020;22:1862-72.
Kian W, Roisman LC, Goldstein IM, Abo-Quider A, Samueli B, Wallach N, et al
. Vismodegib as first-line treatment of mutated sonic hedgehog pathway in adult medulloblastoma. JCO Precis Oncol 2020;4:PO.19.00264.
Climans SA, Macdonald DR, Sutherland DE, Mason WP. Prolonged response to vismodegib in a patient with systemic medulloblastoma metastases. BMJ Case Rep 2020;13:e236406.
Cho YJ, Tsherniak A, Tamayo P, Santagata S, Ligon A, Greulich H, et al
. Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. J Clin Oncol 2011;29:1424-30.
Northcott PA, Korshunov A, Witt H, Hielscher T, Eberhart CG, Mack S, et al
. Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 2011;29:1408-14.
Pfister S, Remke M, Benner A, Mendrzyk F, Toedt G, Felsberg J, et al
. 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 2009;27:1627-36.
Pietsch T, Schmidt R, Remke M, Korshunov A, Hovestadt V, Jones DT, et al
. Prognostic significance of clinical, histopathological, and molecular characteristics of medulloblastomas in the prospective HIT2000 multicenter clinical trial cohort. Acta Neuropathol 2014;128:137-49.
Northcott PA, Lee C, Zichner T, Stütz AM, Erkek S, Kawauchi D, et al
. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 2014;511:428-34.
Clifford SC, Lannering B, Schwalbe EC, Hicks D, O'Toole K, Nicholson SL, et al
. Biomarker-driven stratification of disease-risk in non-metastatic medulloblastoma: Results from the multi-center HIT-SIOP-PNET4 clinical trial. Oncotarget 2015;6:38827-39.
Lafay-Cousin L, Smith A, Chi SN, Wells E, Madden J, Margol A, et al
. Clinical, pathological, and molecular characterization of infant medulloblastomas treated with sequential high-dose chemotherapy. Pediatr Blood Cancer 2016;63:1527-34.
Mazewski C, Kang G, Kellie S, Gossett J, Leary S, Li B, et al
. MBCL-34. Efficacy of methotrexate (MTX) according to molecular sub-type in young children with medulloblastoma (MB): A report from Children's Oncology group phase III trial ACNS0334. Neuro Oncol 2020;22:iii396.
Zapotocky M, Mata-Mbemba D, Sumerauer D, Liby P, Lassaletta A, Zamecnik J, et al
. Differential patterns of metastatic dissemination across medulloblastoma subgroups. J Neurosurg Pediatr 2018;21:145-52.
Kumar R, Smith KS, Deng M, Terhune C, Robinson GW, Orr BA, et al
. Clinical outcomes and patient-matched molecular composition of relapsed medulloblastoma. J Clin Oncol 2021;39:807-21.
Huether R, Dong L, Chen X, Wu G, Parker M, Wei L, et al
. The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes. Nat Commun 2014;5:3630.
Robinson G, Parker M, Kranenburg TA, Lu C, Chen X, Ding L, et al
. Novel mutations target distinct subgroups of medulloblastoma. Nature 2012;488:43-8.
Leung JW, Makharashvili N, Agarwal P, Chiu LY, Pourpre R, Cammarata MB, et al
. ZMYM3 regulates BRCA1 localization at damaged chromatin to promote DNA repair. Genes Dev 2017;31:260-74.
Pugh TJ, Weeraratne SD, Archer TC, Pomeranz Krummel DA, Auclair D, Bochicchio J, et al
. Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature 2012;488:106-10.
Jones DT, Jäger N, Kool M, Zichner T, Hutter B, Sultan M, et al
. Dissecting the genomic complexity underlying medulloblastoma. Nature 2012;488:100-5.
Mendrzyk F, Radlwimmer B, Joos S, Kokocinski F, Benner A, Stange DE, et al
. Genomic and protein expression profiling identifies CDK6 as novel independent prognostic marker in medulloblastoma. J Clin Oncol 2005;23:8853-62.
Korshunov A, Remke M, Kool M, Hielscher T, Northcott PA, Williamson D, et al
. Biological and clinical heterogeneity of MYCN-amplified medulloblastoma. Acta Neuropathol 2012;123:515-27.
Ramaswamy V, Remke M, Shih D, Wang X, Northcott PA, Faria CC, et al
. Duration of the pre-diagnostic interval in medulloblastoma is subgroup dependent. Pediatr Blood Cancer 2014;61:1190-4.
Raybaud C, Ramaswamy V, Taylor MD, Laughlin S. Posterior fossa tumors in children: Developmental anatomy and diagnostic imaging. Childs Nerv Syst 2015;31:1661-76.
Lin CY, Erkek S, Tong Y, Yin L, Federation AJ, Zapatka M, et al
. Active medulloblastoma enhancers reveal subgroup-specific cellular origins. Nature 2016;530:57-62.
Sharma T, Schwalbe EC, Williamson D, Sill M, Hovestadt V, Mynarek M, et al
. Second-generation molecular subgrouping of medulloblastoma: An international meta-analysis of Group 3 and Group 4 subtypes. Acta Neuropathol 2019;138:309-26.
Schwalbe EC, Lindsey JC, Nakjang S, Crosier S, Smith AJ, Hicks D, et al
. Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: A cohort study. Lancet Oncol 2017;18:958-71.