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Molecular Aspects of Hepatoblastoma

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Book cover Pediatric Liver Tumors

Part of the book series: Pediatric Oncology ((PEDIATRICO))

Abstract

Hepatoblastoma (HB) is a rare malignancy of the liver affecting mainly children between 6 months and 3 years of age. As this tumor recapitulates the phenotypic and biological features of the developing liver, many processes known to be essential in early embryonic development are implicated in the genesis of HB. This chapter describes the molecular mechanisms by which HB is thought to develop and progress, including alterations of the Wnt and hedgehog signaling pathways, the insulin-like growth factor axis, the hepatocytes growth factor/c-Met pathway, and epigenetically regulated genes. How this knowledge is currently translated into clinics is furthermore discussed, with a focus on establishing diagnostic tools, systems for predicting prognosis, response to therapy, and potential novel therapeutic strategies.

Hepatoblastoma (HB) is a rare malignancy of the liver affecting mainly children between 6 months and 3 years of age. As this tumor recapitulates the phenotypic and biological features of the developing liver, many processes known to be essential in early embryonic development are implicated in the genesis of HB. This chapter describes the molecular mechanisms by which HB is thought to develop and progress, including alterations of the Wnt and hedgehog signaling pathways, the insulin-like growth factor axis, the hepatocytes growth factor/c-Met pathway, and epigenetically regulated genes. How this knowledge is currently translated into clinics is furthermore discussed, with a focus on establishing diagnostic tools, systems for predicting prognosis, response to therapy, and potential novel therapeutic strategies.

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References

  • Adesina AM, Nguyen Y, Guanaratne P, Pulliam J, Lopez-Terrada D, Margolin J, Finegold M (2007) FOXG1 is overexpressed in hepatoblastoma. Hum Pathol 38:400–409

    Article  CAS  PubMed  Google Scholar 

  • Albrecht S, von Schweinitz D, Waha A, Kraus JA, von Deimling A, Pietsch T (1994) Loss of maternal alleles on chromosome arm 11p in hepatoblastoma. Cancer Res 54:5041–5044

    CAS  PubMed  Google Scholar 

  • Anderson J, Gordon A, McManus A, Shipley J, Pritchard-Jones K (1999) Disruption of imprinted genes at chromosome region 11p15.5 in paediatric rhabdomyosarcoma. Neoplasia 1:340–348

    Article  CAS  PubMed  Google Scholar 

  • Aretz S, Koch A, Uhlhaas S, Friedl W, Propping P, von Schweinitz D, Pietsch T (2006) Should children at risk for familial adenomatous polyposis be screened for hepatoblastoma and children with apparently sporadic hepatoblastoma be screened for APC germline mutations? Pediatr Blood Cancer 47:811–818

    Article  PubMed  Google Scholar 

  • Avruch J, Xavier R, Bardeesy N, Zhang XF, Praskova M, Zhou D, Xia F (2009) Rassf family of tumor suppressor polypeptides. J Biol Chem 284:11001–11005

    Article  CAS  PubMed  Google Scholar 

  • Baylin SB, Ohm JE (2006) Epigenetic gene silencing in cancer – a mechanism for early oncogenic pathway addiction? Nat Rev Cancer 6:107–116

    Article  CAS  PubMed  Google Scholar 

  • Behmel A, Plochl E, Rosenkranz W (1984) A new X-linked dysplasia gigantism syndrome: identical with the Simpson dysplasia syndrome? Hum Genet 67:409–413

    Article  CAS  PubMed  Google Scholar 

  • Bigelow RL, Chari NS, Unden AB, Spurgers KB, Lee S, Roop DR, Toftgard R, McDonnell TJ (2004) Transcriptional regulation of bcl-2 mediated by the sonic hedgehog signaling pathway through gli-1. J Biol Chem 279:1197–1205

    Article  CAS  PubMed  Google Scholar 

  • Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF (2003) Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4:915–925

    Article  CAS  PubMed  Google Scholar 

  • Cairo S, Armengol C, De Reynies A, Wei Y, Thomas E, Renard CA, Goga A, Balakrishnan A, Semeraro M, Gresh L, Pontoglio M, Strick-Marchand H, Levillayer F, Nouet Y, Rickman D, Gauthier F, Branchereau S, Brugieres L, Laithier V, Bouvier R, Boman F, Basso G, Michiels JF, Hofman P, Arbez-Gindre F, Jouan H, Rousselet-Chapeau MC, Berrebi D, Marcellin L, Plenat F, Zachar D, Joubert M, Selves J, Pasquier D, Bioulac-Sage P, Grotzer M, Childs M, Fabre M, Buendia MA (2008) Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer. Cancer Cell 14:471–484

