Literature Analysis

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Tag cloud generated 10 March, 2017 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (28)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

CTNNB1 3p22.1 CTNNB, MRD19, armadillo GWS
-CTNNB1 and Medullobalastoma
TP53 17p13.1 P53, BCC7, LFS1, TRP53 GWS
-TP53 mutation in Medulloblastoma
NTRK3 15q25 TRKC, gp145(trkC) Prognostic
-NTRK3 expression in Medulloblastoma
MYC 8q24.21 MRTL, MYCC, c-Myc, bHLHe39 Amplification
-MYC expression and amplification in Medulloblastoma
GLI1 12q13.2-q13.3 GLI -GLI1 and Medulloblastoma
MYCN 2p24.3 NMYC, ODED, MODED, N-myc, bHLHe37 Amplification
-MYCN Amplification in Medulloblastoma
SMO 7q32.3 Gx, SMOH, FZD11 -SMO and Medulloblastoma
-PTCH1 and Medulloblastoma
OTX2 14q22.3 CPHD6, MCOPS5 -OTX2 and Medulloblastoma
SUFU 10q24.32 SUFUH, SUFUXL, PRO1280 -SUFU and Medulloblastoma
-SUFU germline mutations in Medulloblastoma associated with Gorlin Syndrome
REST 4q12 XBR, NRSF -REST and Medulloblastoma
SSTR2 17q24 -SSTR2 Expresssion in Medulloblastoma
SMARCA4 19p13.2 BRG1, CSS4, SNF2, SWI2, MRD16, RTPS2, BAF190, SNF2L4, SNF2LB, hSNF2b, BAF190A GWS
-SMARCA4 and Medulloblastoma
ATOH1 4q22 ATH1, HATH1, MATH-1, bHLHa14 -ATOH1 and Medulloblastoma
HIC1 17p13.3 hic-1, ZBTB29, ZNF901 -HIC1 and Medulloblastoma
NGFR 17q21-q22 CD271, p75NTR, TNFRSF16, p75(NTR), Gp80-LNGFR -NGFR and Medulloblastoma
ERBB2 17q12 NEU, NGL, HER2, TKR1, CD340, HER-2, MLN 19, HER-2/neu -ERBB2 and Medulloblastoma
DDX3X Xp11.3-p11.23 DBX, DDX3, HLP2, DDX14, CAP-Rf GWS
-DDX3X and Medulloblastoma
KMT2D 12q13.12 ALR, KMS, MLL2, MLL4, AAD10, KABUK1, TNRC21, CAGL114 GWS
-MLL2 (KMT2D) and Medulloblastoma
KDM6A Xp11.2 UTX, KABUK2, bA386N14.2 GWS
-KDM6A and Medulloblastma
MSI1 12q24 -MSI1 and Medulloblastoma
MYCL 1p34.2 LMYC, L-Myc, MYCL1, bHLHe38 -MYCL1 expression in Medulloblastoma
DONSON 21q22.1 B17, C21orf60 -DONSON and Medulloblastoma
FUT4 11q21 LeX, CD15, ELFT, FCT3A, FUTIV, SSEA-1, FUC-TIV -FUT4 and Medulloblastoma
ERBB4 2q33.3-q34 HER4, ALS19, p180erbB4 -ERBB4 and Medulloblastoma
ZNF521 18q11.2 EHZF, Evi3 -ZNF521 and Medulloblastoma
NEURL1 10q25.1 neu, NEUR1, NEURL, RNF67, neu-1, bA416N2.1 -NEURL1 and Medulloblastoma
FSTL3 19p13 FLRG, FSRP -FSTL3 and Medulloblastoma

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

GWS - Genome/Exome Wide Study, large-scale/significant (selected):
Parsons DW et al. The genetic landscape of the childhood cancer medulloblastoma. Science. 2011; 331(6016):435-9
Jones DT et al. Dissecting the genomic complexity underlying medulloblastoma. Nature. 2012; 488(7409):100-5
Pugh TJ et al. Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature. 2012; 488(7409)

Molecular Subgroups of Medulloblastoma

Molecular Subgroups of Medulloblastoma

Taylor MD, Northcott PA, Korshunov A, et al.
Molecular subgroups of medulloblastoma: the current consensus.
Acta Neuropathol. 2012; 123(4):465-72 [PubMed] Free Access to Full Article Related Publications
Medulloblastoma, a small blue cell malignancy of the cerebellum, is a major cause of morbidity and mortality in pediatric oncology. Current mechanisms for clinical prognostication and stratification include clinical factors (age, presence of metastases, and extent of resection) as well as histological subgrouping (classic, desmoplastic, and large cell/anaplastic histology). Transcriptional profiling studies of medulloblastoma cohorts from several research groups around the globe have suggested the existence of multiple distinct molecular subgroups that differ in their demographics, transcriptomes, somatic genetic events, and clinical outcomes. Variations in the number, composition, and nature of the subgroups between studies brought about a consensus conference in Boston in the fall of 2010. Discussants at the conference came to a consensus that the evidence supported the existence of four main subgroups of medulloblastoma (Wnt, Shh, Group 3, and Group 4). Participants outlined the demographic, transcriptional, genetic, and clinical differences between the four subgroups. While it is anticipated that the molecular classification of medulloblastoma will continue to evolve and diversify in the future as larger cohorts are studied at greater depth, herein we outline the current consensus nomenclature, and the differences between the medulloblastoma subgroups.

Kool M, Korshunov A, Remke M, et al.
Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas.
Acta Neuropathol. 2012; 123(4):473-84 [PubMed] Free Access to Full Article Related Publications
Medulloblastoma is the most common malignant brain tumor in childhood. Molecular studies from several groups around the world demonstrated that medulloblastoma is not one disease but comprises a collection of distinct molecular subgroups. However, all these studies reported on different numbers of subgroups. The current consensus is that there are only four core subgroups, which should be termed WNT, SHH, Group 3 and Group 4. Based on this, we performed a meta-analysis of all molecular and clinical data of 550 medulloblastomas brought together from seven independent studies. All cases were analyzed by gene expression profiling and for most cases SNP or array-CGH data were available. Data are presented for all medulloblastomas together and for each subgroup separately. For validation purposes, we compared the results of this meta-analysis with another large medulloblastoma cohort (n = 402) for which subgroup information was obtained by immunohistochemistry. Results from both cohorts are highly similar and show how distinct the molecular subtypes are with respect to their transcriptome, DNA copy-number aberrations, demographics, and survival. Results from these analyses will form the basis for prospective multi-center studies and will have an impact on how the different subgroups of medulloblastoma will be treated in the future.

