Hepatoblastoma

Chapter
Part of the Molecular Pathology Library book series (MPLB, volume 5)

Abstract

Primary liver cancer is rare in children, making up 1% of all pediatric malignancies. In children under 5 years of age, the major form of liver cancer is hepatoblastoma (HB), a malignant embryonal neoplasm thought to be derived from immature liver progenitors or stem cells. HB differs from hepatocellular carcinoma (HCC) by morphological patterns evoking prenatal stages of liver development. Multiple epithelial tumor components have been described, ranging from the small-cell undifferentiated pattern to the well-differentiated fetal pattern. Most HBs present heterogeneous epithelial histotypes that are frequently admixed with mesenchymal derivatives. Unlike HCC, HB develops in the absence of underlying liver disease and viral etiology, and it is sensitive to chemotherapy and presents with favorable outcome in more than 60% of cases. However, both types of liver cancer share common deregulation of oncogenic pathways such as Wnt/β-catenin signaling. This chapter will discuss the role of the pathologist and the contribution of molecular genomics in HB diagnosis and classification, as well as prognostic factors that may lead to improve the management of this tumor.

Keywords

Hepatitis Urea Petroleum Anemia Doxorubicin 

References

  1. 1.
    Perilongo G, Shafford EA. Liver tumours. Eur J Cancer. 1999;35:953–9.PubMedGoogle Scholar
  2. 2.
    Schnater JM, Kohler SE, Lamers WH, et al. Where do we stand with hepatoblastoma? A review. Cancer. 2003;98:668–78.PubMedGoogle Scholar
  3. 3.
    Darbari A, Sabin KM, Shapiro CN, et al. Epidemiology of primary hepatic malignancies in US children. Hepatology. 2003;38:560–6.PubMedGoogle Scholar
  4. 4.
    Isaacs HJ. Fetal and neonatal hepatic tumors. J Pediatr Surg. 2007;42:1797–803.PubMedGoogle Scholar
  5. 5.
    Harada T, Matsuo K, Kodama S, et al. Adult hepatoblastoma: case report and review of the literature. Aust N Z J Surg. 1995;65:686–8.PubMedGoogle Scholar
  6. 6.
    Stiller CA, Pritchard J, Steliarova-Foucher E. Liver cancer in European children: incidence and survival, 1978–1997. Report from the Automated Childhood Cancer Information System project. Eur J Cancer. 2006;42:2115–23.PubMedGoogle Scholar
  7. 7.
    Litten JB, Tomlinson GE. Liver tumors in children. Oncologist. 2008;13:812–20.PubMedGoogle Scholar
  8. 8.
    Stocker JT, Conran RM. Hepatoblastoma. In: Okuda K, Tabor E, editors. Liver cancer. PA: Churchill Livingstone; 1997. p. 263–78.Google Scholar
  9. 9.
    Ishak KG, Glunz PR. Hepatoblastoma and hepatocarcinoma in infancy and childhood: report of 47 cases. Cancer. 1967;20:396–422.PubMedGoogle Scholar
  10. 10.
    Weinberg AG, Finegold MJ. Primary hepatic tumors of childhood. Hum Pathol. 1983;14:512–37.PubMedGoogle Scholar
  11. 11.
    Ikeda H, Matsuyama S, Tanimura M. Association between hepatoblastoma and very low birth weight: a trend or a chance? J Pediatr. 1997;130:557–60.PubMedGoogle Scholar
  12. 12.
    Tanimura M, Matsui I, Abe J, et al. Increased risk of hepatoblastoma among immature children with a lower birth weight. Cancer Res. 1998;58:3032–5.PubMedGoogle Scholar
  13. 13.
    Ross JA, Gurney JG. Hepatoblastoma incidence in the United States from 1973 to 1992. Med Pediatr Oncol. 1998;30:141–2.PubMedGoogle Scholar
  14. 14.
    Reynolds P, Urayama KY, Von Behren J, et al. Birth characteristics and hepatoblastoma risk in young children. Cancer. 2004;100:1070–6.PubMedGoogle Scholar
  15. 15.
