Tuesday, February 26, 2019

Childhood Cancer Genomics (PDQ®) 5/8 —Health Professional Version - National Cancer Institute

Childhood Cancer Genomics (PDQ®)—Health Professional Version - National Cancer Institute



National Cancer Institute



Medulloepithelioma
Medulloepithelioma is identified as a histologically discrete tumor within the WHO classification system.[110,111] Medulloepithelioma tumors are rare and tend to arise most commonly in infants and young children. Medulloepitheliomas, which histologically recapitulate the embryonal neural tube, tend to arise supratentorially, primarily intraventricularly, but may arise infratentorially, in the cauda, and even extraneurally, along nerve roots.[110,111] Medulloepithelioma with the classic molecular change is considered an ETMR.
Pineoblastoma
Pineoblastoma, which was previously conventionally grouped with embryonal tumors, is now categorized by the WHO as a pineal parenchymal tumor. Given that therapies for pineoblastoma are quite similar to those utilized for embryonal tumors, the previous convention of including pineoblastoma with the CNS embryonal tumors is followed here. Pineoblastoma is associated with germline mutations in both the retinoblastoma (RB1) gene and in DICER1, as described below:
  • Pineoblastoma is associated with germline mutations in RB1, with the term trilateral retinoblastoma used to refer to ocular retinoblastoma in combination with a histologically similar brain tumor generally arising in the pineal gland or other midline structures. Historically, intracranial tumors have been reported in 5% to 15% of children with heritable retinoblastoma.[112] Rates of pineoblastoma among children with heritable retinoblastoma who undergo current treatment programs may be lower than these historical estimates.[113-115]
  • Germline DICER1 mutations have also been reported in patients with pineoblastoma.[116] Among 18 patients with pineoblastoma, three patients with DICER1 germline mutations were identified, and an additional three patients known to be carriers of germline DICER1 mutations developed pineoblastoma.[116] The DICER1 mutations in patients with pineoblastoma are loss-of-function mutations that appear to be distinct from the mutations observed in DICER1 syndrome–related tumors such as pleuropulmonary blastoma.[116]
(Refer to the PDQ summary on Childhood Central Nervous System Embryonal Tumors Treatment for information about the treatment of childhood PNETs.)

Ependymomas

Molecular characterization studies have identified several biological subtypes of ependymoma based on their distinctive DNA methylation and gene expression profiles and on their distinctive spectrum of genomic alterations (refer to Figure 6).[117-119]
  • Infratentorial tumors.
    • Posterior fossa A, CpG island methylator phenotype (CIMP)-positive ependymoma, termed EPN-PFA.
    • Posterior fossa B, CIMP-negative ependymoma, termed EPN-PFB.
  • Supratentorial tumors.
    • C11orf95-RELA–positive ependymoma.
    • C11orf95-RELA–negative and YAP1 fusion–positive ependymoma.
  • Spinal tumors.
ENLARGEGraph showing key molecular and clinical characteristics of ependymal tumor subgroups.
Figure 6. Graphical summary of key molecular and clinical characteristics of ependymal tumor subgroups. Schematic representation of key genetic and epigenetic findings in the nine molecular subgroups of ependymal tumors as identified by methylation profiling. CIN, Chromosomal instability. Reprinted from Cancer Cell, Volume 27, Kristian W. Pajtler, Hendrik Witt, Martin Sill, David T.W. Jones, Volker Hovestadt, Fabian Kratochwil, Khalida Wani, Ruth Tatevossian, Chandanamali Punchihewa, Pascal Johann, Juri Reimand, Hans-Jorg Warnatz, Marina Ryzhova, Steve Mack, Vijay Ramaswamy, David Capper, Leonille Schweizer, Laura Sieber, Andrea Wittmann, Zhiqin Huang, Peter van Sluis, Richard Volckmann, Jan Koster, Rogier Versteeg, Daniel Fults, Helen Toledano, Smadar Avigad, Lindsey M. Hoffman, Andrew M. Donson, Nicholas Foreman, Ekkehard Hewer, Karel Zitterbart, Mark Gilbert, Terri S. Armstrong, Nalin Gupta, Jeffrey C. Allen, Matthias A. Karajannis, David Zagzag, Martin Hasselblatt, Andreas E. Kulozik, Olaf Witt, V. Peter Collins, Katja von Hoff, Stefan Rutkowski, Torsten Pietsch, Gary Bader, Marie-Laure Yaspo, Andreas von Deimling, Peter Lichter, Michael D. Taylor, Richard Gilbertson, David W. Ellison, Kenneth Aldape, Andrey Korshunov, Marcel Kool, and Stefan M. Pfister, Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups, Pages 728–743, Copyright (2015), with permission from Elsevier.
Approximately two-thirds of childhood ependymomas arise in the posterior fossa, and two major genomically defined subtypes of posterior fossa tumors are recognized. Similarly, most pediatric supratentorial tumors can be categorized into one of two genomic subtypes. These subtypes and their associated clinical characteristics are described below.[117] Among these subtypes, the 2016 World Health Organization (WHO) classification has accepted ependymoma, RELA fusion–positive, as a distinct diagnostic entity.[1]
The most common posterior fossa ependymoma subtype is EPN-PFA and is characterized by the following:
  • Presentation in young children (median age, 3 years).[117]
  • Low rates of mutations that affect protein structure (approximately five per genome), with no recurring mutations.[118]
  • A balanced chromosomal profile (refer to Figure 7) with few chromosomal gains or losses.[117,118]
    ENLARGEChart showing the identification of subgroup-specific copy number alterations in the posterior fossa ependymoma genome.