Pietsch T, Schmidt R, Remke M, et al.
Prognostic significance of clinical, histopathological, and molecular characteristics of medulloblastomas in the prospective HIT2000 multicenter clinical trial cohort.
Acta Neuropathol. 2014; 128(1):137-49 [PubMed] Free Access to Full Article Related Publications
This study aimed to prospectively evaluate clinical, histopathological and molecular variables for outcome prediction in medulloblastoma patients. Patients from the HIT2000 cooperative clinical trial were prospectively enrolled based on the availability of sufficient tumor material and complete clinical information. This revealed a cohort of 184 patients (median age 7.6 years), which was randomly split at a 2:1 ratio into a training (n = 127), and a test (n = 57) dataset in order to build and test a risk score for this population. Independent validation was performed in a non-overlapping cohort (n = 83). All samples were subjected to thorough histopathological investigation, CTNNB1 mutation analysis, quantitative PCR, MLPA and FISH analyses for cytogenetic variables, and methylome analysis. By univariable analysis, clinical factors (M-stage), histopathological variables (large cell component, endothelial proliferation, synaptophysin pattern), and molecular features (chromosome 6q status, MYC amplification, subgrouping) were found to be prognostic. Molecular consensus subgrouping (WNT, SHH, Group 3, Group 4) was validated as an independent feature to stratify patients into different risk groups. When comparing methods for the identification of WNT-driven medulloblastoma, this study identified CTNNB1 sequencing and methylation profiling to most reliably identify these patients. After removing patients with particularly favorable (CTNNB1 mutation, extensive nodularity) or unfavorable (MYC amplification) markers, a risk score for the remaining "intermediate molecular risk" population dependent on age, M-stage, pattern of synaptophysin expression, and MYCN copy-number status was identified, with speckled synaptophysin expression indicating worse outcome. Test and independent validation of the score confirmed significant discrimination of patients by risk profile. Methylation subgrouping and CTNNB1 mutation status represent robust tools for the risk stratification of medulloblastoma. A simple clinico-pathological risk score was identified, which was confirmed in a test set and by independent clinical validation.

Predisposing Conditions

The vast majority of medulloblastoma cases are sporadic (non-inherited). However, a small proportion of medulloblastoma cases occur the context of hereditary syndromes which have an increased risk of cancer. Syndromes known to be associated with medulloblastoma include the following:

Disease Gene(s) Notes
Basal Cell Nevus SyndromePTCH1 SMO SUFU PTCH2 Basal Cell Nevus Syndrome (also known as Gorlin Syndrome) is an autosomal dominant condition characterised by the appearance of basal cell carcinomas, together with skeletal abnormalities, odontogenic keratocysts and increased risk of Medulloblastoma. Medulloblastoma develops in about 5 out of every 100 children with the syndrome.
Fanconi AnaemiaBRCA2 FANCD2 PALB2 FANCC FANCA more...Fanconi Anemia (FA) is a rare autosomal recessive genetic disorder characterised clinically by progressive bone marrow failure, skeletal deformities and a predisposition to leukaemia and a wide range of cancers. Affected children usually develop severe aplastic anemia by age 8 to 9 years.
Li-Fraumeni syndromeTP53 A rare inherited autosomal dominant disorder that greatly increases the risk of developing several types of cancer, particularly in children and young adults. The most frequent types of cancer associated with Li-Fraumeni syndrome are breast cancer, osteosarcoma, and soft tissue sarcomas. People affected also have increase risk of brain tumuors, leukaemias, adrenocortical carcinoma and other types of cancer.
Rubinstein-Taybi SyndromeCREBBP EP300 Rubinstein-Taybi Syndrome (RTS) ia an autosomal dominant chromosomal disorder characterized by broad thumbs, webbing of fingers and toes, mental retardation, beaked nose, short upper lip, pouting lower lip. Individuals with RTS have an increased risk of brain tumors and occasionally other tumours. Approximately 5 % of RTS patients develop a malignancy or a benign tumor.
Turcot SyndromePMS2 MLH1 APC MSH2 MSH6 Turcot Syndrome is characterised by malignant tumors of the central nervous system (mostly astrocytomas and medulloblastoma) associated with familial polyposis of the colon. There are different sub-types (Paraf F et al, 1997).

Latest Publications

Pietsch T, Haberler C
Update on the integrated histopathological and genetic classification of medulloblastoma - a practical diagnostic guideline.
Clin Neuropathol. 2016 Nov/Dec; 35(6):344-352 [PubMed] Free Access to Full Article Related Publications
The revised WHO classification of tumors of the CNS 2016 has introduced the concept of the integrated diagnosis. The definition of medulloblastoma entities now requires a combination of the traditional histological information with additional molecular/genetic features. For definition of the histopathological component of the medulloblastoma diagnosis, the tumors should be assigned to one of the four entities classic, desmoplastic/nodular (DNMB), extensive nodular (MBEN), or large cell/anaplastic (LC/A) medulloblastoma. The genetically defined component comprises the four entities WNT-activated, SHH-activated and TP53 wildtype, SHH-activated and TP53 mutant, or non-WNT/non-SHH medulloblastoma. Robust and validated methods are available to allow a precise diagnosis of these medulloblastoma entities according to the updated WHO classification, and for differential diagnostic purposes. A combination of immunohistochemical markers including β-catenin, Yap1, p75-NGFR, Otx2, and p53, in combination with targeted sequencing and copy number assessment such as FISH analysis for MYC genes allows a precise assignment of patients for risk-adapted stratification. It also allows comparison to results of study cohorts in the past and provides a robust basis for further treatment refinement.

Yang D, Zhou J, Wang H, et al.
High expression of BAG3 predicts a poor prognosis in human medulloblastoma.
Tumour Biol. 2016; 37(10):13215-13224 [PubMed] Related Publications
Bcl2-associated athanogene 3 (BAG3), a co-chaperone of the heat shock protein (Hsp) 70, regulates various physiological and pathological processes. However, its role in human medulloblastoma has not been clarified. First of all, the expression of BAG3 was examined in formalin-fixed, paraffin-embedded specimens by immunohistochemical staining. And then, the prognostic role of BAG3 was analyzed in 51 medulloblastoma samples. Finally, the roles of BAG3 in the proliferation, migration, and invasion of Daoy medulloblastoma cell were investigated using a specific short hairpin RNA (shRNA). The expression of BAG3 in medulloblastoma tissues was higher than nontumorous samples. Furthermore, BAG3 overexpression significantly correlated with poor prognosis of patients with medulloblastoma. The overall survival and tumor-free survival in patients with BAG3 low expression were higher than high expression. Univariate and multivariate analysis showed that BAG3 overexpression was an independent prognostic marker for medulloblastoma. After the BAG3 knockdown, the Daoy cells exhibited decreased the ability to proliferate and form neurosphere. The preliminary mechanism study showed that overexpression of BAG3 might facilitate the cell cycle transition from G1 to S phase by modulating the cyclin-dependent kinase 2 (CDK2) and cyclin E expression. Additionally, we found that BAG3 might enhance the medulloblastoma cell migratory and invasive ability. In summary, BAG3 overexpression may regulate the survival and invasive properties of medulloblastoma and may serve as a potential therapy target for medulloblastoma.