    McLaughlin CC, Baptiste MS, Schymura MJ, et al. Maternal and infant birth characteristics and hepatoblastoma. Am J Epidemiol. 2006;163:818–28.PubMedGoogle Scholar
  16. 16.
    Trobaugh-Lotrario AD, Greffe B, Garza-Williams S, et al. Erythropoietin receptor presence in hepatoblastoma: a possible link to increased incidence of hepatoblastoma in very low birthweight infants. Pediatr Blood Cancer. 2007;49:365–6.PubMedGoogle Scholar
  17. 17.
    Ansell P, Mitchell CD, Roman E, et al. Relationships between perinatal and maternal characteristics and hepatoblastoma: a report from the UKCCS. Eur J Cancer. 2005;41:741–8.PubMedGoogle Scholar
  18. 18.
    Buckley J, Sather H, Ruccione K, et al. A case-control study of risk factors for hepatoblastoma. A report from the Childrens Cancer Study Group. Cancer. 1989;64:1169–76.PubMedGoogle Scholar
  19. 19.
    Feinberg AP, Tycko B. The history of cancer epigenetics. Nat Cancer Rev. 2004;4:143–53.Google Scholar
  20. 20.
    Albrecht S, von Schweinitz D, Waha A, et al. Loss of maternal alleles on chromosome arm 11p in hepatoblastoma. Cancer Res. 1994;54:5041–4.PubMedGoogle Scholar
  21. 21.
    Gray SG, Eriksson T, Ekstrom C, et al. Altered expression of members of the IGF-axis in hepatoblastomas. Br J Cancer. 2000;82:1561–7.PubMedGoogle Scholar
  22. 22.
    Honda S, Arai Y, Haruta M, et al. Loss of imprinting of IGF2 correlates with hypermethylation of the H19 differentially methylated region in hepatoblastoma. Br J Cancer. 2008;99:1891–9.PubMedGoogle Scholar
  23. 23.
    Kurahashi H, Takami K, Oue T, et al. Biallelic inactivation of the APC gene in hepatoblastoma. Cancer Res. 1995;55:5007–11.PubMedGoogle Scholar
  24. 24.
    Hirschman BA, Pollock BH, Tomlinson GE. The spectrum of APC mutations in children with hepatoblastoma from familial adenomatous polyposis kindreds. J Pediatr. 2005;147:263–6.PubMedGoogle Scholar
  25. 25.
    Aretz S, Koch A, Uhlhaas S, et al. 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. 2006;47:811–8.PubMedGoogle Scholar
  26. 26.
    Boman F, Bossard C, Fabre M, et al. Mesenchymal hamartomas of the liver may be associated with increased serum alpha foetoprotein concentrations and mimic hepatoblastomas. Eur J Pediatr Surg. 2004;14:63–6.PubMedGoogle Scholar
  27. 27.
    Meyers RL, Rowland JR, Krailo M, et al. Predictive power of pretreatment prognostic factors in children with hepatoblastoma: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2009;53:1016–22.PubMedGoogle Scholar
  28. 28.
    Roebuck DJ, Olsen Ø, Pariente D. Radiological staging in children with hepatoblastoma. Pediatr Radiol. 2006;36:176–82.PubMedGoogle Scholar
  29. 29.
    Pham TH, Iqbal CW, Grams JM, et al. Outcomes of primary liver cancer in children: an appraisal of experience. J Pediatr Surg. 2007;42:834–9.PubMedGoogle Scholar
  30. 30.
    Perilongo G, Shafford E, Plaschkes J. SIOPEL trials using preoperative chemotherapy in hepatoblastoma. Lancet Oncol. 2000;1:94–100.PubMedGoogle Scholar
  31. 31.
    Perilongo G, Shafford E, Maibach R, et al. Risk-adapted treatment for childhood hepatoblastoma. Final report of the second study of the International Society of Paediatric Oncology-SIOPEL 2. Eur J Cancer. 2004;40:411–21.PubMedGoogle Scholar
  32. 32.
    Czauderna P, Otte JB, Roebuck DJ, et al. Surgical treatment of hepatoblastoma in children. Pediatr Radiol. 2006;36:187–91.PubMedGoogle Scholar
  33. 33.
