Hepatocellular adenoma associated with familial adenomatous polyposis coli

Sakaguchi, Takanori; Kurachi, Kiyotaka; Mori, Hiroki; Hong, Tao; Nakamura, Toshio; Takehara, Yasuo; Baba, Shigeaki; Maekawa, Masato; Sugimura, Haruhiko; Konno, Hiroyuki

doi:10.4254/wjh.v4.i11.322

Cited by 11 publications

(7 citation statements)

References 27 publications

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“…In our series, activated WNT signalling was found in 10% of HCA (8% b-HCA and 2% b-IHCA, respectively). Although individual cases have been reported in the context of familial adenomatous polyposis coli (due to germ-line mutations of the adenomatous polyposis coli gene)31 as present in one patient with b-IHCA in this series, CTNNB1 mutations are considered the driving force of the vast majority of β-catenin-activated HCAs 11 6–9 which was confirmed in our series and emphasises that the reliable identification of b-HCA and b-IHCA subtypes among all HCAs has particular clinical relevance.…”

Section: Discussionmentioning

confidence: 99%

RSPO2 gene rearrangement: a powerful driver of β-catenin activation in liver tumours

Longerich

Endris

Neumann

et al. 2019

Gut

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ObjectiveWe aimed at the identification of genetic alterations that may functionally substitute for CTNNB1 mutation in ß-catenin-activated hepatocellular adenomas (HCAs) and hepatocellular carcinoma (HCC).DesignLarge cohorts of HCA (n=185) and HCC (n=468) were classified using immunohistochemistry. The mutational status of the CTNNB1 gene was determined in ß-catenin-activated HCA (b-HCA) and HCC with at least moderate nuclear CTNNB1 accumulation. Ultra-deep sequencing was used to characterise CTNNB1wild-type and ß-catenin-activated HCA and HCC. Expression profiling of HCA subtypes was performed.ResultsA roof plate-specific spondin 2 (RSPO2) gene rearrangement resulting from a 46.4 kb microdeletion on chromosome 8q23.1 was detected as a new morphomolecular driver of β-catenin-activated HCA. RSPO2 fusion positive HCA displayed upregulation of RSPO2 protein, nuclear accumulation of β-catenin and transcriptional activation of β-catenin-target genes indicating activation of Wingless-Type MMTV Integration Site Family (WNT) signalling. Architectural and cytological atypia as well as interstitial invasion indicated malignant transformation in one of the RSPO2 rearranged b-HCAs. The RSPO2 gene rearrangement was also observed in three β-catenin-activated HCCs developing in context of chronic liver disease. Mutations of the human telomerase reverse transcriptase promoter—known to drive malignant transformation of CTNNB1-mutated HCA—seem to be dispensable for RSPO2 rearranged HCA and HCC.ConclusionThe RSPO2 gene rearrangement leads to oncogenic activation of the WNT signalling pathway in HCA and HCC, represents an alternative mechanism for the development of b-HCA and may drive malignant transformation without additional TERT promoter mutation.

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Section: Discussionmentioning

confidence: 99%

RSPO2 gene rearrangement: a powerful driver of β-catenin activation in liver tumours

Longerich

Endris

Neumann

et al. 2019

Gut

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“…The highest prevalence is described in females taking oral contraceptives, but other risk factors, such as anabolic steroid use, obesity and metabolic syndrome are described [ 2 – 5 ]. Inherited syndromes such as glycogenosis type 1, maturity-onset diabetes of the young type 3 (MODY3), and familial adenomatous polyposis have also been linked to the development of HCA [ 3 , 5 , 6 ]. HCA can be solitary or multiple, with “liver adenomatosis” defined as presence of multiple HCA (>10) of any size involving all liver segments [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Hepatocellular adenoma classification: a comparative evaluation of immunohistochemistry and targeted mutational analysis

et al. 2016

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BackgroundFour subtypes of hepatocellular adenomas (HCA) are recognized: hepatocyte-nuclear-factor-1α mutated (H-HCA), β-catenin-mutated type with upregulation of glutamine synthetase (b-HCA), inflammatory type (IHCA) with serum-amyloid-A overexpression, and unclassified type. Subtyping may be useful since b-HCA appear to have higher risk of malignant transformation. We sought to apply subtype analysis and assess histological atypia, correlating these with next-generation sequencing analysis.MethodsTwenty-six HCA were stained with serum amyloid A (SAA), liver fatty acid-binding protein (LFABP), glutamine synthetase (GS), and β-catenin IHC, followed by analysis with a targeted multiplex sequencing panel.ResultsBy IHC, 4 HCA (15.4 %) were classified as b-HCA, 11 (42.3 %) as IHCA, 9 (34.6 %) as H-HCA, and two (7.7 %) unclassifiable. Eight HCA (30.8 %) showed atypia (3 b-HCA, 4 IHCA and 1 H-HCA). Targeted sequencing confirmed HNF1A mutations in all H-HCA, confirming reliability of LFABP IHC in identifying these lesions. CTNNB1 mutations were detected in 1 of 4 (25 %) of GS/β-catenin-positive cases, suggesting that positive GS stain does not always correlate with CTNNB1 mutations.ConclusionsImmunohistochemistry does not consistently identify b-HCA. Mutational analysis improves the diagnostic accuracy of β-catenin-mutated HCA and is an important tool to assess risk of malignancy in HCA.

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“…Apc, a tumor suppressor in the Wnt signaling pathway, is commonly mutated in hepatic adenomas (28), hepatoblastomas (29) and HCCs (30). Our Apc TALENs were designed to target exon 9 (Fig.…”

Section: Resultsmentioning

confidence: 99%

TALEN-Mediated Somatic Mutagenesis in Murine Models of Cancer

Zhang

Kendrick

et al. 2014

Cancer Research

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Cancer genome sequencing has identified numerous somatic mutations whose biological relevance is uncertain. In this study, we used genome-editing tools to create and analyze targeted somatic mutations in murine models of liver cancer. TALEN were designed against β-catenin (Ctnnb1) and Apc, two commonly mutated genes in hepatocellular carcinoma (HCC), to generate isogenic HCC cell lines. Both mutant cell lines exhibited evidence of Wnt pathway dysregulation. We asked if these TALENs could create targeted somatic mutations after hydrodynamic transfection (HDT) into mouse liver. TALENs targeting β-catenin promoted endogenous HCC carrying the intended gain-of-function mutations. However, TALENs targeting Apc were not as efficient in inducing in vivo homozygous loss-of-function mutations. We hypothesized that hepatocyte polyploidy might be protective against TALEN-induced loss of heterozygosity (LOH), and indeed Apc gene editing was less efficient in tetraploid than in diploid hepatocytes. To increase efficiency, we administered adenoviral Apc TALENs and found that we could achieve a higher mutagenesis rate in vivo. Our results demonstrate that genome-editing tools can enable the in vivo study of cancer genes and faithfully recapitulate the mosaic nature of mutagenesis in mouse cancer models.

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Hepatocellular adenoma associated with familial adenomatous polyposis coli

Cited by 11 publications

References 27 publications

RSPO2 gene rearrangement: a powerful driver of β-catenin activation in liver tumours

RSPO2 gene rearrangement: a powerful driver of β-catenin activation in liver tumours

Hepatocellular adenoma classification: a comparative evaluation of immunohistochemistry and targeted mutational analysis

TALEN-Mediated Somatic Mutagenesis in Murine Models of Cancer

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