Chen YS, Li SP, Xiao H, et al.
Metastasis-associated gene 1 expression in human medulloblastoma and its association with invasion and metastasis in medulloblastoma Daoy cell lines.
Genet Mol Res. 2016; 15(2) [PubMed] Related Publications
This study aims to investigate the expression of metastasis-associated gene 1 (MTA1) in human medulloblastoma, and its significance in the invasion and metastasis in a medulloblastoma cell line. Positive expression rate of MTA1 protein in medulloblastoma and adjacent normal tissues collected from 29 medulloblastoma patients was detected by immunohistochemistry assay in vivo. In in vitro experiments, Daoy cells were transfected with MTA1-targeted small interfering RNA (siRNA, MTA1-siRNA group), niRNA (MTA1-niRNA group), and plasmid vectors (control group). Transfection efficiency was evaluated by PT-PCR and western blot; cell adhesion, migration, and invasion capacity was assessed by adhesion assays, scratch assays, and transwell chamber invasion assays, respectively. Results indicated that the positive expression rate of MTA1 protein in the medulloblastoma tissues was higher as compared with that of the adjacent normal tissues (P < 0.05). In addition, mRNA and protein expression of MTA1 in the MTA1-siRNA group was lower than that in the control and MTA1- niRNA groups (P < 0.05). Adhesion, migration, and invasion capacity of Daoy cells in the MTA1-siRNA group was inhibited as compared with the control and MTA1-niRNA groups (P < 0.05). In conclusion, MTA1 expression was increased in medulloblastoma cells, while MTA1 knockdown in medulloblastoma cells inhibited MTA1 expression. In addition, MTA1 knockdown inhibited the adhesion, migration, and invasive capabilities of medulloblastoma cells. It is possible that MTA1 can serve as a biomarker and a potential therapeutic target for medulloblastoma.

Phoenix TN, Patmore DM, Boop S, et al.
Medulloblastoma Genotype Dictates Blood Brain Barrier Phenotype.
Cancer Cell. 2016; 29(4):508-22 [PubMed] Article available free on PMC after 11/04/2017 Related Publications
The childhood brain tumor, medulloblastoma, includes four subtypes with very different prognoses. Here, we show that paracrine signals driven by mutant β-catenin in WNT-medulloblastoma, an essentially curable form of the disease, induce an aberrant fenestrated vasculature that permits the accumulation of high levels of intra-tumoral chemotherapy and a robust therapeutic response. In contrast, SHH-medulloblastoma, a less curable disease subtype, contains an intact blood brain barrier, rendering this tumor impermeable and resistant to chemotherapy. The medulloblastoma-endothelial cell paracrine axis can be manipulated in vivo, altering chemotherapy permeability and clinical response. Thus, medulloblastoma genotype dictates tumor vessel phenotype, explaining in part the disparate prognoses among medulloblastoma subtypes and suggesting an approach to enhance the chemoresponsiveness of other brain tumors.

Coluccia D, Figuereido C, Isik S, et al.
Medulloblastoma: Tumor Biology and Relevance to Treatment and Prognosis Paradigm.
Curr Neurol Neurosci Rep. 2016; 16(5):43 [PubMed] Related Publications
Medulloblastoma is a malignant embryonic brain tumor arising in the posterior fossa and typically occurring in pediatric patients. Current multimodal treatment regimes have significantly improved the survival rates; however, a marked heterogeneity in therapy response is observed, and one third of all patients die within 5 years after diagnosis. Large-scale genetic and transcriptome analysis revealed four medulloblastoma subgroups (WNT, SHH, Group 3, and Group 4) associated with different demographic parameters, tumor manifestation, and clinical behavior. Future treatment protocols will integrate molecular classification schemes to evaluate subgroup-specific intensification or de-escalation of adjuvant therapies aimed to increase tumor control and reduce iatrogenic induced morbidity. Furthermore, the identification of genetic drivers allows assessing target therapies in order to increase the chemotherapeutic armamentarium. This review highlights the biology behind the current classification system and elucidates relevant aspects of the disease influencing forthcoming clinical trials.

Di Pietro C, Marazziti D, La Sala G, et al.
Primary Cilia in the Murine Cerebellum and in Mutant Models of Medulloblastoma.
Cell Mol Neurobiol. 2017; 37(1):145-154 [PubMed] Related Publications
Cellular primary cilia crucially sense and transduce extracellular physicochemical stimuli. Cilium-mediated developmental signaling is tissue and cell type specific. Primary cilia are required for cerebellar differentiation and sonic hedgehog (Shh)-dependent proliferation of neuronal granule precursors. The mammalian G-protein-coupled receptor 37-like 1 is specifically expressed in cerebellar Bergmann glia astrocytes and participates in regulating postnatal cerebellar granule neuron proliferation/differentiation and Bergmann glia and Purkinje neuron maturation. The mouse receptor protein interacts with the patched 1 component of the cilium-associated Shh receptor complex. Mice heterozygous for patched homolog 1 mutations, like heterozygous patched 1 humans, have a higher incidence of Shh subgroup medulloblastoma (MB) and other tumors. Cerebellar cells bearing primary cilia were identified during postnatal development and in adulthood in two mouse strains with altered Shh signaling: a G-protein-coupled receptor 37-like 1 null mutant and an MB-susceptible, heterozygous patched homolog 1 mutant. In addition to granule and Purkinje neurons, primary cilia were also expressed by Bergmann glia astrocytes in both wild-type and mutant animals, from birth to adulthood. Variations in ciliary number and length were related to the different levels of neuronal and glial cell proliferation and maturation, during postnatal cerebellar development. Primary cilia were also detected in pre-neoplastic MB lesions in heterozygous patched homolog 1 mutant mice and they could represent specific markers for the development and analysis of novel cerebellar oncogenic models.

Chowell D, Boddy AM, Mallo D, et al.
When (distant) relatives stay too long: implications for cancer medicine.
Genome Biol. 2016; 17:34 [PubMed] Article available free on PMC after 11/04/2017 Related Publications
Whole-genome analyses of human medulloblastomas show that the dominant clone at relapse is present as a rare subclone at primary diagnosis.

Cao C, Wang W, Jiang P
Clustering of self-organizing map identifies five distinct medulloblastoma subgroups.
Cancer Biomark. 2016; 16(3):327-32 [PubMed] Related Publications
BACKGROUND: Medulloblastoma is one the most malignant paediatric brain tumours. Molecular subgrouping these medulloblastomas will not only help identify specific cohorts for certain treatment but also improve confidence in prognostic prediction.
OBJECTIVE: Currently, there is a consensus of the existences of four distinct subtypes of medulloblastoma. We proposed a novel bioinformatics method, clustering of self-organizing map, to determine the subgroups and their molecular diversity.
METHODS: Microarray expression profiles of 46 medulloblastoma samples were analysed and five clusters with distinct demographics, clinical outcome and transcriptional profiles were identified.
RESULTS: The previously reported Wnt subgroup was identified as expected. Three other novel subgroups were proposed for later investigation.
CONCLUSIONS: Our findings underscore the value of SOM clustering for discovering the medulloblastoma subgroups. When the suggested subdivision has been confirmed in large cohorts, this method should serve as a part of routine classification of clinical samples.

Ernst A, Jones DT, Maass KK, et al.
Telomere dysfunction and chromothripsis.
Int J Cancer. 2016; 138(12):2905-14 [PubMed] Related Publications
Chromothripsis is a recently discovered form of genomic instability, characterized by tens to hundreds of clustered DNA rearrangements resulting from a single dramatic event. Telomere dysfunction has been suggested to play a role in the initiation of this phenomenon, which occurs in a large number of tumor entities. Here, we show that telomere attrition can indeed lead to catastrophic genomic events, and that telomere patterns differ between cells analyzed before and after such genomic catastrophes. Telomere length and telomere stabilization mechanisms diverge between samples with and without chromothripsis in a given tumor subtype. Longitudinal analyses of the evolution of chromothriptic patterns identify either stable patterns between matched primary and relapsed tumors, or loss of the chromothriptic clone in the relapsed specimen. The absence of additional chromothriptic events occurring between the initial tumor and the relapsed tumor sample points to telomere stabilization after the initial chromothriptic event which prevents further shattering of the genome.