    Sasaki F, Matsunaga T, Iwafuchi M, et al. Outcome of hepatoblastoma treated with the JPLT-1 (Japanese Study Group for Pediatric Liver Tumor) Protocol-1: A report from the Japanese Study Group for Pediatric Liver Tumor. J Pediatr Surg. 2002;37:851–6.PubMedGoogle Scholar
  34. 34.
    Otte JB, Pritchard J, Aronson DC, et al. Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience. Pediatr Blood Cancer. 2004;42:74–83.PubMedGoogle Scholar
  35. 35.
    Tiao G, Bobey N, Allen S, et al. The current management of hepatoblastoma: a combination of chemotherapy, conventional resection, and liver transplantation. J Pediatr. 2005;146:204–11.PubMedGoogle Scholar
  36. 36.
    Kasahara M, Ueda M, Haga H, et al. Living-donor liver transplantation for hepatoblastoma. Am J Transplant. 2005;5:2229–35.PubMedGoogle Scholar
  37. 37.
    Otte JB, de Ville de Goyet J, and Reding R. Liver transplantation for hepatoblastoma: indications and contraindications in the modern era. Pediatr Transplant. 2005;9:557–65.Google Scholar
  38. 38.
    Austin MT, Leys CM, Feurer ID, et al. Liver transplantation for childhood hepatic malignancy: a review of the United Network for Organ Sharing (UNOS) database. J Pediatr Surg. 2006;41:182–6.PubMedGoogle Scholar
  39. 39.
    Li JP, Chu JP, Yang JY, et al. Preoperative transcatheter selective arterial chemoembolization in treatment of unresectable hepatoblastoma in infants and children. Cardiovasc Intervent Radiol. 2008;31:117–23.Google Scholar
  40. 40.
    Ye J, Shu Q, Li M, et al. Percutaneous radiofrequency ablation for treatment of hepatoblastoma recurrence. Pediatr Radiol. 2008;38:1021–3.PubMedGoogle Scholar
  41. 41.
    Zimmermann A. The emerging family of hepatoblastoma tumours: from ontogenesis to oncogenesis. Eur J Cancer. 2005;41:1503–14.PubMedGoogle Scholar
  42. 42.
    Haas JE, Muczynski KA, Krailo M, et al. Histopathology and prognosis in childhood hepatoblastoma and hepatocarcinoma. Cancer. 1989;64:1082–95.PubMedGoogle Scholar
  43. 43.
    Saxena R, Leake JL, Shafford EA, et al. Chemotherapy effects on hepatoblastoma. A histological study. Am J Surg Pathol. 1993;17:1266–71.PubMedGoogle Scholar
  44. 44.
    Gonzalez-Crussi F. Undifferentiated small cell (“anaplastic”) hepatoblastoma. Pediatr Pathol. 1991;11:155–61.PubMedGoogle Scholar
  45. 45.
    Rowland JM. Hepatoblastoma: assessment of criteria for histologic classification. Med Pediatr Oncol. 2002;39:478–83.PubMedGoogle Scholar
  46. 46.
    Wagner LM, Garrett JK, Ballard ET, et al. Malignant rhabdoid tumor mimicking hepatoblastoma: a case report and literature review. Pediatr Dev Pathol. 2007;10:409–15.PubMedGoogle Scholar
  47. 47.
    Trobaugh-Lotrario AD, Tomlinson GE, Finegold MJ, et al. Small cell undifferentiated variant of hepatoblastoma: adverse clinical and molecular features similar to rhabdoid tumors. Pediatr Blood Cancer. 2009;52:328–34.PubMedGoogle Scholar
  48. 48.
    Prokurat A, Kluge P, Kościesza A, et al. Transitional liver cell tumors (TLCT) in older children and adolescents: a novel group of aggressive hepatic tumors expressing beta-catenin. Med Pediatr Oncol. 2002;39:510–8.PubMedGoogle Scholar
  49. 49.
    Cajaiba MM, Neves JI, Casarotti FF, et al. Hepatoblastomas and liver development: a study of cytokeratin immunoexpression in twenty-nine hepatoblastomas. Pediatr Dev Pathol. 2006;9:196–202.PubMedGoogle Scholar
  50. 50.
