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. 2016 Feb;6(2):a026278. doi: 10.1101/cshperspect.a026278

p53 and Meduloblastoma

Vijay Ramaswamy 1,2,3, Carolina Nör 3,4, Michael D Taylor 2,3,4
PMCID: PMC4743072  PMID: 26684332

Abstract

Our understanding of medulloblastoma biology has increased dramatically over the past decade, in part a result of the recognition that there exists tremendous intertumoral heterogeneity not apparent by morphology alone. A particular area that significantly changed our approach to medulloblastoma has been an increased understanding of the role of p53. A role for p53 in medulloblastoma has been established over the past 20 years, however, not until recently has its significance been identified. Recent developments in the understanding of intertumor heterogeneity has clarified the role of TP53 mutations, as the importance of TP53 mutations is highly dependent on the molecular subgroup of medulloblastoma, with TP53 mutant Sonic Hedgehog medulloblastomas forming an extremely high-risk group of patients. As such, there is now a tremendous push to understand the role that p53 plays in treatment resistance of medulloblastoma. In this review, we will summarize the current understanding of p53 in medulloblastoma drawn primarily from recent advances in integrated genomics.

There are four molecular subgroups of medulloblastomas, and the importance of TP53 mutations is dependent on these subgroups. For example, patients with TP53-mutant Sonic Hedgehog medulloblastomas have a poor prognosis.

Medulloblastoma is the most common malignant brain tumor of childhood. It arises in the cerebellum with an incidence of ∼0.74 per 100,000 person-years (CBTRUS 2011; Ostrom et al. 2015). Current therapy for medulloblastoma consists of maximal safe surgical resection followed by adjuvant external beam irradiation and chemotherapy (Gajjar et al. 2006; Packer et al. 2006; Ramaswamy et al. 2011). Clinical risk stratification relies on extent of surgical resection, presence of leptomeningeal dissemination, and age, to classify patients as high or average risk (Zeltzer et al. 1999). This is based largely on a morphological classification, in which the majority of tumors look identical. As such, historically, medulloblastoma has been considered a single clinicopathological entity, and treated as such.

Advances in integrated genomics over the past decade have yielded tremendous insight into the biology of medulloblastoma. Specifically, it is now well accepted that medulloblastoma actually comprises four distinct entities, termed molecular subgroups (Taylor et al. 2012). These four subgroups termed WNT, Sonic Hedgehog (SHH), and group 3 and group 4 have distinct transcriptional profiles, genetics, demographics, recurrence patterns, and outcomes (Northcott et al. 2009, 2011, 2012a,b; Remke et al. 2011a,b; Kool et al. 2012; Dubuc et al. 2013; Ramaswamy et al. 2013). WNT tumors are characterized by activation of the WNT pathway, occur primarily in noninfant children, and have an excellent prognosis. WNT tumors are characterized genetically by frequent mutations in exon 3 of CTNNB1, which encodes β-catenin and monosomy 6 (Ellison et al. 2011; Northcott et al. 2012c). SHH tumors are characterized by activation of the SHH pathway and can occur across all ages with an intermediate prognosis. Genetically, they frequently harbor mutations activating the SHH pathway, such as in Patched1, SUFU, and Smoothened. In addition, they commonly harbor amplifications of GLI2 and MYCN, along with activating mutations in the TERT promoter (Jones et al. 2012; Northcott et al. 2012a,c; Remke et al. 2013). SHH medulloblastoma are currently the focus of targeted therapies with smoothened inhibitors (Gajjar et al. 2013; Shou et al. 2015). Group 3 medulloblastoma occur most frequently in infants and young children who are regularly metastatic at diagnosis, have a poor prognosis and in ∼20% of cases harbor amplifications of the MYC oncogene (Cho et al. 2011; Taylor et al. 2012). Group 4 medulloblastoma are the most common subgroup, comprising >40% of cases. Group 4 medulloblastoma is frequently metastatic at diagnosis, harbors tandem duplications of SNCAIP, amplifications of MYCN, and in >80% of cases harbors isochromosome 17q (Northcott et al. 2011, 2012c). As such, the identification of these four biological subgroups has fundamentally changed our understanding of medulloblastoma, whereby it is now accepted that medulloblastoma is a very heterogeneous entity and most genomic and biological observations of medulloblastoma need to be interpreted in the context of subgroup specificity.

