Exon 3 mutations of<i>CTNNB1</i>drive tumorigenesis: a review

Gao, Chao; Wang, Yingmei; Broaddus, Russell R.; Sun, Longhao; Xue, Fengxia; Zhang, Wei

doi:10.18632/oncotarget.23695

Cited by 170 publications

(149 citation statements)

References 184 publications

(186 reference statements)

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“…As reported by previous studies, the majority of deleterious alterations in the CTNNB1 gene were restricted to the serine/threonine phosphorylation sites T41 and S45. In our study, T41A (n = 111/204; 54.4%), S45F (n = 40/204; 19.6%) and S45P (n = 18/204; 8.8%) were the most frequent amino acid exchanges affecting sites involved in the modulation of the interaction of β-catenin with several kinases: Sequential phosphorylation at T41, S33 and S37 is mediated by the glycogen synthase kinase 3 beta (GSK-3β), while S45 is phosphorylated by the casein kinase-1 alpha (CK1α) targeting β-catenin for ubiquitination and subsequently proteasomal www.nature.com/scientificreports www.nature.com/scientificreports/ degradation 5,22,23 . Mutations affecting these phosphorylation sites lead to stabilization and translocation of β-catenin into the nucleus where it acts as a transcriptional regulator.…”

Section: Discussionmentioning

confidence: 99%

Novel pathogenic alterations in pediatric and adult desmoid-type fibromatosis – A systematic analysis of 204 cases

Trautmann

Rehkämper

Gevensleben

et al. 2020

Sci Rep

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Desmoid-type fibromatosis (DTF, aggressive fibromatosis) is a non-metastasizing mesenchymal neoplasm of deep soft tissue with a tendency towards local recurrence. Genetic alterations affecting canonical Wnt/β-catenin signaling are reported in the majority of DTF. While most sporadic DTF harbor somatic mutations in CTNNB1, germline mutations in adenomatous polyposis coli (APC) are known to occur in hereditary DTF types (FAP, Gardner-Syndrome). Additional single nucleotide variants (SNVs) in AKT1 (E17K) and BRAF (V600E) were reported in pediatric DTF with potential clinical implications. We performed targeted next-generation sequencing (NGS) in a large cohort of 204 formalin-fixed DTF samples, comprising 22 pediatric cases (patients age ≤18 years). The mutational status was correlated with clinicopathological characteristics. Overall, deleterious CTNNB1 mutations were detected in 89% of DTF, most frequently affecting the serine/threonine phosphorylation sites T41 and S45 of β-catenin. While the T41A CTNNB1 mutation was significantly more often identified in the mesenterial localization, DTF originating from extra-intestinal sites more frequently harbored the S45P CTNNB1 alteration. Beyond common mutations in CTNNB1, additional SNVs were demonstrated in 7% of the DTF cohort and in 18% of the pediatric DTF subgroup. The mutational spectrum included deleterious mutations in AKT1 (G311S/D and T312I), ALK (R806H and G924S), AR (A159T), EGFR (P848L), ERBB2 (H174Y), IDH2 (H354Y), KIT (V559D), RET (T1038A), SDHA (R325M), and SDHD (R115W), as characterized by in silico prediction tools. In conclusion, our study indicates that DTF may harbor a broader mutational spectrum beyond CTNNB1 mutations, comprising targetable alterations including the herewith first reported imatinib-sensitive KIT V559D mutation in DTF. Desmoid-type fibromatosis (aggressive fibromatosis, desmoid tumor, DTF) is an infiltrating, locally aggressive myofibroblastic neoplasm of intermediate malignant potential highly prone to local recurrence without the potential for metastatic spread. The tumors typically arise in deep soft tissue compartments of intra-and extra-abdominal localization. Pediatric forms usually affect the extremities, while in adults also the mesenterium and the abdominal wall are commonly involved sites; the latter predominantly affected in women 1. The majority of DTF harbor mutations affecting the canonical Wnt/β-catenin signaling pathway 2. While in patients with familial adenomatous polyposis (FAP) β-catenin is not degraded through inactivating mutations in APC, most sporadic DTF harbor alterations in CTNNB1; both leading to a nuclear accumulation of β-catenin and an oncogenic activation of the Wnt/β-catenin signal transduction pathway 3-6. In the sporadic subtype, alterations in CTNNB1 seem to be focused on the serine/threonine phosphorylation sites T41 and S45 7,8 with a higher risk of local recurrence reported in association with the S45F CTNNB1 mutation 8,9. Currently, no evidence-based approach for the treatment of DTF is establ...