    Cairo S, Armengol C, De Reynies A, et al. Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer. Cancer Cell. 2008;14:471–84.PubMedGoogle Scholar
  51. 51.
    Zynger DL, Gupta A, Luan C, et al. Expression of glypican 3 in hepatoblastoma: an immunohistochemical study of 65 cases. Hum Pathol. 2008;39:224–30.PubMedGoogle Scholar
  52. 52.
    Lopez-Terrada D, Gunaratne PH, Adesina AM, et al. Histologic subtypes of hepatoblastoma are characterized by differential canonical Wnt and Notch pathway activation in DLK+ precursors. Hum Pathol. 2009;40:783–94.PubMedGoogle Scholar
  53. 53.
    Fasano M, Theise ND, Nalesnik M, et al. Immunohistochemical evaluation of hepatoblastomas with use of the hepatocyte-specific marker, hepatocyte paraffin 1, and the polyclonal anti-carcinoembryonic antigen. Mod Pathol. 1998;11:934–8.PubMedGoogle Scholar
  54. 54.
    Halasz J, Holczbauer A, Paska C, et al. Claudin-1 and claudin-2 differentiate fetal and embryonal components in human hepatoblastoma. Hum Pathol. 2006;37:555–61.PubMedGoogle Scholar
  55. 55.
    Cadoret A, Ovejero C, Terris B, et al. New targets of beta-catenin signaling in the liver are involved in the glutamine metabolism. Oncogene. 2002;21:8293–301.PubMedGoogle Scholar
  56. 56.
    Gebhardt R, Mecke D. Heterogeneous distribution of glutamine synthetase among rat liver parenchymal cells in situ and in primary culture. EMBO J. 1983;2:567–70.PubMedGoogle Scholar
  57. 57.
    Wei Y, Fabre M, Branchereau S, et al. Activation of beta-catenin in epithelial and mesenchymal hepatoblastomas. Oncogene. 2000;19:498–504.PubMedGoogle Scholar
  58. 58.
    Takayasu H, Horie H, Hiyama E, et al. Frequent deletions and mutations of the beta-catenin gene are associated with overexpression of cyclin D1 and fibronectin and poorly differentiated histology in childhood hepatoblastoma. Clin Cancer Res. 2001;7:901–8.PubMedGoogle Scholar
  59. 59.
    Park WS, Oh RR, Park JY, et al. Nuclear localization of beta-catenin is an important prognostic factor in hepatoblastoma. J Pathol. 2001;193:483–90.PubMedGoogle Scholar
  60. 60.
    Rugge M, Sonego F, Pollice L, et al. Hepatoblastoma: DNA nuclear content, proliferative indices, and pathology. Liver. 1998;18:128–33.PubMedGoogle Scholar
  61. 61.
    Ara T, Fukuzawa M, Oue T, et al. Immunohistochemical assessment of the MIB-1 labeling index in human hepatoblastoma and its prognostic relevance. J Pediatr Surg. 1997;32:1690–4.PubMedGoogle Scholar
  62. 62.
    Krober S, Ruck P, Xiao JC, et al. Flow cytometric evaluation of nuclear DNA content in hepatoblastoma: further evidence for the inhomogeneity of the different subtypes. Pathol Int. 1995;45:501–5.PubMedGoogle Scholar
  63. 63.
    Bardi G, Johansson B, Pandis N, et al. Trisomy 2 as the sole chromosomal abnormality in a hepatoblastoma. Genes Chromosomes Cancer. 1992;4:78–80.PubMedGoogle Scholar
  64. 64.
    Bove KE, Soukup S, Ballard ET, et al. Hepatoblastoma in a child with trisomy 18: cytogenetics, liver anomalies, and literature review. Pediatr Pathol Lab Med. 1996;16:253–62.PubMedGoogle Scholar
  65. 65.
    Fletcher JA, Kozakewich HP, Pavelka K, et al. Consistent cytogenetic aberrations in hepatoblastoma: a common pathway of genetic alterations in embryonal liver and skeletal muscle malignancies? Genes Chromosomes Cancer. 1991;3:37–43.PubMedGoogle Scholar
  66. 66.