    Figure 7. Identification of Subgroup-Specific Copy Number Alterations in the Posterior Fossa Ependymoma Genome. (A) Copy number profiling of 75 PF ependymomas using 10K array-CGH identifies disparate genetic landscapes between Group A and Group B tumors. Toronto and Heidelberg copy number datasets have been combined and summarized in a heatmap. The heatmap also displays the association of tumors to cytogenetic risk groups 1, 2, and 3 (Korshunov et al., 2010). Statistically significant chromosomal aberrations (black boxes) are also displayed between both subgroups, calculated by Fisher's exact test. Witt H, Mack SC, Ryzhova M, et al.: Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell 20 (2): 143-57, 2011, doi:10.1016/j.ccr.2011.07.007. Copyright © 2011 Elsevier Inc. All rights reserved.
  • Gain of chromosome 1q, a known poor prognostic factor for ependymomas,[120] in approximately 25% of cases.[117,119]
  • Presence of the CIMP (i.e., CIMP positive).[119]
  • High rates of disease recurrence (33% progression-free survival [PFS] at 5 years) and low survival rates compared with other subtypes (68% at 5 years).[117]
The EPN-PFB subtype is less common than the EPN-PFA subtype in children and is characterized by the following:
  • Presentation primarily in adolescents and young adults (median age, 30 years).[117]
  • Low rates of mutations that affect protein structure (approximately five per genome), with no recurring mutations.[119]
  • Numerous cytogenetic abnormalities (refer to Figure 7), primarily involving the gain/loss of whole chromosomes.[117,119]
  • Absence of the CIMP (i.e., CIMP negative).[119]
  • Favorable outcome in comparison to EPN-PFA, with 5-year PFS of 73% and overall survival (OS) of 100%.[117]
The largest subset of pediatric supratentorial (ST) ependymomas are characterized by gene fusions involving RELA,[121,122] a transcriptional factor important in NF-κB pathway activity. This subtype is termed ST-EPN-RELA and is characterized by the following:
  • Represents approximately 70% of supratentorial ependymomas in children,[121,122] and presents at a median age of 8 years.[117]
  • Presence of C11orf95-RELA fusions resulting from chromothripsis involving chromosome 11q13.1.[121]
  • Evidence of NF-κB pathway activation at the protein and RNA level.[121]
  • Low rates of mutations that affect protein structure and absence of recurring mutations outside of C11orf95-RELA fusions.[121]
  • Presence of homozygous deletions of CDKN2A, a known poor prognostic factor for ependymomas,[120] in approximately 15% of cases.[117]
  • Gain of chromosome 1q, a known poor prognostic factor for ependymomas, in approximately one-quarter of cases.[117]
  • Unfavorable outcome in comparison to other ependymoma subtypes, with 5-year PFS of 29% and OS of 75%.[117]
  • Supratentorial clear cell ependymomas with branching capillaries commonly show the C11orf95-RELA fusion,[123] and one series of 20 patients with a median age of 10.4 years showed a relatively favorable prognosis (5-year PFS of 68% and OS of 72%).[123]
A second, less common subset of supratentorial ependymomas, termed ST-EPN-YAP1, has fusions involving YAP1 and are characterized by the following:
  • Median age at diagnosis of 1.4 years.[117]
  • Presence of a gene fusion involving YAP1, with MAMLD1 being the most common fusion partner.[117,121]
  • A relatively stable genome with few chromosomal changes other than the YAP1 fusion.[117]
  • Relatively favorable prognosis (although based on small numbers), with a 5-year PFS of 66% and OS of 100%.[117]
Clinical implications of genomic alterations
The absence of recurring mutations in the EPN-PFA and EPN-PFB subtypes at diagnosis precludes using their genomic profiles to guide therapy. The RELA and YAP1 fusion genes present in supratentorial ependymomas are not directly targetable with agents in the clinic, but can provide leads for future research.
(Refer to the PDQ summary on Childhood Ependymoma Treatment for information about the treatment of childhood ependymoma.)