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Section: Discussionmentioning

confidence: 99%

Novel pathogenic alterations in pediatric and adult desmoid-type fibromatosis – A systematic analysis of 204 cases

Trautmann

Rehkämper

Gevensleben

et al. 2020

Sci Rep

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“…β-Catenin is a protein encoded by CTNNB1 and appears to be a key downstream effector of the Wnt pathway for regulating cell growth/survival [3]. This pathway is activated by genetic mutations including CTNNB1 exon 3 and adenomatous polyposis coli (APC) protein, that stabilize the β-catenin protein which accumulates in the cytoplasm and then translocates to the nucleus [4].…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemical and Molecular Analyses Focusing on Mesenchymal Cells in Papillary Thyroid Carcinoma with Desmoid-Type Fibromatosis

et al. 2018

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Objective: This study was designed to evaluate the prevalence of CTNNB1 (β-catenin) mutations in cases of papillary thyroid carcinoma with desmoid-type fibromatosis (PTC-DTF) expressing aberrant nuclear and cytoplasmic immunoreactivity for β-catenin. Methods: Eight cases of PTC-DTF were available for this study. Immunohistochemistry for β-catenin and BRAF^V600E was performed. CTNNB1 and BRAFV600E mutations were also evaluated by direct sequencing. Results: For β-catenin, although we could demonstrate aberrant nuclear and cytoplasmic immunoreactivity in DTF components in all cases, suggesting activated Wnt signaling, direct sequencing revealed a missense mutation, c.121A>G (p.T41A), in exon 3 in only one case, and no mutations in exons 3, 4, and 5 in the other cases. In the BRAF^V600E analyses, immunohistochemistry revealed positive staining in the carcinoma cells but not DTF components of all cases. These findings were subsequently validated by direct sequencing. Conclusion: This study suggests the significance of the BRAFV600E mutation and activation of Wnt signaling pathway in the carcinoma cells and DTF components, respectively. We believe that the CTNNB1 mutations are not the major factor behind β-catenin translocation indicating Wnt pathway activation. Further study is required to evaluate whether molecular abnormalities other than the CTNNB1 mutation cause activation of Wnt signaling in DTF components of PTC-DTF.

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“…The result of the change includes increased cell proliferation, enhanced immunosuppression, and disruption of metabolic regulation. 54 Reports suggested that mutations in APC can also correlate with high expression levels of CTNNB1, whereas wild-type APC expression can reduce CTNNB1 levels in CRC cells. 55,56 Irrespective of the expression level of this gene, it is regarded as an important indicator of malignancy.…”

Section: Discussionmentioning

confidence: 99%

In silico identification of microRNAs as candidate colorectal cancer biomarkers

2019

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The involvement of microRNA in cancers plays a significant role in their pathogenesis. Specific expressions of these non-coding RNAs also serve as biomarkers for early colorectal cancer diagnosis, but their laboratory/molecular identification is challenging and expensive. The aim of this study was to identify potential microRNAs for colorectal cancer diagnosis using in silico approach. Sequence similarity search was employed to obtain the candidate microRNA from the datasets, and three target prediction software were employed to determine their target genes. To determine the involvement of these microRNAs in colorectal cancer, the microRNA gene list obtained was used alongside with colorectal cancer expressed genes from gbCRC and CoReCG databases for gene intersection analysis. The involvement of these genes in the cancer subtype was further strengthened with the DAVID database. KEGG and Gene Ontology were used for the pathway and functional analysis, while STRING was employed for the interactions of protein network and further visualized by Cytoscape. The cBioPortal database was used to prioritize the target genes; prognostic and expression analysis were finally performed on the candidate microRNAs and the prioritized targets. This study, therefore, identified five candidate microRNAs, two hub genes (CTNNB1 and epidermal growth factor receptor), and seven significant target genes associated with colorectal cancer. The molecular validation studies are ongoing to ascertain the biological fitness of these findings.

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Exon 3 mutations ofCTNNB1drive tumorigenesis: a review

Cited by 170 publications

References 184 publications

Novel pathogenic alterations in pediatric and adult desmoid-type fibromatosis – A systematic analysis of 204 cases

Novel pathogenic alterations in pediatric and adult desmoid-type fibromatosis – A systematic analysis of 204 cases

Immunohistochemical and Molecular Analyses Focusing on Mesenchymal Cells in Papillary Thyroid Carcinoma with Desmoid-Type Fibromatosis

In silico identification of microRNAs as candidate colorectal cancer biomarkers

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