CTNNB1

Definition: Protein encoded by CTNNB1 gene, coordinates cell–cell adhesion and gene transcription.

Function

 Part of Wnt signalling pathway, highly conserved pathway with critical role in embryologic development (Dev Cell 2009;17:9), carcinogenesis and epithelial-to-mesenchymal transition.

 Upon Wnt activation, β-catenin is translocated from membrane (where it interacts with E-cadherin) to cytoplasm and nucleus, where it interacts with transcriptional activators

 Beta-catenin is an adherens junction protein. Beta-Catenin is a multifunctional protein related to the adherens junction and to signal transduction.

 Beta-catenin is a key molecule of cell proliferation. Its role is central to epithelial architecture, regulating the polarity of cells and tissues.

 Beta-catenin (CTNNB1) (MIM.116806) and plakoglobin are substrates for tyrosine phosphorylation following EGF stimulation of cells.

Features

 cadherin-catenin complex
 beta-catenin/APC pathway

Targets - Ligands

 Wnt

Pathology

 somatic mutations in tumors

• somatic mutations in colorectal adenocarcinoma
• somatic mutations in hepatoblastoma (9927029, 10398436, 10698519, 10754205, 11309340, 11666046, 11813174, 12101426)
• somatic mutations in endometrioid ovarian carcinoma
• somatic mutations in medulloblastoma
• somatic mutations in deep desmoid fibromatosis (deep desmoid tumor)
• somatic mutations in pilomatricoma (pilomatrixoma) (MIM.116806) (11472567)
• somatic mutations in adenoid cystic carcinoma (15195113)
• somatic mutations in pancreatic solid-pseudopapillary tumor (83%) (11731417)
• somatic mutations in pancreatoblastoma (11696422)
• somatic mutations in Wilms tumor (10463574, 11103785)
• missense mutations in classic pulmonary blastoma (15223963)
• somatic mutations in adamantinomatous craniopharyngioma
• somatic mutations in calcifying odontogenic cysts (14578169)
• somatic mutations in nasopharyngeal juvenile angiofibroma (11238055)
• somatic mutations in sporadic fundic gland polyps (11238048)
• somatic mutations in poorly differentiated (25%) and undifferentiated thyroid carcinomas (21.4%) (11238046)
• somatic mutations in low-stage hepatocellular carcinoma negative for hepatitis B virus

 promoter swapping

• promoter swapping between the genes for zinc finger protein PLAG1 and beta-catenin CTNNB1 in pleiomorphic adenoma with t(3;8)(p21;q12) translocations

 Mutations and overexpression of β-catenin are associated with various carcinomas
Colon: plays a critical role in tumorigenesis (mutations in APC or β-catenin present in 90% of colon cancers)
 Thyroid: pathway important for anaplastic and possibly papillary thyroid carciomas (Front Endocrinol (Lausanne) 2012;3:31)
 Uterus: endometrioid endometrial carcinoma is associated with β-catenin mutations

Diagnostic immunochemistry

 Nuclear staining is significant in fibroblasts;
 nuclear or cytoplasmic staining is significant in epithelial cells

 hepatocellular adenoma

• Classify hepatocellular adenoma subtypes and distinguish from focal nodular hyperplasia (Am J Surg Pathol 2012;36:1691, Int J Hepatol 2013;2013:268625, Hum Pathol 2013;44:750)

 desmoid fibromatosis

• IHC positive with nuclear positivity
• mutated in fibromatosis (Mod Pathol 2012;25:1551)
• Distinguish mesenteric fibromatosis (positive with nuclear staining due to mutations in APC / β-catenin pathway causing nuclear accumulation) from GIST tumors (negative) and sclerosing mesenteritis (negative, Am J Surg Pathol 2002;26:1296)

 desmoid fibromatosis vs low-grade fibromyxoid sarcoma differential diagnosis

• beta-catenin expression in desmoid fibromatosis / negative in low-grade fibromyxoid sarcoma
• Distinguish fibromatosis (diffuse or rarely focal nuclear staining for deep tumors) from low grade fibromyxoid sarcoma and other myofibroblastic, or fibroblastic tumors / sarcomas (negative for nuclear staining, Am J Surg Pathol 2005;29:653)

 neuroblastoma

• Identify isolated tumor cells in neuroblastoma (Am J Clin Pathol 2009;131:49)

 nasopharyngeal carcinoma

• Poor prognostic factor for nasopharyngeal carcinoma (Hum Pathol 2013;44:1357)

 renal cell carcinoma (RCC)

• Cytoplasmic expression of ß-catenin is an independent predictor of progression of conventional renal cell carcinoma: a simple immunostaining score (doi : 10.1111/his 13059)

Reviews

 Mizumoto K, Sawa H. Two betas or not two betas: regulation of asymmetric division by beta-catenin. Trends Cell Biol. 2007 Oct;17(10):465-73. Epub 2007 Oct 4. Review. PMID: 17919911

 Nathke I. Cytoskeleton out of the cupboard: colon cancer and cytoskeletal changes induced by loss of APC. Nat Rev Cancer. 2006 Dec;6(12):967-74. PMID: 17093505

 Lilien J, Balsamo J. The regulation of cadherin-mediated adhesion by tyrosine phosphorylation/dephosphorylation of beta-catenin. Curr Opin Cell Biol. 2005 Oct;17(5):459-65. PMID: 16099633

 Brembeck FH, Rosario M, Birchmeier W. Balancing cell adhesion and Wnt signaling, the key role of beta-catenin. Curr Opin Genet Dev. 2006 Feb;16(1):51-9. PMID: 16377174

 Harris TJ, Peifer M. Decisions, decisions: beta-catenin chooses between adhesion and transcription. Trends Cell Biol. 2005 May;15(5):234-7. PMID: 15866026

 Bhattacharya B, Dilworth HP, Iacobuzio-Donahue C, Ricci F, Weber K, Furlong MA, Fisher C, Montgomery E. Nuclear beta-Catenin Expression Distinguishes Deep Fibromatosis From Other Benign and Malignant Fibroblastic and Myofibroblastic Lesions. Am J Surg Pathol. 2005 May;29(5):653-659. PMID: 15832090

 Bienz M. beta-Catenin: A Pivot between Cell Adhesion and Wnt Signalling. Curr Biol. 2005 Jan 26;15(2):R64-7. PMID: 15668160

 Moon RT, Kohn AD, Ferrari GV, Kaykas A. WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet. 2004 Sep;5(9):691-701. PMID: 15372092

References

 β-Catenin (CTNNB1) mutations and clinicopathological features of mesenteric desmoid-type fibromatosis. Huss S, Nehles J, Binot E, Wardelmann E, Mittler J, Kleine MA, Künstlinger H, Hartmann W, Hohenberger P, Merkelbach-Bruse S, Buettner R, Schildhaus HU. Histopathology. 2013 Jan;62(2):294-304. doi : 10.1111/j.1365-2559.2012.04355.x PMID: 23020601

 Amary MF, Pauwels P, Meulemans E, Roemen GM, Islam L, Idowu B, Bousdras K, Diss TC, O’Donnell P, Flanagan AM. Detection of beta-catenin mutations in paraffin-embedded sporadic desmoid-type fibromatosis by mutation-specific restriction enzyme digestion (MSRED): an ancillary diagnostic tool. Am J Surg Pathol. 2007 Sep;31(9):1299-309. PMID: 17721184