One particular example has been the role of TP53 and its protein product p53 in medulloblastoma. Over the past three decades, as with most other malignancies, there has been tremendous interest in the role of p53 in the oncogenesis of medulloblastoma. Indeed, there have been numerous conflicting reports in the past; however, in the context of rapid genomic advances, there has recently been a surge in our understanding of the role of p53. Although p53 has been investigated thoroughly from a clinical, genomic, and functional perspective, its role across and within medulloblastoma subgroups remained relatively unknown. Herein, we will summarize the current knowledge of p53 in medulloblastoma including challenges and future directions.

SOMATIC AND GERMLINE ABERRATIONS IN TP53

The initial observation that led to the investigation of the role of p53 in medulloblastoma came from reports that, in >40% of medulloblastoma samples, 17p is frequently deleted as part of isochromosome 17q (Bigner et al. 1988; Friedman et al. 1988; Biegel et al. 1989, 1992). Indeed, this led to the notion that loss of 17p was associated with the pathogenesis of medulloblastoma, which drove several efforts to identify TP53 mutations across cohorts of medulloblastoma. These initial efforts were relatively disappointing as very few somatic mutations were identified across small cohorts of medulloblastoma patients, particularly those patients with 17p loss. This suggested that an alternative tumor suppressor was present on 17p and that 17p loss and TP53 mutations are unrelated (Adesina et al. 1994; Pfaff et al. 2010). The link between TP53 mutations and the pathogenesis of medulloblastoma was revisited later when it was identified that individuals with Li–Fraumeni syndrome, which is caused by a germline mutation in TP53, develop medulloblastoma at a much higher frequency than the general population (Kleihues et al. 1997; Barel et al. 1998). This suggested that loss of p53 likely had a role in the pathogenesis of medulloblastoma; however, this association is relatively rare. Moreover, the prognostic relevance of TP53 mutations in medulloblastoma was unknown, and as such routine sequencing of TP53 was reserved for those patients with a strong family history of Li–Fraumeni syndrome.

The prognostic value of TP53 mutations has recently been the subject of several reports, with conflicting publications suggesting very different roles for p53 in medulloblastoma. An institutional cohort of 108 consecutive medulloblastoma patients from the Hospital for Sick Children suggested that somatic, dominant negative TP53 mutations are almost universally fatal (Tabori et al. 2010). Indeed, in this study, none of the TP53-mutated patients harbored loss of 17p or had an MYC amplification, and only one patient had an MYCN amplification. Most importantly, the majority of patients were clinically average risk, and time to progression was less than a year in all cases. This was the first suggestion that TP53 mutational status was an independent predictor of poor outcome in medulloblastoma. However, two conflicting reports, one from Heidelberg and another from Newcastle, suggested a very different prognostic role, whereby TP53 mutations were commonly associated with mutations in exon 3 of CTNNB1, which is associated with activation of the WNT pathway (Pfaff et al. 2010; Lindsey et al. 2011). Medulloblastoma patients harboring WNT-activated tumors have an excellent prognosis, suggesting that TP53-inactivating mutations on their own do not confer a poor survival.

Further insight into the prognostic role of TP53 mutations in medulloblastoma came from recent integrated genomic analyses. Indeed, when accounting for this heterogeneity, the apparent contradictory prognostic roles of TP53 mutational status across studies can be resolved. A combined report reconciled these two observations through the analysis of a large cohort of 553 medulloblastomas. This study revealed that the prognostic value of somatic TP53 mutations is subgroup dependent. Specifically, patients with WNT tumors harboring somatic TP53 mutations have an excellent prognosis. However, those patients with SHH tumors harboring somatic TP53 mutations had a dismal prognosis (Zhukova et al. 2013). P53 mutations were almost never observed in patients with group 3 and 4 tumors, in which isochromosome 17q is a common aberration; these findings agree with and confirm previous reports. Within the WNT subgroup, the majority of TP53-mutated cases were of the classic histology; however, large-cell and/or diffuse anaplastic histology was commonly observed in the TP53-mutated SHH cases. The age distribution of TP53 mutations is also intriguing. TP53 mutations are commonly observed in the childhood age group (4–16 yr) and rarely observed in infants and adults. In the childhood age group, germline mutations of TP53 are frequently observed in SHH medulloblastoma and, as such, associate Li–Fraumeni syndrome with SHH medulloblastoma (Kool et al. 2014).