References
  1. Louis DN, Perry A, Reifenberger G, et al.: The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 131 (6): 803-20, 2016. [PUBMED Abstract]
  2. Bar EE, Lin A, Tihan T, et al.: Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma. J Neuropathol Exp Neurol 67 (9): 878-87, 2008. [PUBMED Abstract]
  3. Forshew T, Tatevossian RG, Lawson AR, et al.: Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas. J Pathol 218 (2): 172-81, 2009. [PUBMED Abstract]
  4. Jones DT, Kocialkowski S, Liu L, et al.: Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 68 (21): 8673-7, 2008. [PUBMED Abstract]
  5. Jones DT, Kocialkowski S, Liu L, et al.: Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma. Oncogene 28 (20): 2119-23, 2009. [PUBMED Abstract]
  6. Pfister S, Janzarik WG, Remke M, et al.: BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest 118 (5): 1739-49, 2008. [PUBMED Abstract]
  7. Korshunov A, Meyer J, Capper D, et al.: Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. Acta Neuropathol 118 (3): 401-5, 2009. [PUBMED Abstract]
  8. Horbinski C, Hamilton RL, Nikiforov Y, et al.: Association of molecular alterations, including BRAF, with biology and outcome in pilocytic astrocytomas. Acta Neuropathol 119 (5): 641-9, 2010. [PUBMED Abstract]
  9. Yu J, Deshmukh H, Gutmann RJ, et al.: Alterations of BRAF and HIPK2 loci predominate in sporadic pilocytic astrocytoma. Neurology 73 (19): 1526-31, 2009. [PUBMED Abstract]
  10. Lin A, Rodriguez FJ, Karajannis MA, et al.: BRAF alterations in primary glial and glioneuronal neoplasms of the central nervous system with identification of 2 novel KIAA1549:BRAF fusion variants. J Neuropathol Exp Neurol 71 (1): 66-72, 2012. [PUBMED Abstract]
  11. Hawkins C, Walker E, Mohamed N, et al.: BRAF-KIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma. Clin Cancer Res 17 (14): 4790-8, 2011. [PUBMED Abstract]
  12. Becker AP, Scapulatempo-Neto C, Carloni AC, et al.: KIAA1549: BRAF Gene Fusion and FGFR1 Hotspot Mutations Are Prognostic Factors in Pilocytic Astrocytomas. J Neuropathol Exp Neurol 74 (7): 743-54, 2015. [PUBMED Abstract]
  13. Janzarik WG, Kratz CP, Loges NT, et al.: Further evidence for a somatic KRAS mutation in a pilocytic astrocytoma. Neuropediatrics 38 (2): 61-3, 2007. [PUBMED Abstract]
  14. Horbinski C, Nikiforova MN, Hagenkord JM, et al.: Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas. Neuro Oncol 14 (6): 777-89, 2012. [PUBMED Abstract]
  15. Roth JJ, Fierst TM, Waanders AJ, et al.: Whole Chromosome 7 Gain Predicts Higher Risk of Recurrence in Pediatric Pilocytic Astrocytomas Independently From KIAA1549-BRAF Fusion Status. J Neuropathol Exp Neurol 75 (4): 306-15, 2016. [PUBMED Abstract]
  16. Mistry M, Zhukova N, Merico D, et al.: BRAF mutation and CDKN2A deletion define a clinically distinct subgroup of childhood secondary high-grade glioma. J Clin Oncol 33 (9): 1015-22, 2015. [PUBMED Abstract]
  17. Dougherty MJ, Santi M, Brose MS, et al.: Activating mutations in BRAF characterize a spectrum of pediatric low-grade gliomas. Neuro Oncol 12 (7): 621-30, 2010. [PUBMED Abstract]
  18. Dias-Santagata D, Lam Q, Vernovsky K, et al.: BRAF V600E mutations are common in pleomorphic xanthoastrocytoma: diagnostic and therapeutic implications. PLoS One 6 (3): e17948, 2011. [PUBMED Abstract]
  19. Schindler G, Capper D, Meyer J, et al.: Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 121 (3): 397-405, 2011. [PUBMED Abstract]
  20. Lassaletta A, Zapotocky M, Mistry M, et al.: Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas. J Clin Oncol 35 (25): 2934-2941, 2017. [PUBMED Abstract]
  21. Ho CY, Mobley BC, Gordish-Dressman H, et al.: A clinicopathologic study of diencephalic pediatric low-grade gliomas with BRAF V600 mutation. Acta Neuropathol 130 (4): 575-85, 2015. [PUBMED Abstract]
  22. Bandopadhayay P, Ramkissoon LA, Jain P, et al.: MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nat Genet 48 (3): 273-82, 2016. [PUBMED Abstract]
  23. Jones DT, Hutter B, Jäger N, et al.: Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet 45 (8): 927-32, 2013. [PUBMED Abstract]
  24. Zhang J, Wu G, Miller CP, et al.: Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet 45 (6): 602-12, 2013. [PUBMED Abstract]
  25. Ramkissoon LA, Horowitz PM, Craig JM, et al.: Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1. Proc Natl Acad Sci U S A 110 (20): 8188-93, 2013. [PUBMED Abstract]
  26. Franz DN, Belousova E, Sparagana S, et al.: Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 381 (9861): 125-32, 2013. [PUBMED Abstract]
  27. Qaddoumi I, Orisme W, Wen J, et al.: Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology. Acta Neuropathol 131 (6): 833-45, 2016. [PUBMED Abstract]