    Article  CAS  PubMed  Google Scholar 

  • Chuang PT, McMahon AP (1999) Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 397:617–621

    Article  CAS  PubMed  Google Scholar 

  • Clemmons DR (1997) Insulin-like growth factor binding proteins and their role in controlling IGF actions. Cytokine Growth Factor Rev 8:45–62

    Article  CAS  PubMed  Google Scholar 

  • Clericuzio CL, Chen E, McNeil DE, O’Connor T, Zackai EH, Medne L, Tomlinson G, DeBaun M (2003) Serum alpha-fetoprotein screening for hepatoblastoma in children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia. J Pediatr 143:270–272

    Article  PubMed  Google Scholar 

  • Cole TR, Hughes HE (1994) Sotos syndrome: a study of the diagnostic criteria and natural history. J Med Genet 31: 20–32

    Article  CAS  PubMed  Google Scholar 

  • Curia MC, Zuckermann M, De Lellis L, Catalano T, Lattanzio R, Aceto G, Veschi S, Cama A, Otte JB, Piantelli M, Mariani-Costantini R, Cetta F, Battista P (2008) Sporadic childhood hepatoblastomas show activation of beta-catenin, mismatch repair defects and p53 mutations. Mod Pathol 21:7–14

    Article  CAS  PubMed  Google Scholar 

  • Eckschlager T, Adam V, Hrabeta J, Figova K, Kizek R (2009) Metallothioneins and cancer. Curr Protein Pept Sci 10:360–375

    Article  CAS  PubMed  Google Scholar 

  • Eichenmuller M, Gruner I, Hagl B, Haberle B, Muller-Hocker J, von Schweinitz D, Kappler R (2009) Blocking the hedgehog pathway inhibits hepatoblastoma growth. Hepatology 49:482–490

    Article  PubMed  CAS  Google Scholar 

  • Engstrom W, Lindham S, Schofield P (1988) Wiedemann–Beckwith syndrome. Eur J Pediatr 147:450–457

    Article  CAS  PubMed  Google Scholar 

  • Eriksson T, Frisk T, Gray SG, von Schweinitz D, Pietsch T, Larsson C, Sandstedt B, Ekstrom TJ (2001) Methylation changes in the human IGF2 p3 promoter parallel IGF2 expression in the primary tumor, established cell line, and xenograft of a human hepatoblastoma. Exp Cell Res 270: 88–95

    Article  CAS  PubMed  Google Scholar 

  • Esteller M (2002) CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene 21:5427–5440

    Article  CAS  PubMed  Google Scholar 

  • Feinberg AP (1993) Genomic imprinting and gene activation in cancer. Nat Genet 4:110–113

    Article  CAS  PubMed  Google Scholar 

  • Feinberg AP, Tycko B (2004) The history of cancer epigenetics. Nat Rev Cancer 4:143–153

    Article  CAS  PubMed  Google Scholar 

  • Fulda S (2009) Caspase-8 in cancer biology and therapy. Cancer Lett 281:128–133

    Article  CAS  PubMed  Google Scholar 

  • Gan L, Guo K, Li Y, Kang X, Sun L, Shu H, Liu Y (2010) Up-regulated expression of stathmin may be associated with hepatocarcinogenesis. Oncol Rep 23:1037–1043

    CAS  PubMed  Google Scholar 

  • Giardiello FM, Petersen GM, Brensinger JD, Luce MC, Cayouette MC, Bacon J, Booker SV, Hamilton SR (1996) Hepatoblastoma and APC gene mutation in familial adenomatous polyposis. Gut 39:867–869

    Article  CAS  PubMed  Google Scholar 

  • Golabi M, Ito M, Hall BD (1984) A new X-linked multiple congenital anomalies/mental retardation syndrome. Am J Med Genet 17:367–374

    Article  CAS  PubMed  Google Scholar 

  • Goodrich LV, Johnson RL, Milenkovic L, McMahon JA, Scott MP (1996) Conservation of the hedgehog/patched signaling pathway from flies to mice: induction of a mouse patched gene by Hedgehog. Genes Dev 10:301–312

    Article  CAS  PubMed  Google Scholar 

  • Gorlin RJ (1987) Nevoid basal-cell carcinoma syndrome. Medicine (Baltimore) 66:98–113