The majority of treatment failures in SHH medulloblastoma are associated with TP53 mutations. Indeed, this group of medulloblastoma constitutes a very high-risk group and is the focus of international efforts for new and novel therapies (Ramaswamy et al. 2015). A potential explanation for the poor prognosis in TP53-mutated SHH relates to radiation resistance, as the majority of SHH medulloblastoma relapse locally in the tumor bed (Ramaswamy et al. 2013). Indeed, the majority of patients with TP53 mutations are children over age 3, and as such receive upfront radiation (Zhukova et al. 2013, 2014; Kool et al. 2014; Ramaswamy et al. 2015). However, it is unclear whether TP53 mutations confer radiation resistance, or radiation confers genomic instability in TP53-mutated tumors. In fact, there has been some suggestion that survival of patients with TP53 mutant SHH medulloblastoma is possible with a de-escalation of therapy and omission of radiation and/or alkylating agents (Rausch et al. 2012; Kool et al. 2014). This has not, however, been clinically shown and requires further study in the context of controlled clinical trials. Defects in p53 at relapse have also been recently described (Hill et al. 2015; Poschl et al. 2015). Although somatic nucleotide variant (SNV) type TP53 mutations are not observed at diagnosis in group 3 and 4 medulloblastoma, they can be observed at relapse, and are usually associated with MYC amplification. Although typical, dominant negative TP53 SNVs are seldom or never seen in group 3 or group 4 medulloblastoma, these two subgroups often do have complete loss of one copy of TP53, usually in the setting of deletion the entire arm of chromosome 17p as part of isochromosome 17q. The combination of p53-MYC defects results in short survival postrecurrence. The role of TP53 at relapse requires further study. However, the emergence of TP53 mutations at relapse implicates a role for p53 in radiation resistance and treatment failure.

GENOMIC LANDSCAPE OF P53-MUTATED MEDULLOBLASTOMA

Several integrated genomic studies have revealed significant insight into the genomic landscape of TP53-mutated tumors. TP53 mutations associated with WNT pathway activation are still commonly observed to have bland genomes, with the exception of monosomy 6, which is a frequent cytogenetic aberration in WNT subgroup tumors (Jones et al. 2012; Northcott et al. 2012a; Pugh et al. 2012; Robinson et al. 2012). It has previously been suggested that β-catenin protein is down-regulated by activated p53, and that excess β-catenin promotes accumulation of transcriptionally active p53 (Damalas et al. 1999; Sadot et al. 2001; Levina et al. 2004). This implies that, in the presence of activated β-catenin, there is a selective pressure for loss of TP53 to promote a proliferative state. The excellent prognosis for children with TP53-mutated WNT tumors also suggests that somatic TP53 inactivation in this context does not result in radiation resistance.

A recent next-generation sequencing study of SHH medulloblastoma casts further light on the role of TP53 mutations in medulloblastoma (Kool et al. 2014). In this study, it was again suggested that TP53 mutations are frequently found in childhood, but not infant or adult SHH tumors, as the frequency of germline mutations in TP53 is higher in children aged 3–16 yr. Moreover, TP53 mutations infrequently occur with PTCH1, SMO, or SUFU mutations, which are known to activate the SHH pathway; rather, TP53 mutations are more commonly observed in the context of downstream lesions, such as MYCN and GLI2 amplification (Kool et al. 2014). This strongly suggests that TP53-mutated SHH tumors are unlikely to respond to upstream SHH pathway inhibitors, such as the smoothened inhibitors GDC-449 and LDE-225, which are currently in early phase clinical trials for SHH-activated medulloblastoma (Rudin et al. 2009; Gajjar et al. 2013). As TP53-mutated SHH tumors constitute a very high-risk group, and account for the majority of treatment failures within the SHH subgroup, novel therapies beyond SMO inhibition are required to improve outcomes in this group (Ramaswamy et al. 2015). Interestingly, 17p loss was a commonly observed event in the context of TP53 mutations. However, the significance of this is not currently clear.

