β‐catenin accumulation and mutation of the CTNNB1 gene in hepatoblastoma

Bläker, Hendrik; Hofmann, Walter; Rieker, Ralf J.; Penzel, Roland; Graf, Matthias M.; Otto, Herwart F.

doi:10.1002/(sici)1098-2264(199908)25:4<399::aid-gcc14>3.3.co;2-o

Cited by 33 publications

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“…5,26 The detection of b-catenin mutations and/or protein accumulation in the majority of our hepatoblastoma cases (15/21; 71%) confirms that Wnt signal activation is implicated in the pathogenesis of sporadic hepatoblastoma. [5][6][7] Our results are in agreement with the studies of Koch et al, 5,27 who detected b-catenin point mutations in 22 and 25% of their sporadic hepatoblastoma cases, while Taniguchi et al reported a slightly higher percentage (33%) of mutated cases. 28 As reported by Takayasu et al, 25 we observed that the hepatoblastoma cases with b-catenin protein accumulation were much more numerous than the cases with identified b-catenin mutations.…”

Section: Discussionsupporting

confidence: 91%

“…In fact, double-hit inactivation of the APC gene has been demonstrated in familial adenomatous polyposis-associated hepatoblastoma. [4][5][6][7][8] Furthermore, mutations affecting the phosphorylation sites encoded in exon 3 of b-catenin (a mutation hot-spot in several epithelial cancers) have been detected in sporadic hepatoblastoma, where APC mutations seem to be rare. [4][5][6][7][8] Somatic mutations in exons 5-8 of the p53 gene, which encode the DNA-binding region where cancer-associated mutations most frequently occur, [9][10][11] are strongly implicated in the progression of the common adult form of liver cancer, hepatocellular carcinoma.…”

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confidence: 99%

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Sporadic childhood hepatoblastomas show activation of β-catenin, mismatch repair defects and p53 mutations

et al. 2008

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Hepatoblastoma, a rare embryonic tumor that may arise sporadically or in the context of hereditary syndromes (familial adenomatous polyposis and Beckwith-Wiedemann's) is the most frequent liver cancer of childhood. Deregulation of the APC/b-catenin pathway occurs in a consistent fraction of hepatoblastomas, with mutations in the APC and b-catenin genes implicated in familial adenomatous polyposis-associated and sporadic hepatoblastomas, respectively. Alterations in other cancer-related molecular pathways have not been reported. We investigated a series of 21 sporadic paraffin-embedded hepatoblastoma cases for mutations in the p53 (exons 5-8) and b-catenin (exon 3) genes, loss of heterozygosity at APC, microsatellite instability and immunohistochemical expression of b-catenin and of the two main mismatch repair proteins, MLH1 and MSH2. No loss of heterozygosity at APC was detected. We found mutations in b-catenin and p53 in 4/21 (19%) and 5/21 (24%) cases respectively, b-catenin protein accumulation in 14/21 cases (67%), microsatellite instability in 17/21 cases (81%), of which eight resulted positive for high-level of microsatellite instability (in four cases associated with loss of MLH1/MSH2 immunostaining). No correlations between involved molecular pathway(s) and hepatoblastoma histotype(s) emerged. This study confirms that b-catenin deregulation is involved in sporadic hepatoblastoma and also suggests that mismatch repair defects and p53 mutations contribute to this rare liver cancer. Sporadic hepatoblastoma appears to be molecularly and phenotypically heterogeneous and may reflect different pathways of liver carcinogenesis.

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Section: Discussionsupporting

confidence: 91%

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confidence: 99%

Sporadic childhood hepatoblastomas show activation of β-catenin, mismatch repair defects and p53 mutations

et al. 2008

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“…Involvement of the canonical and non-canonical Wnt pathway in liver oncogenesis has been described by various investigators [59][60][61][62][63][64][65][66][67]. One of the most frequently described mechanisms for activation of the canonical signaling pathway in HCC involves activation of β-catenin through mutations in the CTNNB1 gene.…”

Section: Disturbances In Wnt/β-catenin Pathway In Liver Carcinogenesismentioning

confidence: 99%

“…This is accompanied by overexpression/repression of other genes involved in transmission of signals to the cell nucleus, with the resulting intensification of proliferation, migration and cellular invasion. At the molecular level, a characteristic trait described in hepatocellular tumors involves nuclear or cytoplasmic accumulation of β-catenin, detected in a higher proportion of cells in cases of hepatoblastoma (50-80%) than in HCC (8-40%) [60,[62][63][64]68]. Taniguchi et al detected CTNNB1 mutations in 19% of HCC and in 70% of hepatoblastoma cases.…”