    CAS  Google Scholar 

  • Gray SG, Eriksson T, Ekstrom C, Holm S, von Schweinitz D, Kogner P, Sandstedt B, Pietsch T, Ekstrom TJ (2000a) Altered expression of members of the IGF-axis in hepatoblastomas. Br J Cancer 82:1561–1567

    Article  CAS  PubMed  Google Scholar 

  • Gray SG, Kytola S, Matsunaga T, Larsson C, Ekstrom TJ (2000b) Comparative genomic hybridization reveals population-based genetic alterations in hepatoblastomas. Br J Cancer 83:1020–1025

    Article  CAS  PubMed  Google Scholar 

  • Grotegut S, von Schweinitz D, Christofori G, Lehembre F (2006) Hepatocyte growth factor induces cell scattering through MAPK/Egr-1-mediated upregulation of Snail. EMBO J 25:3534–3545

    Article  CAS  PubMed  Google Scholar 

  • Grotegut S, Kappler R, Tarimoradi S, Lehembre F, Christofori G, Von Schweinitz D (2010) Hepatocyte growth factor protects hepatoblastoma cells from chemotherapy-induced apoptosis by AKT activation. Int J Oncol 36:1261–1267

    CAS  PubMed  Google Scholar 

  • Haas JE, Feusner JH, Finegold MJ (2001) Small cell undifferentiated histology in hepatoblastoma may be unfavorable. Cancer 92:3130–3134

    Article  CAS  PubMed  Google Scholar 

  • Hahn H, Wojnowski L, Specht K, Kappler R, Calzada-Wack J, Potter D, Zimmer A, Muller U, Samson E, Quintanilla-Martinez L (2000) Patched target Igf2 is indispensable for the formation of medulloblastoma and rhabdomyosarcoma. J Biol Chem 275:28341–28344

    Article  CAS  PubMed  Google Scholar 

  • Harada K, Toyooka S, Maitra A, Maruyama R, Toyooka KO, Timmons CF, Tomlinson GE, Mastrangelo D, Hay RJ, Minna JD, Gazdar AF (2002) Aberrant promoter methylation and silencing of the RASSF1A gene in pediatric tumors and cell lines. Oncogene 21:4345–4349

    Article  CAS  PubMed  Google Scholar 

  • Hartmann W, Waha A, Koch A, Goodyer CG, Albrecht S, von Schweinitz D, Pietsch T (2000) p57(KIP2) is not mutated in hepatoblastoma but shows increased transcriptional activity in a comparative analysis of the three imprinted genes p57(KIP2), IGF2, and H19. Am J Pathol 157:1393–1403

    CAS  PubMed  Google Scholar 

  • Hartmann W, Kuchler J, Koch A, Friedrichs N, Waha A, Endl E, Czerwitzki J, Metzger D, Steiner S, Wurst P, Leuschner I, von Schweinitz D, Buettner R, Pietsch T (2009) Activation of phosphatidylinositol-3′-kinase/AKT signaling is essential in hepatoblastoma survival. Clin Cancer Res 15:4538–4545

    Article  CAS  PubMed  Google Scholar 

  • He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW (1998) Identification of c-MYC as a target of the APC pathway. Science 281:1509–1512

    Article  CAS  PubMed  Google Scholar 

  • Honda S, Arai Y, Haruta M, Sasaki F, Ohira M, Yamaoka H, Horie H, Nakagawara A, Hiyama E, Todo S, Kaneko Y (2008a) Loss of imprinting of IGF2 correlates with hypermethylation of the H19 differentially methylated region in hepatoblastoma. Br J Cancer 99:1891–1899

    Article  CAS  PubMed  Google Scholar 

  • Honda S, Haruta M, Sugawara W, Sasaki F, Ohira M, Matsunaga T, Yamaoka H, Horie H, Ohnuma N, Nakagawara A, Hiyama E, Todo S, Kaneko Y (2008b) The methylation status of RASSF1A promoter predicts responsiveness to chemotherapy and eventual cure in hepatoblastoma patients. Int J Cancer 123:1117–1125

    Article  CAS  PubMed  Google Scholar 

  • Hughes LJ, Michels VV (1992) Risk of hepatoblastoma in familial adenomatous polyposis. Am J Med Genet 43: 1023–1025

    Article  CAS  PubMed  Google Scholar 

  • Jones SE, Jomary C (2002) Secreted frizzled-related proteins: searching for relationships and patterns. Bioessays 24: 811–820