The chromosomal landscape of TP53-mutated SHH tumors is also unique. Unlike the bland genomes observed in TP53-mutated tumors of the WNT subgroup, genomic instability is a hallmark of TP53-mutated SHH tumors, particularly germline mutations (Rausch et al. 2012). A detailed next-generation sequencing study of a germline TP53-mutated SHH tumor showed an association with the presence of chromothripsis, a genomic state characterized by catastrophic DNA rearrangements as a result of chromosome shattering (Rausch et al. 2012). In this study, chromothripsis was a frequent occurrence in TP53-mutated SHH medulloblastomas, whereas it was nonexistent in WNT medulloblastoma. This was extended to three additional TP53-mutated SHH samples that revealed multiple chromosomes showing chromothripsis. Chromothripsis-associated rearrangements were frequently associated with MYCN and GLI2 amplifications, although chromosome 2 was not affected by chromothripsis. Recurrent fusions, such as the PVT1–MYC fusion in group 3 medulloblastoma or the C11orf95–RELA fusion observed in supratentorial ependymoma as a result of chromothripsis, were not observed in the SHH samples (Northcott et al. 2012c; Parker et al. 2014). Chromothripsis is also commonly observed in TP53-mutated AML suggesting a common mechanism in certain TP53-mutated cancers (Rausch et al. 2012). Although the role of chromothripsis in medulloblastoma initiation is unclear, the association between germline TP53 mutations and chromothripsis suggests that the TP53 mutation precedes the massive shattering and chromosomal rearrangements. This provides a possible explanation for the absence of chromothripsis in WNT-activated medulloblastoma in that TP53 mutations are a late event found in association with mutations of exon 3 of CTNNB1. The observation that chromothripsis was present in Ptch+/−;Tp53−/− mice further strengthens the link between chromothripsis and p53 in SHH medulloblastoma (Wetmore et al. 2001; Rausch et al. 2012).

The role of p53 defects in group 3 and 4 medulloblastoma is unclear. Although 17p loss is a commonly observed event in the context of isochromosome 17q, SNVs of TP53 have not been observed at diagnosis in either of these subgroups. As such, the role of 17p loss is in these two subgroups is unclear, as is the question of whether loss of one copy of TP53 helps to drive clonal selection of cells lacking one copy of chromosome 17p. Negative regulators of p53 have been shown to have aberrant expression in group 3 and 4 medulloblastoma. One such example is WIP1, an oncogene present on 17q, which when highly expressed, inhibits p53 (Castellino et al. 2008). WIP1 is highly expressed in group 3 and 4 medulloblastoma suggesting a role for p53 defects in these two subgroups. However, the extent of a role for p53 in the tumorigenesis of group 3 and 4 medulloblastoma is unclear and requires further study.

PRECLINICAL MODELS OF p53 DEFICIENT MEDULLOBLASTOMA

The development of numerous preclinical models has provided further insight into the role of p53 defects in medulloblastoma tumorigenesis. Several preclinical medulloblastoma models have been developed, most of which rely on inactivation of Ptch1 (Goodrich et al. 1997; Wu et al. 2011, 2012). Ptch1 heterozygosity is sufficient to promote tumorigenesis. However, the incidence of medulloblastoma in Ptch+/− mice is <20% (Goodrich et al. 1997; Wetmore et al. 2000; Wu et al. 2011). When Ptch1 loss is combined with Tp53 loss (i.e., Ptch+/−;Tp53−/−), mice have a tumor incidence exceeding 90%; it has been suggested that genomic instability is promoted by p53 loss, which accelerates the incidence of tumors (Wetmore et al. 2000, 2001; Wu et al. 2011; Rausch et al. 2012). p53 loss in isolation is insufficient to drive medulloblastoma formation. However, Tp53−/− mice do form other tumor types, such as lymphoma (Jacks et al. 1994; Wetmore et al. 2001; Lee et al. 2007; Wu et al. 2012). As such, it is unclear if p53 loss is exclusively a cooperating event in murine medulloblastoma formation. Sufu mutations are frequently observed in infant medulloblastoma. However, Sufu loss alone is insufficient to promote medulloblastoma formation. When Sufu loss is combined with p53 loss, SHH-driven tumor formation was frequently observed. p53 loss has been shown to accelerate tumorigenesis in a variety of genetic backgrounds, including Rb loss, Lig4 loss, Xrcc4 loss, Cdkn2a loss, and Sleeping Beauty under the Math1 promoter (Frank et al. 2000; Marino et al. 2000; Lee and McKinnon 2002; Kawauchi et al. 2012).

WNT-driven medulloblastoma can also be induced through combined mutant Ctnnb1 and Tp53 loss when crossed to Blbp–Cre (Gibson et al. 2010). This model results in medulloblastoma formation in up to 15% of mice, suggesting that loss of p53 is required for transformation of progenitor cells in the lower rhombic lip, the presumed cell of origin of WNT tumors. Indeed, this combined with the relatively frequent occurrence of TP53 mutations in human WNT tumors suggests a role for both CTNNB1 and TP53 in the pathogenesis of WNT medulloblastoma.