    Mascarello JT, Jones MC, Kadota RP, et al. Hepatoblastoma characterized by trisomy 20 and double minutes. Cancer Genet Cytogenet. 1990;47:243–7.PubMedGoogle Scholar
  67. 67.
    Rodriguez E, Reuter VE, Mies C, et al. Abnormalities of 2q: a common genetic link between rhabdomyosarcoma and hepatoblastoma? Genes Chromosomes Cancer. 1991;3:122–7.PubMedGoogle Scholar
  68. 68.
    Soukup SW, Lampkin BL. Trisomy 2 and 20 in two hepatoblastomas. Genes Chromosomes Cancer. 1991;3:231–4.PubMedGoogle Scholar
  69. 69.
    Tonk VS, Wilson KS, Timmons CF, et al. Trisomy 2, trisomy 20, and del(17p) as sole chromosomal abnormalities in three cases of hepatoblastoma. Genes Chromosomes Cancer. 1994;11:199–202.PubMedGoogle Scholar
  70. 70.
    Sainati L, Leszl A, Stella M, et al. Cytogenetic analysis of hepatoblastoma: hypothesis of cytogenetic evolution in such tumors and results of a multicentric study. Cancer Genet Cytogenet. 1998;104:39–44.PubMedGoogle Scholar
  71. 71.
    Schneider NR, Cooley LD, Finegold MJ, et al. The first recurring chromosome translocation in hepatoblastoma: der(4)t(1;4)(q12;q34). Genes Chromosomes Cancer. 1997;19:291–4.PubMedGoogle Scholar
  72. 72.
    Parada LA, Limon J, Iliszko M, et al. Cytogenetics of hepatoblastoma: further characterization of 1q rearrangements by fluorescence in situ hybridization: an international collaborative study. Med Pediatr Oncol. 2000;34:165–70.PubMedGoogle Scholar
  73. 73.
    Yeh YA, Rao PH, Cigna CT, et al. Trisomy 1q, 2, and 20 in a case of hepatoblastoma: possible significance of 2q35-q37 and 1q12-q21 rearrangements. Cancer Genet Cytogenet. 2000;123:140–3.PubMedGoogle Scholar
  74. 74.
    Tomlinson GE, Douglass EC, Pollock BH, et al. Cytogenetic evaluation of a large series of hepatoblastomas: numerical abnormalities with recurring aberrations involving 1q12-q21. Genes Chromosomes Cancer. 2005;44:177–84.PubMedGoogle Scholar
  75. 75.
    Gray SG, Kytola S, Matsunaga T, et al. Comparative genomic hybridization reveals population-based genetic alterations in hepatoblastomas. Br J Cancer. 2000;83:1020–5.PubMedGoogle Scholar
  76. 76.
    Hu J, Wills M, Baker BA, et al. Comparative genomic hybridization analysis of hepatoblastomas. Genes Chromosomes Cancer. 2000;27:196–201.PubMedGoogle Scholar
  77. 77.
    Steenman M, Tomlinson G, Westerveld A, et al. Comparative genomic hybridization analysis of hepatoblastomas: additional evidence for a genetic link with Wilms tumor and rhabdomyosarcoma. Cytogenet Cell Genet. 1999;86:157–61.PubMedGoogle Scholar
  78. 78.
    Weber RG, Pietsch T, von Schweinitz D, et al. Characterization of genomic alterations in hepatoblastomas. A role for gains on chromosomes 8q and 20 as predictors of poor outcome. Am J Pathol. 2000;157:571–8.PubMedGoogle Scholar
  79. 79.
    Kumon K, Kobayashi H, Namiki T, et al. Frequent increase of DNA copy number in the 2q24 chromosomal region and its association with a poor clinical outcome in hepatoblastoma: cytogenetic and comparative genomic hybridization analysis. Jpn J Cancer Res. 2001;92:854–62.PubMedGoogle Scholar
  80. 80.