    Article  CAS  PubMed  Google Scholar 

  • Kanda M, Nomoto S, Okamura Y, Nishikawa Y, Sugimoto H, Kanazumi N, Takeda S, Nakao A (2009) Detection of metallothionein 1G as a methylated tumor suppressor gene in human hepatocellular carcinoma using a novel method of double combination array analysis. Int J Oncol 35:477–483

    Article  CAS  PubMed  Google Scholar 

  • Kato M, Takita J, Takahashi K, Mimaki M, Chen Y, Koh K, Ida K, Oka A, Mizuguchi M, Ogawa S, Igarashi T (2009) Hepatoblastoma in a patient with sotos syndrome. J Pediatr 155:937–939

    Article  PubMed  Google Scholar 

  • Kenney AM, Rowitch DH (2000) Sonic hedgehog promotes G(1) cyclin expression and sustained cell cycle progression in mammalian neuronal precursors. Mol Cell Biol 20:9055–9067

    Article  CAS  PubMed  Google Scholar 

  • Kenney AM, Cole MD, Rowitch DH (2003) Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors. Development 130:15–28

    Article  CAS  PubMed  Google Scholar 

  • Klaus A, Birchmeier W (2008) Wnt signalling and its impact on development and cancer. Nat Rev Cancer 8:387–398

    Article  CAS  PubMed  Google Scholar 

  • Koch A, Denkhaus D, Albrecht S, Leuschner I, von Schweinitz D, Pietsch T (1999) Childhood hepatoblastomas frequently carry a mutated degradation targeting box of the beta-catenin gene. Cancer Res 59:269–273

    CAS  PubMed  Google Scholar 

  • Koch A, Weber N, Waha A, Hartmann W, Denkhaus D, Behrens J, Birchmeier W, von Schweinitz D, Pietsch T (2004) Mutations and elevated transcriptional activity of conductin (AXIN2) in hepatoblastomas. J Pathol 204:546–554

    Article  CAS  PubMed  Google Scholar 

  • Koch A, Waha A, Hartmann W, Hrychyk A, Schuller U, Wharton KA Jr, Fuchs SY, von Schweinitz D, Pietsch T (2005) Elevated expression of Wnt antagonists is a common event in hepatoblastomas. Clin Cancer Res 11:4295–4304

    Article  CAS  PubMed  Google Scholar 

  • Kraus JA, Albrecht S, Wiestler OD, von Schweinitz D, Pietsch T (1996) Loss of heterozygosity on chromosome 1 in human hepatoblastoma. Int J Cancer 67:467–471

    Article  CAS  PubMed  Google Scholar 

  • Krush AJ, Traboulsi EI, Offerhaus JA, Maumenee IH, Yardley JH, Levin LS (1988) Hepatoblastoma, pigmented ocular fundus lesions and jaw lesions in Gardner syndrome. Am J Med Genet 29:323–332

    Article  CAS  PubMed  Google Scholar 

  • Kurahashi H, Takami K, Oue T, Kusafuka T, Okada A, Tawa A, Okada S, Nishisho I (1995) Biallelic inactivation of the APC gene in hepatoblastoma. Cancer Res 55:5007–5011

    CAS  PubMed  Google Scholar 

  • Lapunzina P (2005) Risk of tumorigenesis in overgrowth syndromes: a comprehensive review. Am J Med Genet C Semin Med Genet 137C:53–71

    Article  PubMed  Google Scholar 

  • Li FP, Fraumeni JF Jr, Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA, Miller RW (1988) A cancer family syndrome in twenty-four kindreds. Cancer Res 48:5358–5362

    CAS  PubMed  Google Scholar 

  • Li X, Adam G, Cui H, Sandstedt B, Ohlsson R, Ekstrom TJ (1995) Expression, promoter usage and parental imprinting status of insulin-like growth factor II (IGF2) in human hepatoblastoma: uncoupling of IGF2 and H19 imprinting. Oncogene 11:221–229

    CAS  PubMed  Google Scholar 

  • Li M, Shuman C, Fei YL, Cutiongco E, Bender HA, Stevens C, Wilkins-Haug L, Day-Salvatore D, Yong SL, Geraghty MT, Squire J, Weksberg R (2001) GPC3 mutation analysis in a spectrum of patients with overgrowth expands the phenotype of Simpson–Golabi–Behmel syndrome. Am J Med Genet 102:161–168

    Article  CAS  PubMed  Google Scholar 

  • Little MH, Thomson DB, Hayward NK, Smith PJ (1988) Loss of alleles on the short arm of chromosome 11 in a hepatoblastoma from a child with Beckwith–Wiedemann syndrome. Hum Genet 79:186–189