Šoukalová J, Vejmělková K, Cermanová T, et al.
[Identification of a Family with SUFU Germline Deletion Based on a Case of Desmoplastic Medulloblastoma in an Infant].
Klin Onkol. 2016; 29 Suppl 1:S83-8 [PubMed] Related Publications
BACKGROUND: Medulloblastoma, an embryonal neuroectodermal tumor of the cerebellum, is the most common malignant brain tumor in children. There are approximately 15 cases diagnosed in the Czech Republic each year. The recent World Health Organization classification recognizes several histopathological subtypes of medulloblastoma: classical, desmoplastic/ nodular with its extensive-nodularity variant, and anaplastic/ large-cell variant. Further molecular analysis identified four basic subgroups of medulloblastoma: WNT, SHH, Group 3, and Group 4. The subgroup of SHH meduloblastoma is associated with somatic mutations of SHH, PTCH1, SUFU, SMO and TP53, while the most common mutations found in infants up to three years of age were PTCH1 and SUFU. The majority of medulloblastomas are sporadic diseases, whereas only about 5- 10% of all cases occur in connection with hereditary genetic syndromes.
CASE: We present a case of a 21-months old girl diagnosed with a localized posterior fossa tumor. The histopathological examination revealed a desmoplastic/ nodular medulloblastoma. The treatment comprised a radical exstirpation of the tumor followed by adjuvant chemotherapy. With the use of array-CGH, a partial biallelic deletion of the SUFU gene (locus 10q24.32) was detected in the tumor DNA, whereas a monoallelic deletion was found in the peripheral lymphocyte DNA of the patient. These findings were confirmed by an independent qPCR method. Monoallelic germline deletion of SUFU was also identified in the patients mother, who was a healthy carrier. Pedigree of the family suggested a transition of the germline deletion of SUFU, since another brain tumors (including one case diagnosed before the age of three years) were identified in previous generations.
CONCLUSION: Germline mutations in SUFU gene are believed to predispose to infant desmoplastic/ nodular medulloblastomas, basal cell carcinomas and meningiomas. The susceptibility gene shows autosomal dominant inheritance with an incomplete penetrance. There is no evidence-based surveillance strategy suggested for the carriers of germline SUFU mutations/ deletions so far. Our recommendation is based both on a family history of our patient and similar cases described in the literature. Since the germinal mutations in SUFU are responsible for up to 50% of all desmoplastic medulloblastomas in children under three years of age, genetic testing of SUFU should be encouraged in this population of patients.

Ramaswamy V, Nör C, Taylor MD
p53 and Meduloblastoma.
Cold Spring Harb Perspect Med. 2015; 6(2):a026278 [PubMed] Related Publications
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.

Alioto TS, Buchhalter I, Derdak S, et al.
A comprehensive assessment of somatic mutation detection in cancer using whole-genome sequencing.
Nat Commun. 2015; 6:10001 [PubMed] Article available free on PMC after 11/04/2017 Related Publications
As whole-genome sequencing for cancer genome analysis becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Here using tumour-normal sample pairs from two different types of cancer, chronic lymphocytic leukaemia and medulloblastoma, we conduct a benchmarking exercise within the context of the International Cancer Genome Consortium. We compare sequencing methods, analysis pipelines and validation methods. We show that using PCR-free methods and increasing sequencing depth to ∼ 100 × shows benefits, as long as the tumour:control coverage ratio remains balanced. We observe widely varying mutation call rates and low concordance among analysis pipelines, reflecting the artefact-prone nature of the raw data and lack of standards for dealing with the artefacts. However, we show that, using the benchmark mutation set we have created, many issues are in fact easy to remedy and have an immediate positive impact on mutation detection accuracy.

Khatua S
Evolving molecular era of childhood medulloblastoma: time to revisit therapy.
Future Oncol. 2016; 12(1):107-17 [PubMed] Related Publications
Currently medulloblastoma is treated with a uniform therapeutic approach based on histopathology and clinico-radiological risk stratification, resulting in unpredictable treatment failure and relapses. Improved understanding of the biological, molecular and genetic make-up of these tumors now clearly identifies it as a compendium of four distinct subtypes (WNT, SHH, group 3 and 4). Advances in utilization of the genomic and epigenomic machinery have now delineated genetic aberrations and epigenetic perturbations in each subgroup as potential druggable targets. This has resulted in endeavors to profile targeted therapy. The challenge and future of medulloblastoma therapeutics will be to keep pace with the evolving novel biological insights and translating them into optimal targeted treatment regimens.

Ji MH, Kim SK, Kim CY, et al.
Physiological Expression and Accumulation of the Products of Two Upstream Open Reading Frames mrtl and MycHex1 Along With p64 and p67 Myc From the Human c-myc Locus.
J Cell Biochem. 2016; 117(6):1407-18 [PubMed] Related Publications
In addition to the canonical c-Myc p64 and p67 proteins, the human c-myc locus encodes two distinct proteins, mrtl (myc-related translation/localization regulatory factor) and MycHex1 (Myc Human Exon 1), from the upstream open reading frames within the 5'-untranslated region of the c-myc P0 mRNA. The aim of this study is to examine simultaneously, for the first time, mrtl, MycHex1, c-Myc p64, and p67 in human tumor cell lines and pediatric brain tumor tissues. Western blot analysis demonstrated endogenous mrtl, MycHex1, c-Myc p64, and p67 simultaneously. The relative abundance of mrtl and MycHex1 were consistent among a variety of human tumor cell lines, and the relative intensities of mrtl and MycHex1 correlated positively. Confocal imaging revealed mrtl predominantly localized to the nuclear envelope, along with prominent reticular pattern in the cytoplasm. MycHex1 was observed as a series of bright foci located within the nucleus, a subset of which colocalized with fibrillarin. mrtl and MycHex1 co-immunoprecipitated with RACK1, c-Myc, fibrillarin, coilin, and with each other. These findings suggest that mrtl and MycHex1 have multiple interaction partners in both the nucleus and cytoplasm. Sequence analyses confirmed a known polymorphism of mrtl at base 1965 (G>T) and new mutations at bases 1900 (C>G) and 1798 (C>G). Evidence is presented for expression and stable accumulation of all four proteins encoded by three distinct non-overlapping open reading frames within the human c-myc locus. Additional work is warranted to further elucidate the functional or regulatory roles of these molecules in regulation of c-Myc and in oncogenesis.