    Terracciano LM, Bernasconi B, Ruck P, et al. Comparative genomic hybridization analysis of hepatoblastoma reveals high frequency of X-chromosome gains and similarities between epithelial and stromal components. Hum Pathol. 2003;34:864–71.PubMedGoogle Scholar
  81. 81.
    Suzuki M, Kato M, Yuyan C, et al. Whole-genome profiling of chromosomal aberrations in hepatoblastoma using high-density single-nucleotide polymorphism genotyping microarrays. Cancer Sci. 2008;99:564–70.PubMedGoogle Scholar
  82. 82.
    Byrne JA, Simms LA, Little MH, et al. Three non-overlapping regions of chromosome arm 11p allele loss identified in infantile tumors of adrenal and liver. Genes Chromosomes Cancer. 1993;8:104–11.PubMedGoogle Scholar
  83. 83.
    Kraus JA, Albrecht S, Wiestler OD, et al. Loss of heterozygosity on chromosome 1 in human hepatoblastoma. Int J Cancer. 1996;67:467–71.PubMedGoogle Scholar
  84. 84.
    Terada Y, Matsumoto S, Bando K, et al. Comprehensive allelotyping of hepatoblastoma. Hepatogastroenterology. 2009;56:199–204.PubMedGoogle Scholar
  85. 85.
    Scotting PJ, Walker DA, Perilongo G. Childhood solid tumours: a developmental disorder. Nat Rev Cancer. 2005;5:481–8.PubMedGoogle Scholar
  86. 86.
    Cadigan KM, Nusse R. Wnt signaling: a common theme in anaimal development. Genes Dev. 1997;11:3286–305.PubMedGoogle Scholar
  87. 87.
    Polakis P. Wnt signaling and cancer. Genes Dev. 2000;14:1837–51.PubMedGoogle Scholar
  88. 88.
    Giles RH, van Es JH, Clevers H. Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta. 2003;1653:1–24.PubMedGoogle Scholar
  89. 89.
    McLin VA, Rankin SA, Zorn AM. Repression of Wnt\{beta}-catenin signaling in the anterior endoderm is essential for liver and pancreas development. Development. 2007;134:2207–17.PubMedGoogle Scholar
  90. 90.
    Ober EA, Verkade H, Field HA, et al. Mesodermal Wnt2b signalling positively regulates liver specification. Nature. 2006;442:688–91.PubMedGoogle Scholar
  91. 91.
    Goessling W, North TE, Lord AM, et al. APC mutant zebrafish uncover a changing temporal requirement for wnt signaling in liver development. Dev Biol. 2008;320:161–74.PubMedGoogle Scholar
  92. 92.
    Micsenyi A, Tan X, Sneddon T, et al. Beta-catenin is temporally regulated during normal liver development. Gastroenterology. 2004;126:1134–46.PubMedGoogle Scholar
  93. 93.
    Benhamouche S, Decaens T, Godard C, et al. Apc tumor suppressor gene is the “zonation-keeper” of mouse liver. Dev Cell. 2006;10:759–70.PubMedGoogle Scholar
  94. 94.
    Chafey P, Finzi L, Boisgard R, et al. Proteomic analysis of beta-catenin activation in mouse liver by DIGE analysis identifies glucose metabolism as a new target of the Wnt pathway. Proteomics. 2009;9:3889–900.PubMedGoogle Scholar
  95. 95.
    Colletti M, Cicchini C, Conigliaro A, et al. Convergence of Wnt signaling on the HNF4alpha-driven transcription in controlling liver zonation. Gastroenterology. 2009;137:660–72.PubMedGoogle Scholar
  96. 96.
    Reed KR, Athineos D, Meniel VS, et al. B-catenin deficiency, but not Myc deletion, suppresses the immediate phenotypes of APC loss in the liver. Proc Natl Acad Sci U S A. 2008;105:18919–23.PubMedGoogle Scholar
  97. 97.
    Burke ZD, Reed KR, Phesse TJ, et al. Liver zonation occurs through a beta-catenin-dependent, c-Myc-independent mechanism. Gastroenterology. 2009;136:2316–24.PubMedGoogle Scholar
  98. 98.
    de La Coste A, Romagnolo B, Billuart P, et al. Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci U S A. 1998;95:8847–51.Google Scholar
  99. 99.