    Article  CAS  PubMed  Google Scholar 

  • Mann JR, Kasthuri N, Raafat F, Pincott JR, Parkes SE, Muir KR, Ingram LC, Cameron AH (1990) Malignant hepatic tumours in children: incidence, clinical features and aetiology. Paediatr Perinat Epidemiol 4:276–289

    Article  CAS  PubMed  Google Scholar 

  • Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129:1261–1274

    Article  CAS  PubMed  Google Scholar 

  • Matsui I, Tanimura M, Kobayashi N, Sawada T, Nagahara N, Akatsuka J (1993) Neurofibromatosis type 1 and childhood cancer. Cancer 72:2746–2754

    Article  CAS  PubMed  Google Scholar 

  • Nagai H, Naka T, Terada Y, Komazaki T, Yabe A, Jin E, Kawanami O, Kishimoto T, Konishi N, Nakamura M, Kobayashi Y, Emi M (2003) Hypermethylation associated with inactivation of the SOCS-1 gene, a JAK/STAT inhibitor, in human hepatoblastomas. J Hum Genet 48:65–69

    Article  CAS  PubMed  Google Scholar 

  • Nagata T, Takahashi Y, Ishii Y, Asai S, Nishida Y, Murata A, Koshinaga T, Fukuzawa M, Hamazaki M, Asami K, Ito E, Ikeda H, Takamatsu H, Koike K, Kikuta A, Kuroiwa M, Watanabe A, Kosaka Y, Fujita H, Miyake M, Mugishima H (2003) Transcriptional profiling in hepatoblastomas using high-density oligonucleotide DNA array. Cancer Genet Cytogenet 145:152–160

    Article  CAS  PubMed  Google Scholar 

  • Naka T, Narazaki M, Hirata M, Matsumoto T, Minamoto S, Aono A, Nishimoto N, Kajita T, Taga T, Yoshizaki K, Akira S, Kishimoto T (1997) Structure and function of a new STAT-induced STAT inhibitor. Nature 387:924–929

    Article  CAS  PubMed  Google Scholar 

  • Nichols KE, Malkin D, Garber JE, Fraumeni JF Jr, Li FP (2001) Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers. Cancer Epidemiol Biomarkers Prev 10:83–87

    CAS  PubMed  Google Scholar 

  • Nishisho I, Nakamura Y, Miyoshi Y, Miki Y, Ando H, Horii A, Koyama K, Utsunomiya J, Baba S, Hedge P (1991) Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253:665–669

    Article  CAS  PubMed  Google Scholar 

  • Oda H, Imai Y, Nakatsuru Y, Hata J, Ishikawa T (1996) Somatic mutations of the APC gene in sporadic hepatoblastomas. Cancer Res 56:3320–3323

    CAS  PubMed  Google Scholar 

  • Oue T, Yoneda A, Uehara S, Yamanaka H, Fukuzawa M (2010) Increased expression of the hedgehog signaling pathway in pediatric solid malignancies. J Pediatr Surg 45:387–392

    Article  PubMed  Google Scholar 

  • Pei Y, Kano J, Iijima T, Morishita Y, Inadome Y, Noguchi M (2009) Overexpression of Dickkopf 3 in hepatoblastomas and hepatocellular carcinomas. Virchows Arch 454:639–646

    Article  CAS  PubMed  Google Scholar 

  • Polakis P (2000) Wnt signaling and cancer. Genes Dev 14:1837–1851

    CAS  PubMed  Google Scholar 

  • Pollak M (2008) Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8:915–928

    Article  CAS  PubMed  Google Scholar 

  • Pollak MN, Schernhammer ES, Hankinson SE (2004) Insulin-like growth factors and neoplasia. Nat Rev Cancer 4:505–518

    Article  CAS  PubMed  Google Scholar 

  • Potempa S, Ridley AJ (1998) Activation of both MAP kinase and phosphatidylinositide 3-kinase by Ras is required for hepatocyte growth factor/scatter factor-induced adherens junction disassembly. Mol Biol Cell 9:2185–2200

    CAS  PubMed  Google Scholar 

  • Regl G, Kasper M, Schnidar H, Eichberger T, Neill GW, Philpott MP, Esterbauer H, Hauser-Kronberger C, Frischauf AM, Aberger F (2004) Activation of the BCL2 promoter in response to Hedgehog/GLI signal transduction is predominantly mediated by GLI2. Cancer Res 64:7724–7731