Paris L, Giardullo P, Leonardi S, et al.
Transgenerational inheritance of enhanced susceptibility to radiation-induced medulloblastoma in newborn Ptch1⁺/⁻ mice after paternal irradiation.
Oncotarget. 2015; 6(34):36098-112 [PubMed] Article available free on PMC after 11/04/2017 Related Publications
The hypothesis of transgenerational induction of increased cancer susceptibility after paternal radiation exposure has long been controversial because of inconsistent results and the lack of a mechanistic interpretation. Here, exploiting Ptch1 heterozygous knockout mice, susceptible to spontaneous and radiation-induced medulloblastoma, we show that exposure of paternal germ cells to 1 Gy X-rays, at the spermatogonial stage, increased by a considerable 1.4-fold the offspring susceptibility to medulloblastoma induced by neonatal irradiation. This effect gained further biological significance thanks to a number of supporting data on the immunohistochemical characterization of the target tissue and preneoplastic lesions (PNLs). These results altogether pointed to increased proliferation of cerebellar granule cell precursors and PNLs cells, which favoured the development of frank tumours. The LOH analysis of tumor DNA showed Ptch1 biallelic loss in all tumor samples, suggesting that mechanisms other than interstitial deletions, typical of radiation-induced medulloblastoma, did not account for the observed increased cancer risk. This data was supported by comet analysis showing no differences in DNA damage induction and repair in cerebellar cells as a function of paternal irradiation. Finally, we provide biological plausibility to our results offering evidence of a possible epigenetic mechanism of inheritance based on radiation-induced changes of the microRNA profile of paternal sperm.

Brown AL, Lupo PJ, Okcu MF, et al.
SOD2 genetic variant associated with treatment-related ototoxicity in cisplatin-treated pediatric medulloblastoma.
Cancer Med. 2015; 4(11):1679-86 [PubMed] Article available free on PMC after 11/04/2017 Related Publications
Manganese superoxide dismutase (MnSOD), encoded by the SOD2 gene, is involved in the detoxification of superoxide anion. Superoxide is likely a source of oxidative stress in the cochlea following treatment with platinum agents and radiation. Therefore, we examined SOD2 variants in association with ototoxicity among cisplatin-treated childhood medulloblastoma patients. Blood samples were obtained from 71 eligible patients treated for pediatric medulloblastoma at Texas Children's Cancer Center (1987-2010). Ototoxicity was defined as requiring the use of a hearing aid sometime after the initiation of therapy. DNA was genotyped on the Illumina HumanOmni-1 Quad BeadChip. A linkage disequilibrium (LD)-based single-nucleotide polymorphism (SNP) selection strategy was used to identify a minimal set of informative variants. Associations between SNPs and ototoxicity were assessed using logistic regression. Of the 71 eligible patients, 26 (37%) suffered from cisplatin-related ototoxicity. Study participants were primarily male (73%) and non-Hispanic white (42%). Five SOD2 variants (rs7855, rs5746151, rs5746136, rs2758331, and rs4880) identified by the LD-based selection strategy were genotyped. After correcting for multiple comparisons, the C-allele of the rs4880 variant was significantly associated with ototoxicity (odds ratio = 3.06, 95% confidence interval: 1.30-7.20) in adjusted models. The rs4880 T > C substitution results in a Val > Ala amino acid change at position 16 of the MnSOD mitochondrial targeting sequence. The Ala variant, which has been associated with increased MnSOD activity, was associated with hearing damage in this study. Platinum-based therapies increase the expression of MnSOD, which may result in an abundance of hydrogen peroxide, a reactive oxygen species. Therefore, oxidative stress may be an important mechanism in therapy-related cochlear damage.

Skowron P, Ramaswamy V, Taylor MD
Genetic and molecular alterations across medulloblastoma subgroups.
J Mol Med (Berl). 2015; 93(10):1075-84 [PubMed] Article available free on PMC after 11/04/2017 Related Publications
Medulloblastoma is the most common malignant brain tumour diagnosed in children. Over the last few decades, advances in radiation and chemotherapy have significantly improved the odds of survival. Nevertheless, one third of all patients still succumb to their disease, and many long-term survivors are afflicted with neurocognitive sequelae. Large-scale multi-institutional efforts have provided insight into the transcriptional and genetic landscape of medulloblastoma. Four distinct subgroups of medulloblastoma have been identified, defined by distinct transcriptomes, genetics, demographics and outcomes. Integrated genomic profiling of each of these subgroups has revealed distinct genetic alterations, driving pathways and in some instances cells of origin. In this review, we highlight, in a subgroup-specific manner, our current knowledge of the genetic and molecular alterations in medulloblastoma and underscore the possible avenues for future therapeutic intervention.

Bhatia S, Hirsch K, Baig NA, et al.
Effects of altered ephrin-A5 and EphA4/EphA7 expression on tumor growth in a medulloblastoma mouse model.
J Hematol Oncol. 2015; 8:105 [PubMed] Article available free on PMC after 11/04/2017 Related Publications
BACKGROUND: Members of the Eph/ephrin gene families act as key regulators of cerebellar development during embryogenesis. Aberrant signaling of Eph family of receptor tyrosine kinases and their ephrin ligands has also been implicated in human cancers. Medulloblastoma is an aggressive primitive neuroectodermal tumor that originates from granule neuron precursors in the cerebellum. Previous studies have suggested a role for the ephrin-A5 ligand and its receptors, EphA4 and EphA7, in granule cell-precursor formation and in guiding cell migration. In the present study, we investigated the effects of genetic loss of ephrin-A5, EphA4, and EphA7 on the spatiotemporal development of medulloblastoma tumors in the context of the smoothened transgenic mouse model system.
FINDINGS: Radiographic magnetic resonance imaging (MRI) was performed to monitor tumor growth in a genetically engineered mouse model of medulloblastoma. Tumor tissue was harvested to determine changes in the expression of phosphorylated Akt by Western blotting. This helped to establish a correlation between genotype and/or tumor size and survival. Our in vivo data establish that in ND2-SmoA1 transgenic mice, the homozygous deletion of ephrin-A5 resulted in a consistent pattern of tumor growth inhibition compared to their ephrin-A5 wild-type littermate controls, while the loss of EphA4/EphA7 failed to produce consistent effects versus EphA4/EphA7 wild-type mice. A positive correlation was evident between tumor size, p-Akt, and proliferating cell nuclear antigen (PCNA) expression in our transgenic mouse model system, regardless of genotype.
CONCLUSIONS: Taken together, our findings underscore the importance of targeting specific members of the Eph/ephrin families in conjunction with the Akt pathway in order to inhibit medulloblastoma tumor growth and progression.

Amayiri N, Al-Hussaini M, Swaidan M, et al.
Synchronous glioblastoma and medulloblastoma in a child with mismatch repair mutation.
Childs Nerv Syst. 2016; 32(3):553-7 [PubMed] Related Publications
Synchronous primary malignant brain tumors are rare. We present a 5-year-old boy with synchronous glioblastoma and medulloblastoma. Both tumor samples had positive p53 stain and loss of PMS2 and MLH1 stains. The child had multiple café au lait spots and a significant family history of cancer. After subtotal resection of both tumors, he received craniospinal radiation with concomitant temozolomide followed by chemotherapy, alternating cycles of cisplatin/lomustine/vincristine with temozolomide. Then, he started maintenance treatment with cis-retinoic acid (100 mg/m(2)/day for 21 days). He remained asymptomatic for 34 months despite a follow-up brain MRI consistent with glioblastoma relapse 9 months before his death. Cis-retinoic acid may have contributed to prolong survival in this child with a probable biallelic mismatch repair syndrome.

