The Genetic Landscape of the Childhood Cancer Medulloblastoma

Parsons, D. Williams; Li, Meng; Zhang, Xiaosong; Jones, Siân; Leary, Rebecca J.; Lin, Jimmy; Boca, Simina M.; Carter, Hannah; Samayoa, Josue; Bettegowda, Chetan; Gallia, Gary L.; Jallo, George I.; Binder, Zev A.; Nikolsky, Yuri; Hartigan, James; Smith, Doug; Gerhard, Daniela S.; Fults, Daniel W.; VandenBerg, Scott R.; Berger, Mitchel S.; Marie, Suely Kazue Nagahashi; Oba-Shinjo, Sueli Mieko; Clara, Carlos Afonso; Phillips, Peter C.B.; Minturn, Jane E.; Biegel, Jaclyn A.; Judkins, Alexander R.; Resnick, Adam; Storm, Phillip B.; Curran, Tom; He, Yiping; Rasheed, B. Ahmed; Friedman, Henry S.; Keir, Stephen T.; McLendon, Roger E.; Northcott, Paul A.; Taylor, Michael D.; Burger, Peter C.; Riggins, Gregory J.; Karchin, Rachel; Parmigiani, Giovanni; Bigner, Darell D.; Yan, Hai; Papadopoulos, Nick; Vogelstein, Bert; Kinzler, Kenneth W.; Velculescu, Victor E.

doi:10.1126/science.1198056

Cited by 644 publications

(532 citation statements)

References 45 publications

(50 reference statements)

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“…Like ATM, the recurrent targeting of the same amino acid for multiple substitutions suggests an oncogenic phenotype for these mutations. Truncating mutations were also identified in MLL3, an H3K4 methylase with mutations previously reported in medulloblastoma and TCC (11,15), and in ARID1B, a component of the switch/sucrose non-fermentable chromatin remodeling complex (SWI/SNF) complex like ARID1A with recurrent mutations recently identified in breast cancer (16). SMARCA2, which encodes the BRM ATPase subunit of the SWI/SNF complex was also implicated by 3 somatic missense mutations.…”

Section: Resultsmentioning

confidence: 82%

Whole exome sequencing of adenoid cystic carcinoma

Stephens¹,

Davies²,

Mitani³

et al. 2013

J. Clin. Invest.

233

264

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Adenoid cystic carcinoma (ACC) is a rare malignancy that can occur in multiple organ sites and is primarily found in the salivary gland. While the identification of recurrent fusions of the MYB-NFIB genes have begun to shed light on the molecular underpinnings, little else is known about the molecular genetics of this frequently fatal cancer. We have undertaken exome sequencing in a series of 24 ACC to further delineate the genetics of the disease. We identified multiple mutated genes that, combined, implicate chromatin deregulation in half of cases. Further, mutations were identified in known cancer genes, including PIK3CA, ATM, CDKN2A, SF3B1, SUFU, TSC1, and CYLD. Mutations in NOTCH1/2 were identified in 3 cases, and we identify the negative NOTCH signaling regulator, SPEN, as a new cancer gene in ACC with mutations in 5 cases. Finally, the identification of 3 likely activating mutations in the tyrosine kinase receptor FGFR2, analogous to those reported in ovarian and endometrial carcinoma, point to potential therapeutic avenues for a subset of cases.

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Section: Resultsmentioning

confidence: 82%

Whole exome sequencing of adenoid cystic carcinoma

Stephens¹,

Davies²,

Mitani³

et al. 2013

J. Clin. Invest.

233

264

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“…12,13 A recent study by Parsons and colleagues revealed that children had fewer passenger mutations compared with adults, but they had the same amount of driver mutations (probable cancercausing mutations). 13 Korshunov and colleagues reported that pediatric tumors had gains of chromosomes 1q, 2, 7, and 17q and loss of 16q, whereas adult tumors more frequently had gains of chromosomes 3q, 4, and 19. In addition, adult tumors exclusively had much more monosomy 17, whereas pediatric tumors had trisomy 17.…”

Section: Discussionmentioning

confidence: 99%

“…2,[4][5][6][7][8][9][10] Studies have demonstrated that medulloblastomas in adults and children are histologically and genetically different diseases. [11][12][13] Because of obvious differences in expected survival between adults and children in the general population (with adults more likely to die than children), comparing the survival profiles of children and adults with brain tumors requires a particular approach, namely, the use of relative survival.…”

Section: Introductionmentioning

confidence: 99%

Relative survival of childhood and adult medulloblastomas and primitive neuroectodermal tumors (PNETs)