    Article  CAS  PubMed  Google Scholar 

  • Rubin LL, de Sauvage FJ (2006) Targeting the Hedgehog pathway in cancer. Nat Rev Drug Discov 5:1026–1033

    Article  CAS  PubMed  Google Scholar 

  • Ruiz I, Altaba A, Sanchez P, Dahmane N (2002) Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer 2:361–372

    Article  CAS  Google Scholar 

  • Rustgi AK (2007) The genetics of hereditary colon cancer. Genes Dev 21:2525–2538

    Article  CAS  PubMed  Google Scholar 

  • Sakamoto LH, DEC B, Cajaiba M, Soares FA, Vettore AL (2010) MT1G hypermethylation: a potential prognostic marker for hepatoblastoma. Pediatr Res 67:387–393

    Article  CAS  PubMed  Google Scholar 

  • Salahshor S, Woodgett JR (2005) The links between axin and carcinogenesis. J Clin Pathol 58:225–236

    Article  CAS  PubMed  Google Scholar 

  • Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304:554

    Article  CAS  PubMed  Google Scholar 

  • Schagdarsurengin U, Wilkens L, Steinemann D, Flemming P, Kreipe HH, Pfeifer GP, Schlegelberger B, Dammann R (2003) Frequent epigenetic inactivation of the RASSF1A gene in hepatocellular carcinoma. Oncogene 22:1866–1871

    Article  CAS  PubMed  Google Scholar 

  • Scheil S, Hagen S, Bruderlein S, Leuschner I, Behnisch W, Moller P (2003) Two novel in vitro human hepatoblastoma models, HepU1 and HepU2, are highly characteristic of fetal-embryonal differentiation in hepatoblastoma. Int J Cancer 105:347–352

    Article  CAS  PubMed  Google Scholar 

  • Schneider NR, Cooley LD, Finegold MJ, Douglass EC, Tomlinson GE (1997) The first recurring chromosome translocation in hepatoblastoma: der(4)t(1;4)(q12;q34). Genes Chromosom Cancer 19:291–294

    Article  CAS  PubMed  Google Scholar 

  • Scotting PJ, Walker DA, Perilongo G (2005) Childhood solid tumours: a developmental disorder. Nat Rev Cancer 5:481–488

    Article  CAS  PubMed  Google Scholar 

  • Shih YL, Shyu RY, Hsieh CB, Lai HC, Liu KY, Chu TY, Lin YW (2006) Promoter methylation of the secreted ­frizzled-related protein 1 gene SFRP1 is frequent in hepatocellular carcinoma. Cancer 107:579–590

    Article  CAS  PubMed  Google Scholar 

  • Shih YL, Hsieh CB, Lai HC, Yan MD, Hsieh TY, Chao YC, Lin YW (2007) SFRP1 suppressed hepatoma cells growth through Wnt canonical signaling pathway. Int J Cancer 121:1028–1035

    Article  CAS  PubMed  Google Scholar 

  • Shim YH, Park HJ, Choi MS, Kim JS, Kim H, Kim JJ, Jang JJ, Yu E (2003) Hypermethylation of the p16 gene and lack of p16 expression in hepatoblastoma. Mod Pathol 16:430–436

    Article  PubMed  Google Scholar 

  • Shtutman M, Zhurinsky J, Simcha I, Albanese C, D’Amico M, Pestell R, Ben-Ze’ev A (1999) The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci USA 96:5522–5527

    Article  CAS  PubMed  Google Scholar 

  • Sigalotti L, Fratta E, Coral S, Cortini E, Covre A, Nicolay HJ, Anzalone L, Pezzani L, Di Giacomo AM, Fonsatti E, Colizzi F, Altomonte M, Calabro L, Maio M (2007) Epigenetic drugs as pleiotropic agents in cancer treatment: biomolecular aspects and clinical applications. J Cell Physiol 212:330–344

    Article  CAS  PubMed  Google Scholar 

  • Singer S, Ehemann V, Brauckhoff A, Keith M, Vreden S, Schirmacher P, Breuhahn K (2007) Protumorigenic overexpression of stathmin/Op18 by gain-of-function mutation in p53 in human hepatocarcinogenesis. Hepatology 46:759–768

    Article  CAS  PubMed  Google Scholar 

  • Son G, Hirano T, Seki E, Iimuro Y, Nukiwa T, Matsumoto K, Nakamura T, Fujimoto J (2006) Blockage of HGF/c-Met system by gene therapy (adenovirus-mediated NK4 gene) suppresses hepatocellular carcinoma in mice. J Hepatol 45:688–695

