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Hepatoblastoma (molecular pathology)

Tuesday 13 March 2012

Hepatoblastoma oncogenetics

Summary

Several genetic changes are shared with other embryonal tumors, such as loss of heterozygosity at chromosome 11p15, also described in rhabdomyosarcomas and Wilms tumors.

Acquired mutations of the APC gene and the ß-catenin gene, both members of the Wnt signaling pathway, have also been reported in hepatoblastoma.

The high frequency of ß-catenin mutations in hepatoblastomas and the increased incidence of hepatoblastomas in familial adenomatous polyposis families suggest the important role of an overactivation of wingless/Wnt pathway in the pathogenesis of hepatoblastoma.

- 11p15.15 imprinted genes deregulation

  • LOH at 11p15 (#7923113#)
  • high frequency of inactivation of the imprinted H19 gene in sporadic hepatoblastoma (#10404060#)
  • loss of imprinting at 11p15.5 locus (#7728748#)

- WNT signaling pathway deregulation

  • beta-catenin accumulation (#10398436#)
  • beta-catenin (CTNNB1) activating mutations (#10398436#)
  • AXIN2 somatic inactivating mutations

- TP53 mutations (2.5%) (#8721685#)

  • anaplastic hepatoblastoma (#8721685#)

- amplification and overexpression of the IGF2 regulator PLAG1 at 8q11.2-q13 (#14695992#)

Wnt signaling

Deregulation of the APC/beta-catenin pathway occurs in a consistent fraction of hepatoblastomas, with mutations in the APC and beta-catenin genes implicated in FAP-associated and sporadic hepatoblastomas, respectively.

Mutations of the beta-catenin gene are present in over 90% of hepatoblasto-mas, leading to activating transcription of a number of target genes.

b-Catenin is central to the convergence of the Wnt,
b-catenin, and cadherin signaling pathways, where it forms a signaling complex with axins, APC tumor suppressor pro-tein, glycogen synthase kinase 3b, and other proteins.

The Wnt signalling pathway prevents proteosomal degrada-tion of
b-catenin and allows b-catenin to translocate to the nucleus and initiate gene transcription.

In fact, b-catenin can be immunohistochemically detected in the nucleus, fol-lowing its translocation.

Nuclear staining for b-catenin in hepatoblastomas has been reported to correlate with poor histologic phenotype, higher stage disease, and poor survival.

Other components of the Wnt signaling pathway including Axin gene mutation and loss of APC function have also been have been implicated in hepatoblastoma tumorigenesis.

Giardiello et al. identified an APC gene mutation in all eight hepatoblastoma patients of seven FAP kindreds.

Oda et al. have also noted genetic alterations in the APC (loss of heterozygosity [LOH] or somatic mutations) in 9 of 13 cases of hepato-blastoma in non-FAP patients.

Interestingly, a distinct male predominance (nearly 75%) is seen in APC gene-related hepatoblastomas.A host of other genetic alterations have been described in hepatoblastomas involving cell cycle–related genes, apoptosis pathways, p53 mutations, mismatch repair defects, FOXG1 overexpression, and signal transduction pathways, to name a few.

It is possible that many of these molecular aberrations may be late events in the clonal evolution of these tumors that indicate progressive genomic instability rather than primary events.

López-Terrada et al. have hypothesized that histologic microheterogeneity in hepatoblastoma may correlate with molecular heterogeneity, reflecting different stages of developmental arrest.

They found Wnt activation to be most prevalent in embryonal and mixed types, whereas Notch activation, needed for cholangiocytic differentiation at a more differentiated state, was predominant in pure fetal hepatoblastomas.

Myc signaling (#22201888#)

There are crucial roles of the Wnt and Myc signaling pathways in malignant transformation of liver progenitor cells.

p53 / TP53

p53 protein expression is seen less frequently in hepatoblastoma than in other childhood tumors.

In 10 cases of hepatoblastoma, Chen et al. noted only one case of overexpression of p53 protein in a macrotrabecular type at stage IV.

Ruck et al.noted p53 protein immunoreactivity in two small cell hepatoblastomas and in the embryonal areas of two fetal and embryonal epithelial hepatoblastomas, but not in the fetal areas of eight fetal or fetal and embryonal epithelial tumors or the mesenchymal areas of four mixed tumors.

Somatic mutations, however, were detected in 9 of 10 cases of hepatoblastoma in the five to eight exons of the p53 gene by Oda et al. , who suggest that environmental mutagens may be involved in some cases of hepatoblastoma.

Many aberrations have also been reported at the chromo-somal level in hepatoblastomas.