Section: Disturbances In Wnt/β-catenin Pathway In Liver Carcinogenesismentioning

confidence: 99%

Alterations of Wnt/β-catenin signaling pathway in hepatocellular carcinomas associated with hepatitis C virus

Rogacki¹,

Kasprzak²,

Stępiński³

2015

pjp

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“…Chromosomal variations occur frequently in HB, having been reported in up to 88% of cases in a genome profiling study. 16 The most likely candidate genes identified thus far are CTNNB1 (catenin, beta-1-catenin) 17 and insulin-like growth factor II (IGF2) tumour suppressor at locus 11p15. 18,19 In addition, more than 85% of HBs show accumulation of β-catenin which indicates an activated Wingless-type (Wnt) pathway.…”

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confidence: 99%

Lessons from the hepatoblastoma-familial polyposis connection

2012

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Hepatoblastoma (HB) is the most common primary liver cancer of childhood, accounting for up to 1% of all paediatric malignancies, particularly in the younger child. HB is associated with congenital abnormalities in approximately one-third of patients, suggesting complex genetic and/or epigenetic factors in its pathogenesis. 1,2 In addition to an association with low birth weight, there are several linked genetic diseases including overgrowth syndromes such as Beckwith-Wiedemann syndrome, chromosomally linked conditions (trisomies 2, 8 and 20) and X-linked Simpson-Golabi-Behmel syndrome, type 1 glycogen storage diseases, Li-Fraumeni syndrome, familial adenomatous polyposis (FAP) 3-6 and type 1 neurofibromatosis. 7Familial recurrence of HB is extremely rare outside of associated adenomatous polyposis coli (APC) families, 8 and a causative relationship between HB and interstitial deletions of 5q21.3-q23.3 (the APC gene region) is well known.9 Consequently, offspring of FAP families have a 750 -7 500 times higher risk of developing HB. 10,11 Although 75 -80% of FAP individuals have APC gene mutations, there is a group with non-typical de novo genetic variation.6 As a result, the screening of HB patients for APC gene variation in cases of childhood HB without a family FAP history remains an open discussion. It appears to be important to identify these high-risk individuals and perform long-term screening to improve their management.We aimed to investigate HB-FAP gene associations and clinical implications in a South African population. MethodsBased on available clinical data of 2 known FAP families, a local database of 113 FAP cases (1989113 FAP cases ( -2010 was investigated for HB associations. Data were analysed for details of clinical problem, treatment, complications and management. Long-term morbidity and functional outcome were analysed to identify management difficulties. ResultsHB was evident in the offspring of 3/113 known FAP cases (2.65%). Case 1A 2-year-old child re-presented after absconding half-way through a course of chemotherapy (cisplatinum and doxorubicin (PLADO)) for a stage 4 HB. Lung metastases were excised and a right hemi-hepatectomy of a calcified tumour was performed with removal of an additional localised lesion in the left lobe of the liver (Fig. 1). He has survived into adulthood (22 years) without further HB metastatic events. He presented with rectal bleeding at 14 years of age and a pedunculated adenomatous polyp was identified on colonoscopy and removed. He subsequently developed multiple rectal and colonic polyps, for which a total colectomy was performed. Recurrence of rectal polyps in his rectal stump necessitated revision of the lower rectal stump and fashioning of a pouch. Genetic studies identified an APC gene mutation (exon 6 codon 232 C→T). Further investigation of family history revealed relations to a large well-known FAP mixed-ancestry family with >20 affected patients. Case 2A mixed-ancestry male infant in a family without any FAP history was diagnosed with HB in the l...

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β‐catenin accumulation and mutation of the CTNNB1 gene in hepatoblastoma

Cited by 33 publications

References 0 publications

Sporadic childhood hepatoblastomas show activation of β-catenin, mismatch repair defects and p53 mutations

Sporadic childhood hepatoblastomas show activation of β-catenin, mismatch repair defects and p53 mutations

Alterations of Wnt/β-catenin signaling pathway in hepatocellular carcinomas associated with hepatitis C virus

Lessons from the hepatoblastoma-familial polyposis connection

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