    Article  CAS  PubMed  Google Scholar 

  • Stejskalova E, Malis J, Snajdauf J, Pycha K, Urbankova H, Bajciova V, Stary J, Kodet R, Jarosova M (2009) Cytogenetic and array comparative genomic hybridization analysis of a series of hepatoblastomas. Cancer Genet Cytogenet 194:82–87

    Article  CAS  PubMed  Google Scholar 

  • Sugawara W, Haruta M, Sasaki F, Watanabe N, Tsunematsu Y, Kikuta A, Kaneko Y (2007) Promoter hypermethylation of the RASSF1A gene predicts the poor outcome of patients with hepatoblastoma. Pediatr Blood Cancer 49:240–249

    Article  PubMed  Google Scholar 

  • Suzuki H, Watkins DN, Jair KW, Schuebel KE, Markowitz SD, Chen WD, Pretlow TP, Yang B, Akiyama Y, Van Engeland M, Toyota M, Tokino T, Hinoda Y, Imai K, Herman JG, Baylin SB (2004) Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nat Genet 36:417–422

    Article  CAS  PubMed  Google Scholar 

  • Suzuki M, Kato M, Yuyan C, Takita J, Sanada M, Nannya Y, Yamamoto G, Takahashi A, Ikeda H, Kuwano H, Ogawa S, Hayashi Y (2008) Whole-genome profiling of chromosomal aberrations in hepatoblastoma using high-density single-nucleotide polymorphism genotyping microarrays. Cancer Sci 99:564–570

    Article  CAS  PubMed  Google Scholar 

  • Taniguchi T, Sullivan MJ, Ogawa O, Reeve AE (1995) Epigenetic changes encompassing the IGF2/H19 locus associated with relaxation of IGF2 imprinting and silencing of H19 in Wilms tumor. Proc Natl Acad Sci USA 92:2159–2163

    Article  CAS  PubMed  Google Scholar 

  • Taniguchi K, Roberts LR, Aderca IN, Dong X, Qian C, Murphy LM, Nagorney DM, Burgart LJ, Roche PC, Smith DI, Ross JA, Liu W (2002) Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene 21:4863–4871

    Article  CAS  PubMed  Google Scholar 

  • Teh MT, Wong ST, Neill GW, Ghali LR, Philpott MP, Quinn AG (2002) FOXM1 is a downstream target of Gli1 in basal cell carcinomas. Cancer Res 62:4773–4780

    CAS  PubMed  Google Scholar 

  • Tomlinson GE, Douglass EC, Pollock BH, Finegold MJ, Schneider NR (2005) Cytogenetic evaluation of a large series of hepatoblastomas: numerical abnormalities with recurring aberrations involving 1q12-q21. Genes Chromosom Cancer 44:177–184

    Article  CAS  PubMed  Google Scholar 

  • Trobaugh-Lotrario AD, Tomlinson GE, Finegold MJ, Gore L, Feusner JH (2009) Small cell undifferentiated variant of hepatoblastoma: adverse clinical and molecular features similar to rhabdoid tumors. Pediatr Blood Cancer 52:328–334

    Article  PubMed  Google Scholar 

  • Ucar C, Caliskan U, Toy H, Gunel E (2007) Hepatoblastoma in a child with neurofibromatosis type I. Pediatr Blood Cancer 49:357–359

    Article  PubMed  Google Scholar 

  • von Schweinitz D, Burger D, Bode U, Weinel P, Erttmann R, Hecker H, Mildenberger H (1994) Results of the HB-89 Study in treatment of malignant epithelial liver tumors in childhood and concept of a new HB-94 protocol. Klin Pädiatr 206:282–288

    Article  Google Scholar 

  • von Schweinitz D, Hecker H, Schmidt-von-Arndt G, Harms D (1997) Prognostic factors and staging systems in childhood hepatoblastoma. Int J Cancer 74:593–599

    Article  Google Scholar 

  • von Schweinitz D, Fuchs J, Gluer S, Pietsch T (1998) The occurrence of liver growth factor in hepatoblastoma. Eur J Pediatr Surg 8:133–136

    Article  Google Scholar 

  • von Schweinitz D, Faundez A, Teichmann B, Birnbaum T, Koch A, Hecker H, Gluer S, Fuchs J, Pietsch T (2000) Hepatocyte growth-factor-scatter factor can stimulate post-operative tumor-cell proliferation in childhood hepatoblastoma. Int J Cancer 85:151–159