LOH

Genome-wide allelotyping of hepatoblastomas have shown frequent allelic losses at many microsatellite loci implicating chromosome instability as an important factor in development and progression of hepatoblastoma.

Trisomy 2, trisomy 20, and 4q structural rearrangement are the most common chromo-somal abnormalities in hepatoblastoma.

A derivative chromosome 4 from an unbalanced translocation between the long arms of chromosomes 1 and 4 has been noted as a recurring abnormality in hepatoblastoma, while it is rarely seen in other types of neoplasms.

In 32 cases, Kraus et al. have shown LOH on chromosome 1p in seven cases, LOH on 1q in seven cases, and LOH on both 1p and 1q in three more, suggesting that tumor suppressor genes at the telomeric region of chromosome arm 1p and different regions of chromosome arm 1q may be involved in the pathogenesis of hepatoblastoma.

Albrecht et al. noted LOH in 6 of 18 hepatoblastomas in 11p restricted to the telomeric region 11p15.5 and determined that the parental origin was exclusively maternal.

DNA analysis by fl ow cytometry has been reported in more than 70 cases, with a diploid pattern noted in the well-differenti-ated (fetal) portions of the tumors and an aneuploid pattern present in embryonal portions or in small cell (anaplastic) tumors.

Krober et al. noted an aneuploid peak in tumors with embryonal and fetal com-ponents when the areas were analyzed together and encour-aged analysis of all differing areas of a tumor if ploidy is to be used in drawing conclusions about the prognosis in individual cases.

Hata et al. noted an increased incidence of vascular invasion and a poorer prognosis in patients with an aneuploid tumor.

Terracciano et al. studied 35 hepatoblastoma specimens by CGH and found significant gains of genetic material.

The most frequent alterations were gains of Xp (15 cases, 43%) and Xq (21 cases, 60%), while other common alterations were 1p−, 2q+, 2q−, 4q−, and 4q+.

There was no difference between different histologic subtypes, suggesting a common clonal origin for the different components (179)

Cytogenetics (#15981236#)

Karyotyping of hepatoblastomas has revealed a recurrent pattern of chromosomal abnormalities.

The most common karyotypic changes are extra copies of entire
chromosomes (trisomies), sometimes in conjunction with other complex structural changes and often in association with double-minute chromosomes.

Trisomies of chromosomes 2 and 20 have each been reported most commonly, and each of these trisomies has been reported as a sole karyotypic event, suggesting that they may represent an early stage of tumor evolution.

Trisomy of chromosome 20 and duplication of the long arm of chromosome 20 have been also observed in rhabdomyosarcoma, suggesting a link between these 2 embryonal tumors, both of which are associated also with losses at the Beckwith-Wiedemann syndrome locus.

Trisomy of chromosome 8 is also common; other trisomies are seen with lesser frequency. Occasional losses of entire chromosomes are seen, and these, too, are not random.

The clinical significance of trisomies is at present unknown, although a recent study using comparative genomic hybridization has suggested that chromosomal gains at chromosome 8 and 20 may be associated with an adverse prognosis.

A unique translocation has been reported in undifferentiated small cell hepatoblastoma, a variant associated with a poor prognosis, although this cytogenetic variant has not been reported in other cases.

Constitutional cytogenetics

- constitutional trisomy 18-associated hepatoblastoma

  • constitutional trisomy 18 (Edward syndrome) (#19830224#, #11380930#, #9267879#, #9025831#, #1329941#, #2546426#, #3037903#)
  • constitutional mosaic trisomy 18 (#21113936#)

- partial trisomy 9p syndrome (#15588861#)

Tumoral cytogenetics

- abnormal karyotypes (50%)

- numerical aberrations (36%)

  • trisomies or gains
    • trisomy 1q, tetrasomy 1q (#10565309#, #11150606#)
    • trisomy 2, gains of 2q (#11150606#, #9351578#)
    • trisomy 8
    • trisomy 14, tetrasomy 14 (#10565309#)
    • trisomy 19 (#10565309#)
    • trisomy 20 (#11150606#, #9351578#)
  • deletions
    • del(1)(p22) (#15588850#)
    • del(3)(q11.2;q13.2)(#12034532#)
    • del(12)(p12) (#15588850#)
    • del(17p): del(17)(p12) (#7530489#)