  28. Pollack IF, Hamilton RL, Sobol RW, et al.: IDH1 mutations are common in malignant gliomas arising in adolescents: a report from the Children's Oncology Group. Childs Nerv Syst 27 (1): 87-94, 2011. [PUBMED Abstract]
  29. Paugh BS, Qu C, Jones C, et al.: Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J Clin Oncol 28 (18): 3061-8, 2010. [PUBMED Abstract]
  30. Bax DA, Mackay A, Little SE, et al.: A distinct spectrum of copy number aberrations in pediatric high-grade gliomas. Clin Cancer Res 16 (13): 3368-77, 2010. [PUBMED Abstract]
  31. Ward SJ, Karakoula K, Phipps KP, et al.: Cytogenetic analysis of paediatric astrocytoma using comparative genomic hybridisation and fluorescence in-situ hybridisation. J Neurooncol 98 (3): 305-18, 2010. [PUBMED Abstract]
  32. Sturm D, Witt H, Hovestadt V, et al.: Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22 (4): 425-37, 2012. [PUBMED Abstract]
  33. Korshunov A, Ryzhova M, Hovestadt V, et al.: Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers. Acta Neuropathol 129 (5): 669-78, 2015. [PUBMED Abstract]
  34. Mackay A, Burford A, Carvalho D, et al.: Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma. Cancer Cell 32 (4): 520-537.e5, 2017. [PUBMED Abstract]
  35. Buczkowicz P, Hoeman C, Rakopoulos P, et al.: Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nat Genet 46 (5): 451-6, 2014. [PUBMED Abstract]
  36. Taylor KR, Mackay A, Truffaux N, et al.: Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. Nat Genet 46 (5): 457-61, 2014. [PUBMED Abstract]
  37. Korshunov A, Schrimpf D, Ryzhova M, et al.: H3-/IDH-wild type pediatric glioblastoma is comprised of molecularly and prognostically distinct subtypes with associated oncogenic drivers. Acta Neuropathol 134 (3): 507-516, 2017. [PUBMED Abstract]
  38. Gielen GH, Gessi M, Buttarelli FR, et al.: Genetic Analysis of Diffuse High-Grade Astrocytomas in Infancy Defines a Novel Molecular Entity. Brain Pathol 25 (4): 409-17, 2015. [PUBMED Abstract]
  39. Ryall S, Krishnatry R, Arnoldo A, et al.: Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberrations in paediatric thalamic glioma. Acta Neuropathol Commun 4 (1): 93, 2016. [PUBMED Abstract]
  40. Wu G, Broniscer A, McEachron TA, et al.: Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 44 (3): 251-3, 2012. [PUBMED Abstract]
  41. Wu G, Diaz AK, Paugh BS, et al.: The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet 46 (5): 444-50, 2014. [PUBMED Abstract]
  42. Fontebasso AM, Papillon-Cavanagh S, Schwartzentruber J, et al.: Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. Nat Genet 46 (5): 462-6, 2014. [PUBMED Abstract]
  43. Schwartzentruber J, Korshunov A, Liu XY, et al.: Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482 (7384): 226-31, 2012. [PUBMED Abstract]
  44. Hoffman LM, DeWire M, Ryall S, et al.: Spatial genomic heterogeneity in diffuse intrinsic pontine and midline high-grade glioma: implications for diagnostic biopsy and targeted therapeutics. Acta Neuropathol Commun 4: 1, 2016. [PUBMED Abstract]
  45. Shore EM, Xu M, Feldman GJ, et al.: A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet 38 (5): 525-7, 2006. [PUBMED Abstract]
  46. Zarghooni M, Bartels U, Lee E, et al.: Whole-genome profiling of pediatric diffuse intrinsic pontine gliomas highlights platelet-derived growth factor receptor alpha and poly (ADP-ribose) polymerase as potential therapeutic targets. J Clin Oncol 28 (8): 1337-44, 2010. [PUBMED Abstract]
  47. Paugh BS, Broniscer A, Qu C, et al.: Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma. J Clin Oncol 29 (30): 3999-4006, 2011. [PUBMED Abstract]
  48. Khuong-Quang DA, Buczkowicz P, Rakopoulos P, et al.: K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol 124 (3): 439-47, 2012. [PUBMED Abstract]
  49. Cohen KJ, Heideman RL, Zhou T, et al.: Temozolomide in the treatment of children with newly diagnosed diffuse intrinsic pontine gliomas: a report from the Children's Oncology Group. Neuro Oncol 13 (4): 410-6, 2011. [PUBMED Abstract]
  50. Biegel JA, Tan L, Zhang F, et al.: Alterations of the hSNF5/INI1 gene in central nervous system atypical teratoid/rhabdoid tumors and renal and extrarenal rhabdoid tumors. Clin Cancer Res 8 (11): 3461-7, 2002. [PUBMED Abstract]
  51. Hasselblatt M, Nagel I, Oyen F, et al.: SMARCA4-mutated atypical teratoid/rhabdoid tumors are associated with inherited germline alterations and poor prognosis. Acta Neuropathol 128 (3): 453-6, 2014. [PUBMED Abstract]
  52. Lee RS, Stewart C, Carter SL, et al.: A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers. J Clin Invest 122 (8): 2983-8, 2012. [PUBMED Abstract]
  53. Kieran MW, Roberts CW, Chi SN, et al.: Absence of oncogenic canonical pathway mutations in aggressive pediatric rhabdoid tumors. Pediatr Blood Cancer 59 (7): 1155-7, 2012. [PUBMED Abstract]
