β-Catenin accumulation and S33F mutation of CTNNB1 gene in colorectal cancer in Saudi Arabia

Alomar, Suliman Yousef; Mansour, Lamjed; Abuderman, Abdulwahab; Alkhuriji, Afrah Fahad; Arafah, Maha; Alwasel, Saleh; Harrath, Abdel Halim; Almutairi, Mikhlid H.; Trayhyrn, Paul; Dar, Javid A.

doi:10.5114/pjp.2016.61452

Cited by 12 publications

(13 citation statements)

References 33 publications

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“…Corresponding non-tumorous tissue did not reveal a mutation. Our finding comprehends the previous study carried out by Alomar and colleagues which screened CTNNB1 gene in 60 colorectal cancer patients from Kingdom of Saudi Arabia (KSA) and revealed an activating mutation (S33F) in one of the tumor samples [52]. Our observations also analyzed the grade of β-catenin protein of the CTNNB1 gene in colorectal cancer in Pakistani population.…”

Section: Discussionsupporting

confidence: 88%

Screening and computational analysis of colorectal associated non-synonymous polymorphism in CTNNB1 gene in Pakistani population

et al. 2019

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BackgroundColorectal cancer (CRC) is categorized by alteration of vital pathways such as β-catenin (CTNNB1) mutations, WNT signaling activation, tumor protein 53 (TP53) inactivation, BRAF, Adenomatous polyposis coli (APC) inactivation, KRAS, dysregulation of epithelial to mesenchymal transition (EMT) genes, MYC amplification, etc. In the present study an attempt was made to screen CTNNB1 gene in colorectal cancer samples from Pakistani population and investigated the association of CTNNB1 gene mutations in the development of colorectal cancer.Methods200 colorectal tumors approximately of male and female patients with sporadic or familial colorectal tumors and normal tissues were included. DNA was extracted and amplified through polymerase chain reaction (PCR) and subjected to exome sequence analysis. Immunohistochemistry was done to study protein expression. Molecular dynamic (MD) simulations of CTNNB1WT and mutant S33F and T41A were performed to evaluate the stability, folding, conformational changes and dynamic behaviors of CTNNB1 protein.ResultsSequence analysis revealed two activating mutations (S33F and T41A) in exon 3 of CTNNB1 gene involving the transition of C.T and A.G at amino acid position 33 and 41 respectively (p.C33T and p.A41G). Immuno-histochemical staining showed the accumulation of β-catenin protein both in cytoplasm as well as in the nuclei of cancer cells when compared with normal tissue. Further molecular modeling, docking and simulation approaches revealed significant conformational changes in the N-terminus region of normal to mutant CTNNB1 gene critical for binding with Glycogen synthase kinase 3-B (GSK3) and transducin containing protein1 (TrCp1).ConclusionPresent study on Pakistani population revealed an association of two non-synonymous polymorphisms in the CTNNB1 gene with colorectal cancer. These genetic variants led to the accumulation of the CTNNB1, a hallmark of tumor development. Also, analysis of structure to function alterations in CTNNB1 gene is crucial in understanding downstream biological events.

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Section: Discussionsupporting

confidence: 88%

Screening and computational analysis of colorectal associated non-synonymous polymorphism in CTNNB1 gene in Pakistani population

et al. 2019

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“…As a potential genetic mechanism for ß-catenin nuclear accumulation, Alomar et al identified an activating mutation in exon 3 of CTNNB1 (ß-catenin) gene which resulted in an amino acid change at phosphorylation sites of glycogen synthase kinase-3 (GSK-3β). Failing of phosphorylation was found to decrease sequestration of β-catenin by APC [28]. This effect might explain our finding with low APC mutational frequency but at the same time surprising high rate (29%) of nuclear ß-catenin positivity.…”

Section: Discussionsupporting

confidence: 57%

Prevalence of APC and PTEN Alterations in Urachal Cancer

Nagy

Reis

Hadaschik

et al. 2020

Pathol. Oncol. Res.

