Hepatocellular Carcinomas with Concomitant Mutations of TERT, TP53, and CTNNB1: Is There a Role for Artificial Intelligence?
TP53, CTNNB1, and TERT-promoter mutations are the most common driver mutations in hepatocellular carcinoma (HCC). The morphological and genetical HCC heterogeneities are difficult to discriminate by the eye of the pathologist. Here, we describe two rare cases of HCC with simultaneous co-mutation of all three of genes, which represent a poorly described occurrence in the literature. In these two cases, areas with different tumor grade and different β-catenin and Glutamine Synthetase expression (performed by automated immunohistochemistry) were observed. NGS analysis was performed in these different areas, to check for potential diversity of mutation burden on the different regions, but no differences were found: all micro-areas analyzed showed the co-presence of mutations in TP53, CTNNB1, and TERT. The evidence that all mutations were found in all the different areas analyzed by NGS leads to hypothesize that the tumor is not composed of different clones harboring different mutations. All the variants are harbored by the same neoplastic clone, albeit leading to different phenotypes. Mutation prediction Artificial Intelligence models could help the morpho-genetic classification of HCC in the future, since they can find variabilities not obvious to the human eye, with increased sensitivity, specificity and reproducibility.
GeneCard
TERT gene https://www.genecards.org/Search/Keyword?queryString=TERT
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Telomerase is a ribonucleoprotein polymerase that maintains telomere ends by addition of the telomere repeat TTAGGG. The enzyme consists of a protein component with reverse transcriptase activity, encoded by this gene, and an RNA component which serves as a template for the telomere repeat. Telomerase expression plays a role in cellular senescence, as it is normally repressed in postnatal somatic cells resulting in progressive shortening of telomeres. Deregulation of telomerase expression in somatic cells may be involved in oncogenesis. Studies in mouse suggest that telomerase also participates in chromosomal repair, since de novo synthesis of telomere repeats may occur at double-stranded breaks. Alternatively spliced variants encoding different isoforms of telomerase reverse transcriptase have been identified; the full-length sequence of some variants has not been determined. Alternative splicing at this locus is thought to be one mechanism of regulation of telomerase activity. [provided by RefSeq, Jul 2008
Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes. Active in progenitor and cancer cells. Inactive, or very low activity, in normal somatic cells. Catalytic component of the teleromerase holoenzyme complex whose main activity is the elongation of telomeres by acting as a reverse transcriptase that adds simple sequence repeats to chromosome ends by copying a template sequence within the RNA component of the enzyme. Catalyzes the RNA-dependent extension of 3'-chromosomal termini with the 6-nucleotide telomeric repeat unit, 5'-TTAGGG-3'. The catalytic cycle involves primer binding, primer extension and release of product once the template boundary has been reached or nascent product translocation followed by further extension. More active on substrates containing 2 or 3 telomeric repeats. Telomerase activity is regulated by a number of factors including telomerase complex-associated proteins, chaperones and polypeptide modifiers. Modulates Wnt signaling. Plays important roles in aging and antiapoptosis. ( TERT_HUMAN,O14746 ) .
CTNNB1 gene Aliases for CTNNB1 Gene
NCBI Gene Summary for CTNNB1 Gene
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The protein encoded by this gene is part of a complex of proteins that constitute adherens junctions (AJs). AJs are necessary for the creation and maintenance of epithelial cell layers by regulating cell growth and adhesion between cells. The encoded protein also anchors the actin cytoskeleton and may be responsible for transmitting the contact inhibition signal that causes cells to stop dividing once the epithelial sheet is complete. Finally, this protein binds to the product of the APC gene, which is mutated in adenomatous polyposis of the colon. Mutations in this gene are a cause of colorectal cancer (CRC), pilomatrixoma (PTR), medulloblastoma (MDB), and ovarian cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016
UniProtKB/Swiss-Prot Summary for CTNNB1 Gene
Key downstream component of the canonical Wnt signaling pathway (PubMed:17524503, 18077326, 18086858, 18957423, 21262353, 22155184, 22647378, 22699938). In the absence of Wnt, forms a complex with AXIN1, AXIN2, APC, CSNK1A1 and GSK3B that promotes phosphorylation on N-terminal Ser and Thr residues and ubiquitination of CTNNB1 via BTRC and its subsequent degradation by the proteasome (PubMed:17524503, 18077326, 18086858, 18957423, 21262353, 22155184, 22647378, 22699938). In the presence of Wnt ligand, CTNNB1 is not ubiquitinated and accumulates in the nucleus, where it acts as a coactivator for transcription factors of the TCF/LEF family, leading to activate Wnt responsive genes (PubMed:17524503, 18077326, 18086858, 18957423, 21262353, 22155184, 22647378, 22699938). Involved in the regulation of cell adhesion, as component of an E-cadherin:catenin adhesion complex (By similarity). Acts as a negative regulator of centrosome cohesion (PubMed:18086858). Involved in the CDK2/PTPN6/CTNNB1/CEACAM1 pathway of insulin internalization (PubMed:21262353). Blocks anoikis of malignant kidney and intestinal epithelial cells and promotes their anchorage-independent growth by down-regulating DAPK2 (PubMed:18957423). Disrupts PML function and PML-NB formation by inhibiting RANBP2-mediated sumoylation of PML (PubMed:22155184). Promotes neurogenesis by maintaining sympathetic neuroblasts within the cell cycle (By similarity). Involved in chondrocyte differentiation via interaction with SOX9: SOX9-binding competes with the binding sites of TCF/LEF within CTNNB1, thereby inhibiting the Wnt signaling (By similarity). Acts as a positive regulator of odontoblast differentiation during mesenchymal tooth germ formation, via promoting the transcription of differentiation factors such as LEF1, BMP2 and BMP4 (By similarity). Activity is repressed in a MSX1-mediated manner at the bell stage of mesenchymal tooth germ formation which prevents premature differentiation of odontoblasts (By similarity). ( CTNB1_HUMAN,P35222 )
Tocris Summary for CTNNB1 Gene
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beta-catenin protein is an integral part of the canonical Wnt signaling pathway. Wnt binding to Frizzled (Fz) receptors and LRP co-receptors activates Dishevelled (Dsh) proteins; these in turn inhibit the destruction complex responsible for degrading beta-catenin, which includes GSK-3.
Human Phenotype Ontology for CTNNB1 Genevitreoretinopathy etc.-
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