  54. Hasselblatt M, Isken S, Linge A, et al.: High-resolution genomic analysis suggests the absence of recurrent genomic alterations other than SMARCB1 aberrations in atypical teratoid/rhabdoid tumors. Genes Chromosomes Cancer 52 (2): 185-90, 2013. [PUBMED Abstract]
  55. Biegel JA, Kalpana G, Knudsen ES, et al.: The role of INI1 and the SWI/SNF complex in the development of rhabdoid tumors: meeting summary from the workshop on childhood atypical teratoid/rhabdoid tumors. Cancer Res 62 (1): 323-8, 2002. [PUBMED Abstract]
  56. Schneppenheim R, Frühwald MC, Gesk S, et al.: Germline nonsense mutation and somatic inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor predisposition syndrome. Am J Hum Genet 86 (2): 279-84, 2010. [PUBMED Abstract]
  57. Hasselblatt M, Gesk S, Oyen F, et al.: Nonsense mutation and inactivation of SMARCA4 (BRG1) in an atypical teratoid/rhabdoid tumor showing retained SMARCB1 (INI1) expression. Am J Surg Pathol 35 (6): 933-5, 2011. [PUBMED Abstract]
  58. Torchia J, Picard D, Lafay-Cousin L, et al.: Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis. Lancet Oncol 16 (5): 569-82, 2015. [PUBMED Abstract]
  59. Johann PD, Erkek S, Zapatka M, et al.: Atypical Teratoid/Rhabdoid Tumors Are Comprised of Three Epigenetic Subgroups with Distinct Enhancer Landscapes. Cancer Cell 29 (3): 379-93, 2016. [PUBMED Abstract]
  60. Johann PD, Hovestadt V, Thomas C, et al.: Cribriform neuroepithelial tumor: molecular characterization of a SMARCB1-deficient non-rhabdoid tumor with favorable long-term outcome. Brain Pathol 27 (4): 411-418, 2017. [PUBMED Abstract]
  61. Biegel JA, Fogelgren B, Wainwright LM, et al.: Germline INI1 mutation in a patient with a central nervous system atypical teratoid tumor and renal rhabdoid tumor. Genes Chromosomes Cancer 28 (1): 31-7, 2000. [PUBMED Abstract]
  62. Eaton KW, Tooke LS, Wainwright LM, et al.: Spectrum of SMARCB1/INI1 mutations in familial and sporadic rhabdoid tumors. Pediatr Blood Cancer 56 (1): 7-15, 2011. [PUBMED Abstract]
  63. Bruggers CS, Bleyl SB, Pysher T, et al.: Clinicopathologic comparison of familial versus sporadic atypical teratoid/rhabdoid tumors (AT/RT) of the central nervous system. Pediatr Blood Cancer 56 (7): 1026-31, 2011. [PUBMED Abstract]
  64. Wilson BG, Wang X, Shen X, et al.: Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation. Cancer Cell 18 (4): 316-28, 2010. [PUBMED Abstract]
  65. Knutson SK, Warholic NM, Wigle TJ, et al.: Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc Natl Acad Sci U S A 110 (19): 7922-7, 2013. [PUBMED Abstract]
  66. Kurmasheva RT, Sammons M, Favours E, et al.: Initial testing (stage 1) of tazemetostat (EPZ-6438), a novel EZH2 inhibitor, by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer 64 (3): , 2017. [PUBMED Abstract]
  67. Italiano A, Soria JC, Toulmonde M, et al.: Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study. Lancet Oncol 19 (5): 649-659, 2018. [PUBMED Abstract]
  68. Onvani S, Etame AB, Smith CA, et al.: Genetics of medulloblastoma: clues for novel therapies. Expert Rev Neurother 10 (5): 811-23, 2010. [PUBMED Abstract]
  69. Dubuc AM, Northcott PA, Mack S, et al.: The genetics of pediatric brain tumors. Curr Neurol Neurosci Rep 10 (3): 215-23, 2010. [PUBMED Abstract]
  70. Thompson MC, Fuller C, Hogg TL, et al.: Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol 24 (12): 1924-31, 2006. [PUBMED Abstract]
  71. Kool M, Koster J, Bunt J, et al.: Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PLoS One 3 (8): e3088, 2008. [PUBMED Abstract]
  72. Tabori U, Baskin B, Shago M, et al.: Universal poor survival in children with medulloblastoma harboring somatic TP53 mutations. J Clin Oncol 28 (8): 1345-50, 2010. [PUBMED Abstract]
  73. Pfister S, Remke M, Benner A, et al.: Outcome prediction in pediatric medulloblastoma based on DNA copy-number aberrations of chromosomes 6q and 17q and the MYC and MYCN loci. J Clin Oncol 27 (10): 1627-36, 2009. [PUBMED Abstract]
  74. Ellison DW, Onilude OE, Lindsey JC, et al.: beta-Catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children's Cancer Study Group Brain Tumour Committee. J Clin Oncol 23 (31): 7951-7, 2005. [PUBMED Abstract]
  75. Polkinghorn WR, Tarbell NJ: Medulloblastoma: tumorigenesis, current clinical paradigm, and efforts to improve risk stratification. Nat Clin Pract Oncol 4 (5): 295-304, 2007. [PUBMED Abstract]
  76. Giangaspero F, Wellek S, Masuoka J, et al.: Stratification of medulloblastoma on the basis of histopathological grading. Acta Neuropathol 112 (1): 5-12, 2006. [PUBMED Abstract]
  77. Northcott PA, Korshunov A, Witt H, et al.: Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 29 (11): 1408-14, 2011. [PUBMED Abstract]
  78. Pomeroy SL, Tamayo P, Gaasenbeek M, et al.: Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 415 (6870): 436-42, 2002. [PUBMED Abstract]