p53 defects also have an important role in murine non-WNT/SHH tumors. Sequencing of tumors from the MYCN-driven mouse model (Glt1-tTA/TRE/MYCN-Luc) revealed spontaneous p53 mutations within the DNA-binding domain in 83% of tumors examined (Swartling et al. 2010; Hill et al. 2015). Combining MYC expression with p53 defects also resulted in robust medulloblastoma formation. Two allograft models of MYC-driven medulloblastoma have been generated, and these transcriptionally resemble group 3 medulloblastoma. Both models rely on loss of p53, one requires a Tp53−/− background and the second relies on inactivation of p53 using a dominant negative allele. In both models, MYC expression alone, in the absence of p53 inactivation, was insufficient to result in medulloblastoma formation, suggesting a role for p53 defects in sporadic murine models of medulloblastoma

THERAPEUTIC TARGETING OF TP53 IN MEDULLOBLASTOMA

The subset of patients with TP53 mutant SHH medulloblastomas represents one of the biggest challenges in pediatric neuro-oncology. These patients account for the majority of treatment failures within the SHH subgroup, and they are also the subset of SHH patients least likely to respond to targeted SHH inhibitors. TP53-mutated SHH medulloblastomas commonly harbor downstream genetic events, including MYCN and GLI2 amplifications, which will likely result in resistance to current SHH inhibitors (e.g., vismodegib and sonidegib, which target Smoothened) in phase II clinical trials (Pfaff et al. 2010; Tabori et al. 2010; Gajjar et al. 2013; Kool et al. 2014; Shou et al. 2015). As such, successful therapeutic targeting of this group will require the identification of SHH pathway inhibitors, which act downstream from either MYCN or GLI2. One possible option is arsenic trioxide, which is a GLI2 inhibitor, and a second option is bromodomain inhibitors, which target SHH transcriptional output (Kim et al. 2013; Tang et al. 2014). A recent report also suggested that in an MYCN-driven mouse model with spontaneous p53 mutations, Aurora Kinase inhibitors, such as Alisertib, may confer a survival advantage (Hill et al. 2015). Another intriguing therapeutic possibility in TP53-mutated SHH tumors is lithium. Lithium is an inhibitor of GSK3b, a negative regulator of the WNT pathway, and as such can mimic canonical WNT activation (Stambolic et al. 1996). Thus, one potential therapeutic option is the restoration of radiosensitivity of TP53-mutated medulloblastoma through the administration of lithium (Zhukova et al. 2014). All of these therapeutic options require investigation in phase I clinical trials so their potential can be validated. Another therapeutic option being explored in non-TP53-mutated medulloblastoma is pharmacological activation of the wild-type copy of p53. One agent in particular, nutlin-3, has been shown using in vitro and in vivo systems, to block the interaction of MDM2 and p53, thus restoring p53 function (Kunkele et al. 2012). MDM2 expression has been shown to be increased in medulloblastoma, compared with normal cerebella, suggesting that this is a promising therapeutic strategy in non-TP53-mutated medulloblastoma (Kunkele et al. 2012).

CONCLUSIONS AND FUTURE DIRECTIONS

Our understanding of the role of p53 in medulloblastoma has increased dramatically over the past decade. However, despite these advances, the role of p53 in medulloblastoma initiation, progression, and maintenance is largely unknown and future advances will likely uncover indirect roles for p53-associated proteins in the pathogenesis of group 3 and 4 medulloblastoma. Advances in integrated genomics have brought p53 back to the forefront in the study of medulloblastoma biology. For children with SHH medulloblastoma, it is now clear that TP53 mutations harbor significant prognostic utility and comprise one of the highest risk subsets of medulloblastoma patients. As such, preclinical efforts across many groups is centered squarely on developing novel therapeutics for this very high-risk group of medulloblastoma. Moreover, the identification of this group will also allow more robust preclinical modeling of dominant negative TP53 mutations, which will also lead to the ability to the implementation of preclinical trials for novel therapies.

ACKNOWLEDGMENTS

V.R. is funded by Canadian Institutes of Health Research fellowship, an Alberta Innovates-Health Solutions Clinical Fellowship, and a Young Investigator Award from Alex’s Lemonade Stand Foundation. C.N. is funded by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) of the Ministry of Science, Technology and Innovation of Brazil (201001/2014-4). M.D.T. is funded by the Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children and The University of Toronto, Canadian Institutes of Health Research Operating Grant, National Institutes of Health (R01CA159859 and R01CA148699), and the Pediatric Brain Tumor Foundation.

Footnotes

Editors: Guillermina Lozano and Arnold J. Levine

Additional Perspectives on The p53 Protein available at www.perspectivesinmedicine.org

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