    Koch A, Denkhaus D, Albrecht S, et al. Childhood hepatoblastomas frequently carry a mutated degradation targeting box of the beta-catenin gene. Cancer Res. 1999;59:269–73.PubMedGoogle Scholar
  100. 100.
    Blaker H, Hofmann WJ, Rieker RJ, et al. Beta-catenin accumulation and mutation of the CTNNB1 gene in hepatoblastoma. Genes Chromosomes Cancer. 1999;25:399–402.PubMedGoogle Scholar
  101. 101.
    Jeng YM, Wu MZ, Mao TL, et al. Somatic mutations of beta-catenin play a crucial role in the tumorigenesis of sporadic hepatoblastoma. Cancer Lett. 2000;152:45–51.PubMedGoogle Scholar
  102. 102.
    Taniguchi K, Roberts LR, Aderca IN, et al. Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene. 2002;21:4863–71.PubMedGoogle Scholar
  103. 103.
    Miao J, Kusafuka T, Udatsu Y, et al. Sequence variants of the Axin gene in hepatoblastoma. Hepatol Res. 2003;25:174–9.PubMedGoogle Scholar
  104. 104.
    Koch A, Weber N, Waha A, et al. Mutations and elevated transcriptional activity of conductin (AXIN2) in hepatoblastomas. J Pathol. 2004;204:546–54.PubMedGoogle Scholar
  105. 105.
    Oda H, Imai Y, Nakatsuru Y, et al. Somatic mutations of the APC gene in sporadic hepatoblastomas. Cancer Res. 1996;56:3320–3.PubMedGoogle Scholar
  106. 106.
    Sansom OJ, Meniel VS, Muncan V, et al. Myc deletion rescues Apc deficiency in the small intestine. Nature. 2007;446:676–9.PubMedGoogle Scholar
  107. 107.
    Cadoret A, Ovejero C, Saadi-Kheddouci S, et al. Hepatomegaly in transgenic mice expressing an oncogenic form of beta-catenin. Cancer Res. 2001;61:3245–9.PubMedGoogle Scholar
  108. 108.
    Kim H, Ham EK, Kim YI, et al. Overexpression of cyclin D1 and CDK4 in tumorigenesis of sporadic hepatoblastomas. Cancer Lett. 1998;131:177–83.PubMedGoogle Scholar
  109. 109.
    Renard CA, Labalette C, Armengol C, et al. Tbx3 is a downstream target of the Wnt/beta-catenin pathway and a critical mediator of beta-catenin survival functions in liver cancer. Cancer Res. 2007;67:901–10.PubMedGoogle Scholar
  110. 110.
    Hailfinger S, Jaworski M, Braeuning A, et al. Zonal gene expression in murine liver: lessons from tumors. Hepatology. 2006;43:407–14.PubMedGoogle Scholar
  111. 111.
    Boyault S, Rickman DS, de Reynies A, et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology. 2007;45:42–52.PubMedGoogle Scholar
  112. 112.
    Sekine S, Lan BY, Bedolli M, et al. Liver-specific loss of beta-catenin blocks glutamine synthesis pathway activity and cytochrome p450 expression in mice. Hepatology. 2006;43:817–25.PubMedGoogle Scholar
  113. 113.
    Cavard C, Colnot S, Audard V, et al. Wnt/beta-catenin pathway in hepatocellular carcinoma pathogenesis and liver physiology. Future Oncol. 2008;4:647–60.PubMedGoogle Scholar
  114. 114.
    Wirths O, Waha A, Weggen S, et al. Overexpression of human Dickkopf-1, an antagonist of wingless/WNT signaling, in human hepatoblastomas and Wilms’ tumors. Lab Invest. 2003;83:429–34.PubMedGoogle Scholar
  115. 115.
    Koch A, Waha A, Hartmann W, et al. Elevated expression of Wnt antagonists is a common event in hepatoblastomas. Clin Cancer Res. 2005;11:4295–304.PubMedGoogle Scholar
  116. 116.
