The Role of CTNNB1 in Endometrial Cancer

Abstract

Endometrial cancer (EC) is the most common gynaecologic malignancy in the developed countries. Recent evidence suggests that histopathological subtyping together with molecular subgrouping can lead to more accurate assessment of the risk profile for the patient. Clinical studies suggest the currently used molecular classification improves the risk assessment of women with endometrial cancer but does not explain the differences in recurrence profiles clearly. This could be improved by novel markers. One of such are mutations in the β-catenin (CTNNB1) gene, a frequently mutated gene in endometrial cancer. This shows mutations mostly at phosphorylation sites of the β-catenin and almost exclusively in the endometrial subgroup of no specific molecular profile. CTNNB1 mutations lead to alterations in the Wnt/β-catenin signalling pathway, involved in the carcinogenesis and progression of EC by inducing transcription of target genes, whose function is to regulate the cell cycle. Although tumours with mutations in CTNNB1 tend to have low-risk characteristics, they are related to worse outcomes with significantly increased rate of disease recurrence and lower overall survival.

Figure 1

Diagram of risk stratification for patients with EC based on WHO Classification of Tumours (5^th edition) and ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma considering molecular subtypes of EC [5, 7].

Figure 2

Study selection process.

Figure 3

Intracellular functions of β-catenin. β-Catenin as adherent junction protein is (together with γ-catenin) attached to cadherin via δ-1 catenin or p120 protein, both are also attached to α-catenin, which is connected to the actin filaments of cytoskeleton. Intracellular function of Wnt/β-catenin pathway is shown in the presence and absence of Wnt ligand. (a) In the absence of Wnt ligand, β-catenin is phosphorylated by the destruction complex containing axin, adenomatous polyposis coli protein (APC), glycogen synthase kinase 3 beta (GSK-3β), and casein kinase 1α (CK1α), ubiquitinated by F-box/WD repeat-containing protein 1A (β-TrCP or Fbxw1), and targeted for proteasomal degradation. In the absence of β-catenin, the transcription complex T cell factor/lymphoid enhancer factor family LEF/TCF remains repressed. (b) When Wnt ligands bind to Frizzled (Fzd) receptors and lipoprotein receptor-related protein (LRP) coreceptors the latter being responsible for recruiting dishevelled (Dvl) polymers which inactivate the destruction complex leading to the accumulation of β-catenin in the cytosol. β-Catenin is translocated from the cytosol to the nucleus where it forms and active complex with LEF/TCF proteins and other histone modifying coactivators^∗∗ leading to transcription of multiple genes, involved in the process of cell maturation and proliferation [24].

Figure 4

Mapped mutations of CTNNB1 in EC based on available data from the TCGA, COSIMC, and cBioPortal databases. Diagram represents the number of identified mutations (logarithmic scale) of specific amino acid in the amino acid sequence of CTNNB1 gene. Exon 3 encodes for 75 amino acids (from 5^th to 80^th) where we can see a spike in the number of identified mutations in EC tumours. Other mutations are scattered throughout the whole gene, but few have been detected in more than one tumour sample.