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Urachal carcinoma (UrC) is a rare tumor with remarkable histological and molecular similarities to colorectal cancer (CRC). Adenomatous polyposis coli (APC) is the most frequently affected gene in CRC, but the prevalence and significance of its alterations in UrC is poorly understood. In addition, loss of phosphatase and tensin homologue (PTEN) was shown to be associated with therapy resistance in CRC. Our primary aim was to assess specific genetic alterations including APC and PTEN in a large series of UrC samples in order to identify clinically significant genomic alterations. We analyzed a total of 40 UrC cases. Targeted 5-gene (APC, PTEN, DICER1, PRKAR1A, TSHR, WRN) panel sequencing was performed on the Illumina MiSeq platform (n = 34). In addition, ß-catenin (n = 38) and PTEN (n = 30) expressions were assessed by immunohistochemistry. APC and PTEN genes were affected in 15% (5/34) and 6% (2/34) of cases. Two of five APC alterations (p.Y1075*, p.K1199*) were truncating pathogenic mutations. One of the two PTEN variants was a pathogenic frameshift insertion (p.C211fs). In 29% (11/38) of samples, at least some weak nuclear ß-catenin immunostaining was detected and PTEN loss was observed in 20% (6/30) of samples. The low prevalence of APC mutations in UrC represents a characteristic difference to CRC. Based on APC and ß-catenin results, the Wnt pathway seems to be rarely affected in UrC. Considering the formerly described involvement of PTEN protein loss in anti-EGFR therapy-resistance its immunohistochemical testing may have therapeutic relevance.

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“…Thus, the ΔN(89)-β-catenin mutant mimics the regulation intrinsic to AR-hypomorphic β-TrCP-knockdown lines. We additionally studied ΔN(47)-β-catenin—a mutant with altered regulation similar to ΔN(89)-β-catenin—that has been recorded in cancers (Alomar, et al, 2016), and the point mutant S33Y that inhibits β-TrCP-binding to β-catenin. S33Y—and similar mutations are found in pilomatricomas (Chan, et al, 1999), SW48 colorectal cancer cells (Sparks, et al, 1998) and hepatocarcinomas (Zucman-Rossi, et al, 2006).…”

Section: Resultsmentioning

confidence: 99%

β-TrCP1 Is a Vacillatory Regulator of Wnt Signaling

Long

Lin

Parvez

et al. 2017

Cell Chemical Biology

113

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Summary Simultaneous hyperactivation of Wnt and antioxidant response (AR) are often observed during oncogenesis. However, it remains unclear how the β-catenin-driven Wnt and the Nrf2-driven AR mutually regulate each other. The situation is compounded because many players in these two pathways are redox-sensors, rendering bolus-redox-signal-dosing methods uninformative. Herein we examine the ramifications of single-protein-target-specific AR-upregulation in various knockdown lines. Our data document that Nrf2/AR strongly inhibits β-catenin/Wnt. The magnitude and mechanism of this negative regulation are dependent on the direct interaction between β-catenin-N-terminus and β-TrCP1 (an antagonist of both Nrf2 and β-catenin), and independent of binding between Nrf2 and β-TrCP1. Intriguingly, β-catenin positively regulates AR. Because AR is a negative regulator of Wnt regardless of β-catenin-N-terminus, this switch of function is likely sufficient to establish a new Wnt/AR equilibrium during tumorigenesis.

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β-Catenin accumulation and S33F mutation of CTNNB1 gene in colorectal cancer in Saudi Arabia

Cited by 12 publications

References 33 publications

Screening and computational analysis of colorectal associated non-synonymous polymorphism in CTNNB1 gene in Pakistani population

Screening and computational analysis of colorectal associated non-synonymous polymorphism in CTNNB1 gene in Pakistani population

Prevalence of APC and PTEN Alterations in Urachal Cancer

β-TrCP1 Is a Vacillatory Regulator of Wnt Signaling

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