    Akmal SN, Yun K, MacLay J, et al. Insulin-like growth factor 2 and insulin-like growth factor binding protein 2 expression in hepatoblastoma. Hum Pathol. 1995;26:846–51.PubMedGoogle Scholar
  117. 117.
    Nagata T, Takahashi Y, Ishii Y, et al. Transcriptional profiling in hepatoblastomas using high-density oligonucleotide DNA array. Cancer Genet Cytogenet. 2003;145:152–60.PubMedGoogle Scholar
  118. 118.
    Li X, Kogner P, Sandstedt B, et al. Promoter-specific methylation and expression alterations of igf2 and h19 are involved in human hepatoblastoma. Int J Cancer. 1998;75:176–80.PubMedGoogle Scholar
  119. 119.
    Ross JA, Radloff GA, Davies SM. H19 and IGF-2 allele-specific expression in hepatoblastoma. Br J Cancer. 2000;82:753–6.PubMedGoogle Scholar
  120. 120.
    Zatkova A, Rouillard JM, Hartmann W, et al. Amplification and overexpression of the IGF2 regulator PLAG1 in hepatoblastoma. Genes Chromosomes Cancer. 2004;39:126–37.PubMedGoogle Scholar
  121. 121.
    Ranganathan S, Tan X, Monga SP. Beta-catenin and met deregulation in childhood hepatoblastomas. Pediatr Dev Pathol. 2005;8:435–47.PubMedGoogle Scholar
  122. 122.
    Hartmann W, Küchler J, Koch A, et al. Activation of phosphatidylinositol-3’-kinase/AKT signaling is essential in hepatoblastoma survival. Clin Cancer Res. 2009;15:4538–45.PubMedGoogle Scholar
  123. 123.
    Adesina AM, Lopez-Terrada D, Wong KK, et al. Gene expression profiling reveals signatures characterizing histologic subtypes of hepatoblastoma and global deregulation in cell growth and survival pathways. Hum Pathol. 2009;40:843–53.PubMedGoogle Scholar
  124. 124.
    Svenson U, Roos G. Telomere length as a biological marker in malignancy. Biochim Biophys Acta. 2009;1792:317–23.PubMedGoogle Scholar
  125. 125.
    Hiyama E, Yamaoka H, Matsunaga T, et al. High expression of telomerase is an independent prognostic indicator of poor outcome in hepatoblastoma. Br J Cancer. 2004;91:972–9.PubMedGoogle Scholar
  126. 126.
    Oh BK, Kim H, Park YN, et al. High telomerase activity and long telomeres in advanced hepatocellular carcinomas with poor prognosis. Lab Invest. 2008;88:144–52.PubMedGoogle Scholar
  127. 127.
    Lemaigre F, Zaret KS. Liver development update: new embryo models, cell lineage control, and morphogenesis. Curr Opin Genet Dev. 2004;14:582–90.PubMedGoogle Scholar
  128. 128.
    Oda T, Elkahloun AG, Pike BL, et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet. 1997;16:235–42.PubMedGoogle Scholar
  129. 129.
    Theunissen JW, de Sauvage FJ. Paracrine hedgehog signaling in cancer. Cancer Res. 2009;69:6007–10.PubMedGoogle Scholar
  130. 130.
    Eichenmüller M, Gruner I, Hagl B, et al. Blocking the hedgehog pathway inhibits hepatoblastoma growth. Hepatology. 2009;49:482–90.PubMedGoogle Scholar
  131. 131.
    Luo JH, Ren B, Keryanov S, et al. Transcriptomic and genomic analysis of human hepatocellular carcinomas and hepatoblastomas. Hepatology. 2006;44:1012–24.PubMedGoogle Scholar
  132. 132.
    Warmann SW, Fuchs J, Bitzer M, et al. Emerging gene-directed anti-tumor strategies against human hepatoblastoma. Expert Opin Biol Ther. 2009;9:1155–61.PubMedGoogle Scholar
  133. 133.
    Jiang H, Reinhardt HC, Bartkova J, et al. The combined status of ATM and p53 link tumor development with therapeutic response. Genes Dev. 2009;23:1895–909.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Oncogenesis and Molecular Virology UnitInstitut PasteurParisFrance

Personalised recommendations