  79. Jones DT, Jäger N, Kool M, et al.: Dissecting the genomic complexity underlying medulloblastoma. Nature 488 (7409): 100-5, 2012. [PUBMED Abstract]
  80. Peyrl A, Chocholous M, Kieran MW, et al.: Antiangiogenic metronomic therapy for children with recurrent embryonal brain tumors. Pediatr Blood Cancer 59 (3): 511-7, 2012. [PUBMED Abstract]
  81. Taylor MD, Northcott PA, Korshunov A, et al.: Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol 123 (4): 465-72, 2012. [PUBMED Abstract]
  82. 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 123 (4): 473-84, 2012. [PUBMED Abstract]
  83. 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 128 (1): 137-49, 2014. [PUBMED Abstract]
  84. Morrissy AS, Cavalli FMG, Remke M, et al.: Spatial heterogeneity in medulloblastoma. Nat Genet 49 (5): 780-788, 2017. [PUBMED Abstract]
  85. Wang X, Dubuc AM, Ramaswamy V, et al.: Medulloblastoma subgroups remain stable across primary and metastatic compartments. Acta Neuropathol 129 (3): 449-57, 2015. [PUBMED Abstract]
  86. Cavalli FMG, Remke M, Rampasek L, et al.: Intertumoral Heterogeneity within Medulloblastoma Subgroups. Cancer Cell 31 (6): 737-754.e6, 2017. [PUBMED Abstract]
  87. Northcott PA, Buchhalter I, Morrissy AS, et al.: The whole-genome landscape of medulloblastoma subtypes. Nature 547 (7663): 311-317, 2017. [PUBMED Abstract]
  88. Cho YJ, Tsherniak A, Tamayo P, et al.: Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. J Clin Oncol 29 (11): 1424-30, 2011. [PUBMED Abstract]
  89. Gajjar A, Bowers DC, Karajannis MA, et al.: Pediatric Brain Tumors: Innovative Genomic Information Is Transforming the Diagnostic and Clinical Landscape. J Clin Oncol 33 (27): 2986-98, 2015. [PUBMED Abstract]
  90. Ellison DW, Dalton J, Kocak M, et al.: Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups. Acta Neuropathol 121 (3): 381-96, 2011. [PUBMED Abstract]
  91. Kool M, Jones DT, Jäger N, et al.: Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell 25 (3): 393-405, 2014. [PUBMED Abstract]
  92. Robinson GW, Rudneva VA, Buchhalter I, et al.: Risk-adapted therapy for young children with medulloblastoma (SJYC07): therapeutic and molecular outcomes from a multicentre, phase 2 trial. Lancet Oncol 19 (6): 768-784, 2018. [PUBMED Abstract]
  93. Leary SE, Zhou T, Holmes E, et al.: Histology predicts a favorable outcome in young children with desmoplastic medulloblastoma: a report from the children's oncology group. Cancer 117 (14): 3262-7, 2011. [PUBMED Abstract]
  94. Giangaspero F, Perilongo G, Fondelli MP, et al.: Medulloblastoma with extensive nodularity: a variant with favorable prognosis. J Neurosurg 91 (6): 971-7, 1999. [PUBMED Abstract]
  95. Rutkowski S, von Hoff K, Emser A, et al.: Survival and prognostic factors of early childhood medulloblastoma: an international meta-analysis. J Clin Oncol 28 (33): 4961-8, 2010. [PUBMED Abstract]
  96. Garrè ML, Cama A, Bagnasco F, et al.: Medulloblastoma variants: age-dependent occurrence and relation to Gorlin syndrome--a new clinical perspective. Clin Cancer Res 15 (7): 2463-71, 2009. [PUBMED Abstract]
  97. von Bueren AO, von Hoff K, Pietsch T, et al.: Treatment of young children with localized medulloblastoma by chemotherapy alone: results of the prospective, multicenter trial HIT 2000 confirming the prognostic impact of histology. Neuro Oncol 13 (6): 669-79, 2011. [PUBMED Abstract]
  98. Shih DJ, Northcott PA, Remke M, et al.: Cytogenetic prognostication within medulloblastoma subgroups. J Clin Oncol 32 (9): 886-96, 2014. [PUBMED Abstract]
  99. Schwalbe EC, Williamson D, Lindsey JC, et al.: DNA methylation profiling of medulloblastoma allows robust subclassification and improved outcome prediction using formalin-fixed biopsies. Acta Neuropathol 125 (3): 359-71, 2013. [PUBMED Abstract]
  100. Zhukova N, Ramaswamy V, Remke M, et al.: Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. J Clin Oncol 31 (23): 2927-35, 2013. [PUBMED Abstract]
  101. Gottardo NG, Hansford JR, McGlade JP, et al.: Medulloblastoma Down Under 2013: a report from the third annual meeting of the International Medulloblastoma Working Group. Acta Neuropathol 127 (2): 189-201, 2014. [PUBMED Abstract]
  102. Louis DN, Perry A, Burger P, et al.: International Society Of Neuropathology--Haarlem consensus guidelines for nervous system tumor classification and grading. Brain Pathol 24 (5): 429-35, 2014. [PUBMED Abstract]
  103. Northcott PA, Jones DT, Kool M, et al.: Medulloblastomics: the end of the beginning. Nat Rev Cancer 12 (12): 818-34, 2012. [PUBMED Abstract]
  104. Sturm D, Orr BA, Toprak UH, et al.: New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs. Cell 164 (5): 1060-72, 2016. [PUBMED Abstract]