- structural anomalies

  • translocations
    • 1q12-21 rearrangements (18%) (#15981236#)
      • t(1;1) (#11943350#)
      • t(1;4)(q12;q34) (#9258666#, #10812168#, #15981236#) (6%)
      • t(1;6)(q21;q26) (#19781440#)
    • 1q25
      • t(1;4)(q25.2;q35.1) (#19781440#)
    • t(3;5)(p25;q31) (#1377019#)
    • t(10;22) in undifferentiated small cell hepatoblastoma (#1384017#)
    • t(22;22)(q11;q13) in undifferentiated small cell hepatoblastoma (#12010372#)
    • t(7;8;11) (#11943350#)
    • t(2;11) (#11943350#)

- add(4)(q35) (#15588850#)
- add(5)(q31) (#10812168#)
- dup(4)(q12q26)

CGH (#10934159#, #10612809#, #11509117#)

Gains 1q 2p 2q 7q 8p 8q 12p 12q 17 20 22q
% 60% 70% - - - - - - 40% 30% -
Genes involved - - - - - PLAG1 - - - - -
Losses Chr.4 Chr.11
% 20% 20%

Gain
- 1q (#18271875#)
- 2q24 (#18271875#, #11509117#)

  • poor clinical outcome

High-grade amplifications
- 7q34 amplification
- 14q11.2 amplification
- 11q22.2 amplification (#18271875#)

- 8 (#18271875#)
- 17q (#18271875#)
- 20 (#18271875#)

Losses
- 4q (#18271875#, #11509117#)
- 11q (#18271875#)

Amplified regions

- 8q11.2-q13 amplification (#14695992#)
- 7q34 amplification
- 14q11.2 amplification
- 11q22.2 amplification
- PLAG1 amplification (#14695992#)

LOH

Allelic losses at multiple loci may implicate chromosomal instability as an important factor in development and progression of HB.

- 1q44 (73.3%) (#19453057#)
- 4q21-22 (26.7%) (#19453057#)
- 13q14 (73.3%) (RB1) (#19453057#)
- 17p13 (46.7%) (TP53) (#19453057#)
- 17q11.2 (86.7%) (NF1) (#19453057#)

- LOH at 11p15 (#7923113#, #15239143#)

  • 11p15.15 imprinted genes deregulation
  • high frequency of inactivation of the imprinted H19 gene in sporadic hepatoblastoma (#10404060#)
  • loss of imprinting at 11p15.5 locus (#7728748#)
  • IGF2 is a tumor suppressor gene at locus 11p15.
  • Mixed epithelial and mesenchymal histology is more frequently associated with LOH on chromosome 11p15.5 than pure epithelial histology. (#21053162#)
  • LOH on chromosome 11p15.5 is associated with a significantly increased incidence of relapse and a significantly shorter relapse-free survival in patients with hepatoblastoma. (#21053162#)
  • The risk of relapse is higher and the RFS lower both in standard-risk and high-risk patients with hepatoblastoma if they demonstrate the presence of LOH at 11p15.5. (#21053162#)

- 4q LOH

  • 4q deletions could be a poor prognostic factor

Gene amplification

- 1q32.1 amplification in hepatoblastoma (#20461752#)

  • MDM4 amplification at 1q32.1 (#20461752#)

Gene mutations

- APC mutations (APC-associated hepatoblastoma)

  • Germline APC mutations are not commonly seen in children with sporadic hepatoblastoma. (#18955873#)
  • APC mutations in children with hepatoblastoma from familial adenomatous polyposis kindreds. (#16126064#)

- Mutations of PTCH1, MLL2, and MLL3 are not frequent events in hepatoblastoma. [#22183980#]

Anomalies of methylation

- MT1G hypermethylation is a potential prognostic marker for hepatoblastoma. (#20032811#)

Allelotyping

- 11p15 LOH (#7923113#)

Transcriptional profiling (#12935928#)

siRNA

- Altered microRNA Expression Patterns in Hepatoblastoma Patients. (#19701500#)

Case records

- Case 12619: Small hepatoblastoma

Links

- hepatoblastoma at AGCOH

References

- Cytogenetics of hepatoblastoma. Tomlinson GE. Front Biosci (Elite Ed). 2012 Jan 1;4:1287-92. PMID: #22201954#

- Activation of Wnt and Myc signaling in hepatoblastoma. Cairo S, Armengol C, Buendia MA. Front Biosci (Elite Ed). 2012 Jan 1;4:480-6. PMID: #22201888#

- Loss of heterozygosity on chromosome 11p15.5 and relapse in hepatoblastomas. Chitragar S, Iyer VK, Agarwala S, Gupta SD, Sharma A, Wari MN. Eur J Pediatr Surg. 2011 Jan;21(1):50-3. PMID: #21053162#