    Google Scholar 

  • Voz ML, Agten NS, Van de Ven WJ, Kas K (2000) PLAG1, the main translocation target in pleomorphic adenoma of the salivary glands, is a positive regulator of IGF-II. Cancer Res 60:106–113

    CAS  PubMed  Google Scholar 

  • Weber RG, Pietsch T, von Schweinitz D, Lichter P (2000) Characterization of genomic alterations in hepatoblastomas. A role for gains on chromosomes 8q and 20 as predictors of poor outcome. Am J Pathol 157:571–578

    CAS  PubMed  Google Scholar 

  • Wei Y, Fabre M, Branchereau S, Gauthier F, Perilongo G, Buendia MA (2000) Activation of beta-catenin in epithelial and mesenchymal hepatoblastomas. Oncogene 19:498–504

    Article  CAS  PubMed  Google Scholar 

  • Weinberg AG, Finegold MJ (1983) Primary hepatic tumors of childhood. Hum Pathol 14:512–537

    Article  CAS  PubMed  Google Scholar 

  • Weksberg R, Shen DR, Fei YL, Song QL, Squire J (1993a) Disruption of insulin-like growth factor 2 imprinting in Beckwith-Wiedemann syndrome. Nat Genet 5:143–150

    Article  CAS  PubMed  Google Scholar 

  • Weksberg R, Teshima I, Williams BR, Greenberg CR, Pueschel SM, Chernos JE, Fowlow SB, Hoyme E, Anderson IJ, Whiteman DA et al (1993b) Molecular characterization of cytogenetic alterations associated with the Beckwith–Wiedemann syndrome (BWS) phenotype refines the localization and suggests the gene for BWS is imprinted. Hum Mol Genet 2:549–556

    Article  CAS  PubMed  Google Scholar 

  • Wirths O, Waha A, Weggen S, Schirmacher P, Kuhne T, Goodyer CG, Albrecht S, von Schweinitz D, Pietsch T (2003) Overexpression of human Dickkopf-1, an antagonist of wingless/WNT signaling, in human hepatoblastomas and Wilms’ tumors. Lab Invest 83:429–434

    CAS  PubMed  Google Scholar 

  • Yeh YA, Rao PH, Cigna CT, Middlesworth W, Lefkowitch JH, Murty VV (2000) Trisomy 1q, 2, and 20 in a case of hepatoblastoma: possible significance of 2q35-q37 and 1q12-q21 rearrangements. Cancer Genet Cytogenet 123:140–143

    Article  CAS  PubMed  Google Scholar 

  • Yoshikawa H, Matsubara K, Qian GS, Jackson P, Groopman JD, Manning JE, Harris CC, Herman JG (2001) SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity. Nat Genet 28:29–35

    Article  CAS  PubMed  Google Scholar 

  • Yost C, Torres M, Miller JR, Huang E, Kimelman D, Moon RT (1996) The axis-inducing activity, stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3. Genes Dev 10:1443–1454

    Article  CAS  PubMed  Google Scholar 

  • Zatkova A, Rouillard JM, Hartmann W, Lamb BJ, Kuick R, Eckart M, von Schweinitz D, Koch A, Fonatsch C, Pietsch T, Hanash SM, Wimmer K (2004) Amplification and overexpression of the IGF2 regulator PLAG1 in hepatoblastoma. Genes Chromosom Cancer 39:126–137

    Article  CAS  PubMed  Google Scholar 

  • Zhu W, Shiojima I, Ito Y, Li Z, Ikeda H, Yoshida M, Naito AT, Nishi J, Ueno H, Umezawa A, Minamino T, Nagai T, Kikuchi A, Asashima M, Komuro I (2008) IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis. Nature 454:345–349

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatric Surgery, Dr. von Hauner Children’s Hospital, Ludwig-Maximilians-University Munich, Lindwurmstr. 4, D-80337, Munich, Federal Republic of Germany

    Roland Kappler & Dietrich von Schweinitz

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  1. Roland Kappler
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  2. Dietrich von Schweinitz
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Correspondence to Roland Kappler .

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  1. Inst. Pathologie, Universität Bern, Murtenstr. 31, Bern, 3010, Switzerland

    Arthur Zimmermann

  2. Dipto. Pediatria, Unità di Oncoematologia Pediatrica, Università di Padova, Via Giustiniani 3, Padova, 35128, Italy

    Giorgio Perilongo

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Kappler, R., von Schweinitz, D. (2011). Molecular Aspects of Hepatoblastoma. In: Zimmermann, A., Perilongo, G. (eds) Pediatric Liver Tumors. Pediatric Oncology. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-14504-9_4

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