  105. Korshunov A, Sturm D, Ryzhova M, et al.: Embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, and medulloepithelioma share molecular similarity and comprise a single clinicopathological entity. Acta Neuropathol 128 (2): 279-89, 2014. [PUBMED Abstract]
  106. Kleinman CL, Gerges N, Papillon-Cavanagh S, et al.: Fusion of TTYH1 with the C19MC microRNA cluster drives expression of a brain-specific DNMT3B isoform in the embryonal brain tumor ETMR. Nat Genet 46 (1): 39-44, 2014. [PUBMED Abstract]
  107. Li M, Lee KF, Lu Y, et al.: Frequent amplification of a chr19q13.41 microRNA polycistron in aggressive primitive neuroectodermal brain tumors. Cancer Cell 16 (6): 533-46, 2009. [PUBMED Abstract]
  108. Ueno-Yokohata H, Okita H, Nakasato K, et al.: Consistent in-frame internal tandem duplications of BCOR characterize clear cell sarcoma of the kidney. Nat Genet 47 (8): 861-3, 2015. [PUBMED Abstract]
  109. Roy A, Kumar V, Zorman B, et al.: Recurrent internal tandem duplications of BCOR in clear cell sarcoma of the kidney. Nat Commun 6: 8891, 2015. [PUBMED Abstract]
  110. Louis DN, Ohgaki H, Wiestler OD, et al.: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114 (2): 97-109, 2007. [PUBMED Abstract]
  111. Sharma MC, Mahapatra AK, Gaikwad S, et al.: Pigmented medulloepithelioma: report of a case and review of the literature. Childs Nerv Syst 14 (1-2): 74-8, 1998 Jan-Feb. [PUBMED Abstract]
  112. de Jong MC, Kors WA, de Graaf P, et al.: Trilateral retinoblastoma: a systematic review and meta-analysis. Lancet Oncol 15 (10): 1157-67, 2014. [PUBMED Abstract]
  113. Ramasubramanian A, Kytasty C, Meadows AT, et al.: Incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era. Am J Ophthalmol 156 (4): 825-9, 2013. [PUBMED Abstract]
  114. Abramson DH, Dunkel IJ, Marr BP, et al.: Incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era. Am J Ophthalmol 156 (6): 1319-20, 2013. [PUBMED Abstract]
  115. Turaka K, Shields CL, Meadows AT, et al.: Second malignant neoplasms following chemoreduction with carboplatin, etoposide, and vincristine in 245 patients with intraocular retinoblastoma. Pediatr Blood Cancer 59 (1): 121-5, 2012. [PUBMED Abstract]
  116. de Kock L, Sabbaghian N, Druker H, et al.: Germ-line and somatic DICER1 mutations in pineoblastoma. Acta Neuropathol 128 (4): 583-95, 2014. [PUBMED Abstract]
  117. Pajtler KW, Witt H, Sill M, et al.: Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups. Cancer Cell 27 (5): 728-43, 2015. [PUBMED Abstract]
  118. Witt H, Mack SC, Ryzhova M, et al.: Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell 20 (2): 143-57, 2011. [PUBMED Abstract]
  119. Mack SC, Witt H, Piro RM, et al.: Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 506 (7489): 445-50, 2014. [PUBMED Abstract]
  120. Korshunov A, Witt H, Hielscher T, et al.: Molecular staging of intracranial ependymoma in children and adults. J Clin Oncol 28 (19): 3182-90, 2010. [PUBMED Abstract]
  121. Parker M, Mohankumar KM, Punchihewa C, et al.: C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma. Nature 506 (7489): 451-5, 2014. [PUBMED Abstract]
  122. Pietsch T, Wohlers I, Goschzik T, et al.: Supratentorial ependymomas of childhood carry C11orf95-RELA fusions leading to pathological activation of the NF-κB signaling pathway. Acta Neuropathol 127 (4): 609-11, 2014. [PUBMED Abstract]
  123. Figarella-Branger D, Lechapt-Zalcman E, Tabouret E, et al.: Supratentorial clear cell ependymomas with branching capillaries demonstrate characteristic clinicopathological features and pathological activation of nuclear factor-kappaB signaling. Neuro Oncol 18 (7): 919-27, 2016. [PUBMED Abstract]

Hepatoblastoma and Hepatocellular Carcinoma


Genomic abnormalities related to hepatoblastoma include the following:
  • Hepatoblastoma mutation frequency, as determined by three groups using whole-exome sequencing, was very low (approximately three variants per tumor) in children younger than 5 years.[1-3]
  • Hepatoblastoma is primarily a disease of WNT pathway activation. The primary mechanism for WNT pathway activation is CTNNB1 activating mutations/deletions involving exon 3. CTNNB1 mutations have been reported in 70% of cases.[1] Rare causes of WNT pathway activation include mutations in AXIN1, AXIN2, and APC (APCseen only in cases associated with familial adenomatosis polyposis coli).[4]
  • The frequency of NFE2L2 mutations in hepatoblastoma specimens was reported to be 4 of 62 tumors (7%) in one study [2] and 5 of 51 specimens (10%) in another study.[1]
    Similar mutations have been found in many types of cancer, including hepatocellular carcinoma. These mutations render NFE2L2 insensitive to KEAP1-mediated degradation, leading to activation of the NFE2L2-KEAP1 pathway, which activates resistance to oxidative stress and is believed to confer resistance to chemotherapy.