Smoll

2011

Cancer

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BACKGROUND: Medulloblastomas are 1 of the most common brain tumors in children but can affect individuals of all ages. For this report, the author investigated the impact of medulloblastomas/primitive neuroectodermal tumors (PNETs) on the US population with a focus on age differences. METHODS: Data from the Surveillance, Epidemiology, and End Results (SEER) database were used to describe cumulative relative survival (CRS) using crude, period, and longitudinal period approaches for patients diagnosed with all medulloblastoma subtypes and PNETs. CRS estimates were obtained using SEER expected mortality data and the Ederer II method for expected survival estimation. These data were applied to the construction of rational follow-up scheduling protocols. RESULTS: The 5-year period CRS for all patients who were followed between 2001 and 2006 was 69%. Adults had a worse overall prognosis, but this difference in excess hazard rates appeared only after 4 years of follow-up. Furthermore, the 5-year and 10-year CRS has improved a minimum of 11% in children, adolescents, and adults over the past 25 years. CONCLUSIONS: The survival difference between children, adolescents, and adults with medulloblastomas and PNETs depended on the length of follow-up, which was described in this report as an age-by-follow-up interaction and observed as a ''fork'' on Kaplan-Meier curves. Differences in survival between children and adults emerged only 4 years after diagnosis, and adults fared worse. There has been significant improvement in survival from medulloblastomas/PNETs since the late 1970s and early 1980s. Cancer 2012;118:1313-

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“…Recent genomic platforms have shown that medulloblastomas of different molecular subtypes may originate from distinct precursor and stem cell populations in the cerebellum (Gilbertson and Ellison, 2008;Johnson et al, 2009;Ellison, 2010;Northcott et al, 2010;Parsons et al, 2010). Many mouse models have elegantly established that CD133 þ ventricular zone stem cells are distinct from Math1 þ external granule layer cells (Lee et al, 2005Gibson et al, 2010), and strong evidence suggests that although non-hedgehog pathway medulloblastoma may originate from the former, the Shh subtype of medulloblastoma likely originates from the latter (Rao et al, 2004;Schuller et al, 2008;Read et al, 2009;Sutter et al, 2010).…”

Section: Shh Regulates Bmi1 In Medulloblastoma Bticsmentioning

confidence: 99%

Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells

et al. 2011

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Bmi1 is a key stem cell regulatory gene implicated in the pathogenesis of many aggressive cancers, including medulloblastoma. Overexpression of Bmi1 promotes cell proliferation and is required for hedgehog (Hh) pathwaydriven tumorigenesis. This study aimed to determine if Sonic hedgehog (Shh) modulates the key stem cell regulatory gene Bmi1 in childhood medulloblastoma brain tumor-initiating cells (BTICs). Although current literature suggests that there is a correlation between Shh pathway genes and Bmi1 expression, it is unclear whether there is indeed a direct regulatory mechanism. To address whether Shh induces expression of Bmi1, stem cell-enriched populations from medulloblastoma cell lines and primary samples were treated with Shh ligand and KAAD-cyclopamine (Shh antagonist). Our data indicate that Bmi1 expression positively correlates with increasing Shh ligand concentrations. Chromatin immunoprecipitation reveals that Gli1 preferentially binds to the Bmi1 promoter, and Bmi1 transcript levels are increased and decreased by Gli1 overexpression and downregulation, respectively. Knockdown experiments of Bmi1 in vitro and in vivo demonstrate that Hh signaling not only drives Bmi1 expression, but a feedback mechanism exists wherein downstream effectors of Bmi1 may, in turn, activate Hh pathway genes. These findings implicate Bmi1 and Hh as mutually indispensable pathways in medulloblastoma BTIC maintenance. Recent molecular characterization of medulloblastoma also reveals that Bmi1 is overexpressed across all subgroups of medulloblastoma, particularly in the most aggressive subtypes. Lastly, despite recent identification of BTIC markers, the molecular characterization of these cell populations remains unclear. In this work, we propose that the BTIC marker CD133 may segregate a cell population with a Hh-receptor phenotype, thus demonstrating a cell-cell interaction between the CD133 þ Hh receptor cells and the CD133À Hh-secreting cells.

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The Genetic Landscape of the Childhood Cancer Medulloblastoma

Cited by 644 publications

References 45 publications

Whole exome sequencing of adenoid cystic carcinoma

Whole exome sequencing of adenoid cystic carcinoma

Relative survival of childhood and adult medulloblastomas and primitive neuroectodermal tumors (PNETs)

Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells

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