Dahlin AM, Hollegaard MV, Wibom C, et al.
CCND2, CTNNB1, DDX3X, GLI2, SMARCA4, MYC, MYCN, PTCH1, TP53, and MLL2 gene variants and risk of childhood medulloblastoma.
J Neurooncol. 2015; 125(1):75-8 [PubMed] Article available free on PMC after 11/04/2017 Related Publications
Recent studies have described a number of genes that are frequently altered in medulloblastoma tumors and that have putative key roles in the development of the disease. We hypothesized that common germline genetic variations in these genes may be associated with medulloblastoma development. Based on recent publications, we selected 10 genes that were frequently altered in medulloblastoma: CCND2, CTNNB1, DDX3X, GLI2, SMARCA4, MYC, MYCN, PTCH1, TP53, and MLL2 (now renamed as KMT2D). Common genetic variants (single nucleotide polymorphisms) annotating these genes (n = 221) were genotyped in germline DNA (neonatal dried blood spot samples) from 243 childhood medulloblastoma cases and 247 control subjects from Sweden and Denmark. Eight genetic variants annotating three genes in the sonic hedgehog signaling pathway; CCND2, PTCH1, and GLI2, were found to be associated with the risk of medulloblastoma (P(combined) < 0.05). The findings were however not statistically significant following correction for multiple testing by the very stringent Bonferroni method. The results do not support our hypothesis that common germline genetic variants in the ten studied genes are associated with the risk of developing medulloblastoma.

Lee SJ, Litan A, Li Z, et al.
Na,K-ATPase β1-subunit is a target of sonic hedgehog signaling and enhances medulloblastoma tumorigenicity.
Mol Cancer. 2015; 14:159 [PubMed] Article available free on PMC after 11/04/2017 Related Publications
BACKGROUND: The Sonic hedgehog (Shh) signaling pathway plays an important role in cerebellar development, and mutations leading to hyperactive Shh signaling have been associated with certain forms of medulloblastoma, a common form of pediatric brain cancer. While the fundamentals of this pathway are known, the molecular targets contributing to Shh-mediated proliferation and transformation are still poorly understood. Na,K-ATPase is a ubiquitous enzyme that maintains intracellular ion homeostasis and functions as a signaling scaffold and a cell adhesion molecule. Changes in Na,K-ATPase function and subunit expression have been reported in several cancers and loss of the β1-subunit has been associated with a poorly differentiated phenotype in carcinoma but its role in medulloblastoma progression is not known.
METHODS: Human medulloblastoma cell lines and primary cultures of cerebellar granule cell precursors (CGP) were used to determine whether Shh regulates Na,K-ATPase expression. Smo/Smo medulloblastoma were used to assess the Na,K-ATPase levels in vivo. Na,K-ATPase β1-subunit was knocked down in DAOY cells to test its role in medulloblastoma cell proliferation and tumorigenicity.
RESULTS: Na,K-ATPase β1-subunit levels increased with differentiation in normal CGP cells. Activation of Shh signaling resulted in reduced β1-subunit mRNA and protein levels and was mimicked by overexpression of Gli1and Bmi1, both members of the Shh signaling cascade; overexpression of Bmi1 reduced β1-subunit promoter activity. In human medulloblastoma cells, low β1-subunit levels were associated with increased cell proliferation and in vivo tumorigenesis.
CONCLUSIONS: Na,K-ATPase β1-subunit is a target of the Shh signaling pathway and loss of β1-subunit expression may contribute to tumor development and progression not only in carcinoma but also in medulloblastoma, a tumor of neuronal origin.

Kaid C, Silva PB, Cortez BA, et al.
miR-367 promotes proliferation and stem-like traits in medulloblastoma cells.
Cancer Sci. 2015; 106(9):1188-95 [PubMed] Article available free on PMC after 11/04/2017 Related Publications
In medulloblastoma, abnormal expression of pluripotency factors such as LIN28 and OCT4 has been correlated with poor patient survival. The miR-302/367 cluster has also been shown to control self-renewal and pluripotency in human embryonic stem cells and induced pluripotent stem cells, but there is limited, mostly correlational, information about these pluripotency-related miRNA in cancer. We evaluated whether aberrant expression of such miRNA could affect tumor cell behavior and stem-like traits, thereby contributing to the aggressiveness of medulloblastoma cells. Basal expression of primary and mature forms of miR-367 were detected in four human medulloblastoma cell lines and expression of the latter was found to be upregulated upon enforced expression of OCT4A. Transient overexpression of miR-367 significantly enhanced tumor features typically correlated with poor prognosis; namely, cell proliferation, 3-D tumor spheroid cell invasion and the ability to generate neurosphere-like structures enriched in CD133 expressing cells. A concurrent downregulation of the miR-367 cancer-related targets RYR3, ITGAV and RAB23, was also detected in miR-367-overexpressing cells. Overall, these findings support the pro-oncogenic activity of miR-367 in medulloblastoma and reveal a possible mechanism contributing to tumor aggressiveness, which could be further explored to improve patient stratification and treatment of this important type of pediatric brain cancer.

Wang C, Yun Z, Zhao T, et al.
MiR-495 is a Predictive Biomarker that Downregulates GFI1 Expression in Medulloblastoma.
Cell Physiol Biochem. 2015; 36(4):1430-9 [PubMed] Related Publications
BACKGROUND: Alterations in the expression level of miR-495 were recently observed in various tumours. Medulloblastoma is the most common malignant brain tumour in children. However, the clinical significance of miR-495 in medulloblastomas remains unclear.
METHODS: The expression levels of miR-495 was examined in 62 archival formalin-fixed paraffin-embedded (FFPE) medulloblastoma specimens using TaqMan Real-time Quantitative PCR arrays. Immunohistochemistry was used to determine the expression of Gfi1 in medulloblastoma tissues, and a luciferase reporter assay was carried out to confirm whether Gfi1 is a direct target of miR-495.
RESULTS: MiR-495 expression is repressed in medulloblastoma samples compared with normal cerebellum tissues. Furthermore, patients with a low level of miR- 495 showed significantly poorer survival, as determined by the log-rank test (P = 0.033). The multivariate analysis results showed that the miR-495 expression levels were an independent predictor of overall survival in medulloblastoma patients (P = 0.027; hazard ratio = 0.267). Our study provides the first demonstration that miR-495 directly interacts with the Gfi1 3’UTR to regulate Gfi1 at a post-transcriptional level and that the expression level of miR-495 is inversely correlated with the Gfi1 protein level in medulloblastoma specimens.
CONCLUSION: Our results suggest that miR-495 may be a prognostic predictor in medulloblastoma and that Gfi1 is a potential functional target of miR-495.