  • Somatic mutations were identified in other genes related to regulation of oxidative stress, including inactivating mutations in the thioredoxin-domain containing genes, TXNDC15 and TXNDC16.[2]
  • Figure 8 shows the distribution of CTNNB1, NFE2L2, and TERT mutations in hepatoblastoma.[1]
    ENLARGEChart showing the distribution of CTNNB1, APC, NFE2L2, and TERT mutations for hepatoblastoma.
    Figure 8. Mutational status and functional relevance of NFE2L2 in hepatoblastoma. Clinicopathological characteristics and the mutational status of the CTNNB1, APC, and NFE2L2 genes, as well as the TERT promoter region are color-coded and depicted in rows for each tumor of our cohort of 43 hepatoblastoma (HB) patients and four transitional liver cell tumour (TLCT) patients and 4 HB cell lines. Reprinted from Journal of Hepatology, Volume 61 (Issue 6), Melanie Eichenmüller, Franziska Trippel, Michaela Kreuder, Alexander Beck, Thomas Schwarzmayr, Beate Häberle, Stefano Cairo, Ivo Leuschner, Dietrich von Schweinitz, Tim M. Strom, Roland Kappler, The genomic landscape of hepatoblastoma and their progenies with HCC-like features, Pages 1312–1320, Copyright 2014, with permission from Elsevier.
To date, these genetic mutations have not been used to select therapeutic agents for investigation in clinical trials.
Genomic abnormalities related to hepatocellular carcinoma include the following:
  • A first case of pediatric hepatocellular carcinoma was analyzed by whole-exome sequencing, which showed a higher mutation rate (53 variants) and the coexistence of CTNNB1 and NFE2L2 mutations.[5]
  • Fibrolamellar hepatocellular carcinoma is a rare subtype of hepatocellular carcinoma observed in older children. It is characterized by an approximately 400 kB deletion on chromosome 19 that results in production of a chimeric RNA coding for a protein containing the amino-terminal domain of DNAJB1, a homolog of the molecular chaperone DNAJ, fused in frame with PRKACA, the catalytic domain of protein kinase A.[6]
  • A rare, more aggressive subtype of childhood liver cancer (hepatocellular neoplasm, not otherwise specified, also termed transitional liver cell tumor) occurs in older children, and it has clinical and histopathological findings of both hepatoblastoma and hepatocellular carcinoma.
    TERT mutations were observed in two of four cases tested.[1] TERT mutations are also commonly observed in adults with hepatocellular carcinoma.[7]
To date, these genetic mutations have not been used to select therapeutic agents for investigation in clinical trials.

(Refer to the PDQ summary on Childhood Liver Cancer Treatment for information about the treatment of liver cancer.)
References
  1. Eichenmüller M, Trippel F, Kreuder M, et al.: The genomic landscape of hepatoblastoma and their progenies with HCC-like features. J Hepatol 61 (6): 1312-20, 2014. [PUBMED Abstract]
  2. Trevino LR, Wheeler DA, Finegold MJ, et al.: Exome sequencing of hepatoblastoma reveals recurrent mutations in NFE2L2. [Abstract] Cancer Res 73 (8 Suppl): A-4592, 2013. Also available online. Last accessed November 09, 2018.
  3. Jia D, Dong R, Jing Y, et al.: Exome sequencing of hepatoblastoma reveals novel mutations and cancer genes in the Wnt pathway and ubiquitin ligase complex. Hepatology 60 (5): 1686-96, 2014. [PUBMED Abstract]
  4. Hiyama E, Kurihara S, Onitake Y: Integrated exome analysis in childhood hepatoblastoma: Biological approach for next clinical trial designs. [Abstract] Cancer Res 74 (19 Suppl): A-5188, 2014.
  5. Vilarinho S, Erson-Omay EZ, Harmanci AS, et al.: Paediatric hepatocellular carcinoma due to somatic CTNNB1 and NFE2L2 mutations in the setting of inherited bi-allelic ABCB11 mutations. J Hepatol 61 (5): 1178-83, 2014. [PUBMED Abstract]
  6. Honeyman JN, Simon EP, Robine N, et al.: Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science 343 (6174): 1010-4, 2014. [PUBMED Abstract]
  7. Nault JC, Mallet M, Pilati C, et al.: High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat Commun 4: 2218, 2013. [PUBMED Abstract]
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