- Genome-wide analysis of allelic imbalances reveals 4q deletions as a poor prognostic factor and MDM4 amplification at 1q32.1 in hepatoblastoma. Arai Y, Honda S, Haruta M, Kasai F, Fujiwara Y, Ohshima J, Sasaki F, Nakagawara A, Horie H, Yamaoka H, Hiyama E, Kaneko Y. Genes Chromosomes Cancer. 2010 Jul;49(7):596-609. PMID: #20461752#

- Cytogenetic and array comparative genomic hybridization analysis of a series of hepatoblastomas. Stejskalová E, Malis J, Snajdauf J, Pýcha K, Urbánková H, Bajciová V, Starý J, Kodet R, Jarosová M. Cancer Genet Cytogenet. 2009 Oct 15;194(2):82-7. PMID: #19781440#

- Comprehensive allelotyping of hepatoblastoma. Terada Y, Matsumoto S, Bando K, Tajiri T. Hepatogastroenterology. 2009 Jan-Feb;56(89):199-204. PMID: #19453057#

- Whole-genome profiling of chromosomal aberrations in hepatoblastoma using high-density single-nucleotide polymorphism genotyping microarrays. Suzuki M, Kato M, Yuyan C, Takita J, Sanada M, Nannya Y, Yamamoto G, Takahashi A, Ikeda H, Kuwano H, Ogawa S, Hayashi Y. Cancer Sci. 2008 Mar;99(3):564-70. PMID: #18271875#

- Cytogenetic evaluation of a large series of hepatoblastomas: numerical abnormalities with recurring aberrations involving 1q12-q21. Tomlinson GE, Douglass EC, Pollock BH, Finegold MJ, Schneider NR. Genes Chromosomes Cancer. 2005 Oct;44(2):177-84. PMID: #15981236#

- Cytogenetic abnormalities in hepatoblastoma: report of two new cases and review of the literature suggesting imbalance of chromosomal regions on chromosomes 1, 4, and 12. Nagata T, Nakamura M, Shichino H, Chin M, Sugito K, Ikeda T, Koshinaga T, Fukuzawa M, Inoue M, Mugishima H. Cancer Genet Cytogenet. 2005 Jan 1;156(1):8-13. PMID: #15588850#

- Allelic loss but absence of mutations in the polyspecific transporter gene BWR1A on 11p15.5 in hepatoblastoma. Albrecht S, Hartmann W, Houshdaran F, Koch A, Gärtner B, Prawitt D, Zabel BU, Russo P, Von Schweinitz D, Pietsch T. Int J Cancer. 2004 Sep 10;111(4):627-32. PMID: #15239143#

- Amplification and overexpression of the IGF2 regulator PLAG1 in hepatoblastoma. 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. Genes Chromosomes Cancer. 2004 Feb;39(2):126-37. PMID: #14695992#

- Comparative genomic hybridization analysis of hepatoblastoma reveals high frequency of X-chromosome gains and similarities between epithelial and stromal components. Terracciano LM, Bernasconi B, Ruck P, Stallmach T, Briner J, Sauter G, Moch H, Vecchione R, Pollice L, Pettinato G, Gürtl B, Ratschek M, De Krijger R, Tornillo L, Bruder E. Hum Pathol. 2003 Sep;34(9):864-71. PMID: #14562281#

- Genetic alterations in hepatoblastoma and hepatocellular carcinoma: common and distinctive aspects. Buendia MA. Med Pediatr Oncol. 2002 Nov;39(5):530-5. PMID: #12228912#

- Genetic abnormalities in a pre and post-chemotherapy hepatoblastoma. Mullarkey M, Breen CJ, McDermott M, O’Meara A, Stallings RL. Cytogenet Cell Genet. 2001;95(1-2):9-11. PMID: #11978962#

- 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. Kumon K, Kobayashi H, Namiki T, Tsunematsu Y, Miyauchi J, Kikuta A, Horikoshi Y, Komada Y, Hatae Y, Eguchi H, Kaneko Y. Jpn J Cancer Res. 2001 Aug;92(8):854-62. PMID: #11509117#

- Comparative genomic hybridization reveals population-based genetic alterations in hepatoblastomas. Gray SG, Kytölä S, Matsunaga T, Larsson C, Ekström TJ. Br J Cancer. 2000 Oct;83(8):1020-5. PMID: #10993649# (Free)

- Comparative genomic hybridization analysis of hepatoblastomas: additional evidence for a genetic link with Wilms tumor and rhabdomyosarcoma. Steenman M, Tomlinson G, Westerveld A, Mannens M. Cytogenet Cell Genet. 1999;86(2):157-61. PMID: #10545709#