Gupta T, Shirsat N, Jalali R
Molecular Subgrouping of Medulloblastoma: Impact Upon Research and Clinical Practice.
Curr Pediatr Rev. 2015; 11(2):106-19 [PubMed] Related Publications
Medulloblastoma, the most common primary pediatric malignant brain tumor is a molecularly heterogeneous disease with different developmental origins, distinct phenotypes, diverse biological behaviour, and contrasting clinical outcomes. The current clinico-radiological risk-classification fails to take account of this heterogeneity and existent prognostic variability. It is widely accepted that dysregulation of normal developmental processes constitute a key mechanism of tumorigenesis in at least a subset of medulloblastomas. Several attempts at biological classification have successfully identified distinct subgroups with subgroup-specific gene signatures, demographics, histologic subtypes, and rates of metastases. Several research groups have classified medulloblastoma into molecular subgroups using a variety of different genomic approaches and platforms such as gene expression profiling, microRNA profiling and methylation arrays. Recently, a consensus has emerged that classifies medulloblastoma into four distinct molecular subgroups named as wingless (WNT), sonic hedgehog (SHH), Group 3 and Group 4 respectively. However, such integrative approaches have limited applicability in the clinic due to the need of fresh-frozen tissues and elaborate molecular biology tools. In parallel, some groups have proposed and validated traditional antibody-based approaches using immunohistochemistry on archival specimen for rapid and reliable molecular subgrouping to be applied in any basic neuropathology laboratory. Heterogeneity within each of these four consensus subgroups has also been demonstrated that needs to be considered in the design of future clinical trials. There is a compelling need to integrate molecular biomarkers with clinico-pathologic outcome indicators to refine risk-stratification as well as develop novel molecularly targeted agents for optimizing therapeutic index and personalizing therapy.

Zhao X, Ponomaryov T, Ornell KJ, et al.
RAS/MAPK Activation Drives Resistance to Smo Inhibition, Metastasis, and Tumor Evolution in Shh Pathway-Dependent Tumors.
Cancer Res. 2015; 75(17):3623-35 [PubMed] Article available free on PMC after 11/04/2017 Related Publications
Aberrant Shh signaling promotes tumor growth in diverse cancers. The importance of Shh signaling is particularly evident in medulloblastoma and basal cell carcinoma (BCC), where inhibitors targeting the Shh pathway component Smoothened (Smo) show great therapeutic promise. However, the emergence of drug resistance limits long-term efficacy, and the mechanisms of resistance remain poorly understood. Using new medulloblastoma models, we identify two distinct paradigms of resistance to Smo inhibition. Sufu mutations lead to maintenance of the Shh pathway in the presence of Smo inhibitors. Alternatively activation of the RAS-MAPK pathway circumvents Shh pathway dependency, drives tumor growth, and enhances metastatic behavior. Strikingly, in BCC patients treated with Smo inhibitor, squamous cell cancers with RAS/MAPK activation emerged from the antecedent BCC tumors. Together, these findings reveal a critical role of the RAS-MAPK pathway in drug resistance and tumor evolution of Shh pathway-dependent tumors.

Zindy F, Lee Y, Kawauchi D, et al.
Dicer Is Required for Normal Cerebellar Development and to Restrain Medulloblastoma Formation.
PLoS One. 2015; 10(6):e0129642 [PubMed] Article available free on PMC after 11/04/2017 Related Publications
Dicer, a ribonuclease III enzyme, is required for the maturation of microRNAs. To assess its role in cerebellar and medulloblastoma development, we genetically deleted Dicer in Nestin-positive neural progenitors and in mice lacking one copy for the Sonic Hedgehog receptor, Patched 1. We found that conditional loss of Dicer in mouse neural progenitors induced massive Trp53-independent apoptosis in all proliferative zones of the brain and decreased proliferation of cerebellar granule progenitors at embryonic day 15.5 leading to abnormal cerebellar development and perinatal lethality. Loss of one copy of Dicer significantly accelerated the formation of mouse medulloblastoma of the Sonic Hedgehog subgroup in Patched1-heterozygous mice. We conclude that Dicer is required for proper cerebellar development, and to restrain medulloblastoma formation.

Zuckermann M, Hovestadt V, Knobbe-Thomsen CB, et al.
Somatic CRISPR/Cas9-mediated tumour suppressor disruption enables versatile brain tumour modelling.
Nat Commun. 2015; 6:7391 [PubMed] Article available free on PMC after 11/04/2017 Related Publications
In vivo functional investigation of oncogenes using somatic gene transfer has been successfully exploited to validate their role in tumorigenesis. For tumour suppressor genes this has proven more challenging due to technical aspects. To provide a flexible and effective method for investigating somatic loss-of-function alterations and their influence on tumorigenesis, we have established CRISPR/Cas9-mediated somatic gene disruption, allowing for in vivo targeting of TSGs. Here we demonstrate the utility of this approach by deleting single (Ptch1) or multiple genes (Trp53, Pten, Nf1) in the mouse brain, resulting in the development of medulloblastoma and glioblastoma, respectively. Using whole-genome sequencing (WGS) we characterized the medulloblastoma-driving Ptch1 deletions in detail and show that no off-targets were detected in these tumours. This method provides a fast and convenient system for validating the emerging wealth of novel candidate tumour suppressor genes and the generation of faithful animal models of human cancer.

Staal JA, Lau LS, Zhang H, et al.
Proteomic profiling of high risk medulloblastoma reveals functional biology.
Oncotarget. 2015; 6(16):14584-95 [PubMed] Article available free on PMC after 11/04/2017 Related Publications
Genomic characterization of medulloblastoma has improved molecular risk classification but struggles to define functional biological processes, particularly for the most aggressive subgroups. We present here a novel proteomic approach to this problem using a reference library of stable isotope labeled medulloblastoma-specific proteins as a spike-in standard for accurate quantification of the tumor proteome. Utilizing high-resolution mass spectrometry, we quantified the tumor proteome of group 3 medulloblastoma cells and demonstrate that high-risk MYC amplified tumors can be segregated based on protein expression patterns. We cross-validated the differentially expressed protein candidates using an independent transcriptomic data set and further confirmed them in a separate cohort of medulloblastoma tissue samples to identify the most robust proteogenomic differences. Interestingly, highly expressed proteins associated with MYC-amplified tumors were significantly related to glycolytic metabolic pathways via alternative splicing of pyruvate kinase (PKM) by heterogeneous ribonucleoproteins (HNRNPs). Furthermore, when maintained under hypoxic conditions, these MYC-amplified tumors demonstrated increased viability compared to non-amplified tumors within the same subgroup. Taken together, these findings highlight the power of proteomics as an integrative platform to help prioritize genetic and molecular drivers of cancer biology and behavior.

Gururangan S, Robinson G, Ellison DW, et al.
Gorlin syndrome and desmoplastic medulloblastoma: Report of 3 cases with unfavorable clinical course and novel mutations.
Pediatr Blood Cancer. 2015; 62(10):1855-8 [PubMed] Article available free on PMC after 11/04/2017 Related Publications
We present three cases of genetically confirmed Gorlin syndrome with desmoplastic medulloblastoma (DMB) in whom tumor recurred despite standard therapy. One patient was found to have a novel germline missense PTCH1 mutation. Molecular analysis of recurrent tumor using fluorescent in situ hybridization (FISH) revealed PTEN and/ or PTCH1 loss in 2 patients. Whole exome sequencing (WES) of tumor in one patient revealed loss of heterozygosity of PTCH1 and a mutation of GNAS gene in its non-coding 3' -untranslated region (UTR) with corresponding decreased protein expression. While one patient died despite high-dose chemotherapy (HDC) plus stem cell rescue (ASCR) and palliative radiotherapy, two patients are currently alive for 18+ and 120+ months respectively following retrieval therapy that did not include irradiation. Infants with DMB and GS should be treated aggressively with chemotherapy at diagnosis to prevent relapse but radiotherapy should be avoided. The use of molecular prognostic markers for DMB should be routinely used to identify the subset of tumors that might have an aggressive course.

Cookman CJ, Belcher SM
Estrogen Receptor-β Up-Regulates IGF1R Expression and Activity to Inhibit Apoptosis and Increase Growth of Medulloblastoma.
Endocrinology. 2015; 156(7):2395-408 [PubMed] Article available free on PMC after 11/04/2017 Related Publications
Medulloblastoma (Med) is the most common malignant brain tumor in children. The role of ESR2 [estrogen receptor (ER)-β] in promoting Med growth was comprehensively examined in three in vivo models and human cell lines. In a novel Med ERβ-null knockout model developed by crossing Esr2(-/-) mice with cerebellar granule cell precursor specific Ptch1 conditional knockout mice, the tumor growth rate was significantly decreased in males and females. The absence of Esr2 resulted in increased apoptosis, decreased B-cell lymphoma 2 (BCL2), and IGF-1 receptor (IGF1R) expression, and decreased levels of active MAPKs (ERK1/2) and protein kinase B (AKT). Treatment of Med in Ptch1(+/-) Trp53(-/-) mice with the antiestrogen chemotherapeutic drug Faslodex significantly increased symptom-free survival, which was associated with increased apoptosis and decreased BCL2 and IGF1R expression and signaling. Similar effects were also observed in nude mice bearing D283Med xenografts. In vitro studies in human D283Med cells metabolically stressed by glutamine withdrawal found that 17β-estradiol and the ERβ selective agonist 2,3-bis(4-hydroxyphenyl)-propionitrile dose dependently protected Med cells from caspase-3-dependent cell death. Those effects were associated with increased phosphorylation of IGF1R, long-term increases in ERK1/2 and AKT signaling, and increased expression of IGF-1, IGF1R, and BCL2. Results of pharmacological experiments revealed that the cytoprotective actions of estradiol were dependent on ERβ and IGF1R receptor tyrosine kinase activity and independent of ERα and G protein-coupled estrogen receptor 1 (G protein coupled receptor 30). The presented results demonstrate that estrogen promotes Med growth through ERβ-mediated increases in IGF1R expression and activity, which induce cytoprotective mechanisms that decrease apoptosis.

Further References

Parsons DW, Li M, Zhang X, et al.
The genetic landscape of the childhood cancer medulloblastoma.
Science. 2011; 331(6016):435-9 [PubMed] Free Access to Full Article Related Publications
Medulloblastoma (MB) is the most common malignant brain tumor of children. To identify the genetic alterations in this tumor type, we searched for copy number alterations using high-density microarrays and sequenced all known protein-coding genes and microRNA genes using Sanger sequencing in a set of 22 MBs. We found that, on average, each tumor had 11 gene alterations, fewer by a factor of 5 to 10 than in the adult solid tumors that have been sequenced to date. In addition to alterations in the Hedgehog and Wnt pathways, our analysis led to the discovery of genes not previously known to be altered in MBs. Most notably, inactivating mutations of the histone-lysine N-methyltransferase genes MLL2 or MLL3 were identified in 16% of MB patients. These results demonstrate key differences between the genetic landscapes of adult and childhood cancers, highlight dysregulation of developmental pathways as an important mechanism underlying MBs, and identify a role for a specific type of histone methylation in human tumorigenesis.

Jones DT, Jäger N, Kool M, et al.
Dissecting the genomic complexity underlying medulloblastoma.
Nature. 2012; 488(7409):100-5 [PubMed] Free Access to Full Article Related Publications
Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients.

Pugh TJ, Weeraratne SD, Archer TC, et al.
Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations.
Nature. 2012; 488(7409):106-10 [PubMed] Free Access to Full Article Related Publications
Medulloblastomas are the most common malignant brain tumours in children. Identifying and understanding the genetic events that drive these tumours is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma on the basis of transcriptional and copy number profiles. Here we use whole-exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas have low mutation rates consistent with other paediatric tumours, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were newly identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR and LDB1. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant, but not wild-type, β-catenin. Together, our study reveals the alteration of WNT, hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic β-catenin signalling in medulloblastoma.

Recurring Structural Abnormalities

Selected list of common recurrent structural abnormalities

Abnormality Type Gene(s)
Isochromosome 17q in MedulloblastomaIsochromosome

This is a highly selective list aiming to capture structural abnormalies which are frequesnt and/or significant in relation to diagnosis, prognosis, and/or characterising specific cancers. For a much more extensive list see the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer.

Isochromosome 17q in Medulloblastoma

Biegel JA, Rorke LB, Packer RJ, et al.
Isochromosome 17q in primitive neuroectodermal tumors of the central nervous system.
Genes Chromosomes Cancer. 1989; 1(2):139-47 [PubMed] Related Publications
We have prepared karyotypes from 22 primitive neuroectodermal tumors (PNETs) from pediatric patients ranging in age from 10 months to 16 years. Twenty-one cases were newly diagnosed, primary, posterior fossa tumors. One case was a recurrent tumor in a patient previously treated with radiation. Cytogenetic results were obtained from direct preparations and/or short-term (1-10 day) culture. Three tumors had apparently normal karyotypes. Nineteen tumors demonstrated numerical and/or structural abnormalities. The most frequent structural chromosomal changes were deletions and nonreciprocal translocations. Four tumors contained double minutes. Several chromosomes appear to be nonrandomly involved in PNETs. These include chromosomes 5, 6, 11, 16, 17, and a sex chromosome. The most consistent change, however, was an i(17q), present in one-third (8/22) of the cases. Strikingly, in three of these eight tumors, the i(17q) was the only structural abnormality observed. An i(17q) is not specific for pediatric PNETs, as it is also seen in leukemias and other solid tumors. However, in PNETs it may be a primary change related to tumor development and/or progression. Clinically, there was no correlation of the cytogenetic findings with histologic features of the tumors, size of the tumor, extent of metastasis, or surgical resection.

Giordana MT, Migheli A, Pavanelli E
Isochromosome 17q is a constant finding in medulloblastoma. An interphase cytogenetic study on tissue sections.
Neuropathol Appl Neurobiol. 1998; 24(3):233-8 [PubMed] Related Publications
Isochromosome 17q (i[17q]) is the most frequent chromosomal abnormality in medulloblastoma, occurring in 30-60% of cases by karyotype analysis. In the present study i[17q] was demonstrated in routinely processed tissue sections of 20 medulloblastomas by in situ hybridization (ISH), using a chromosome 17 centromeric alpha satellite DNA probe. All medulloblastomas showed the i[17q] specific signal, i.e. two hybridization spots slightly apart from each other. The specific hybridization signal was not observed in ependymomas, cerebellar astrocytomas, haemangioblastomas, supratentorial neuroblastomas and ependymoblastomas. The constant finding of i[17q] in medulloblastoma depends on the much higher number of nuclei which can be analysed by ISH compared with cytogenetic techniques. Molecular data on medulloblastoma are consistent with the present results. The number of cells with i[17q] in medulloblastoma cases ranged from 3% to 9%; these figures are underestimated because of nuclear truncation in tissue sections. The percentage was not linked to patients' age, location of tumour, MIB-1 labelling index and histological type (classical vs desmoplastic). The present results indicate that i[17q] is a key event in the pathogenesis of medulloblastoma, and suggest a genetic difference between medulloblastoma and other primitive neuroectodermal tumours.

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