Identification and Functional Analysis of a Novel CTNNB1 Mutation in Pediatric Medulloblastoma
<p>Molecular groups of pediatric medulloblastomas. (<b>A</b>): Non-WNT/SHH group are more than 60 cases of the cohort (62/88), Group SHH <span class="html-italic">TP53</span>wt are 15 cases (15/88), Group WNT-activated 9 cases (9/88) and Group SHH <span class="html-italic">TP53</span>mut, 2 cases (2/88). (<b>B</b>): The four groups showed differences in histological distributions.</p> "> Figure 2
<p>DNA sequencing of <span class="html-italic">CTNNB</span><span class="html-italic">1</span> exon 3 from a tumor specimen. Sanger DNA sequencing showed the deletion c.109-111del, resulting in deletion of a TCT codon in the tumor sample (p.Ser37del).</p> "> Figure 3
<p><span class="html-italic">CTNNB1</span> mutation distribution in medulloblastoma and functional characterization of the β-catenin ΔS37 variant. (<b>A</b>): The top line shows β-catenin amino acid composition between residues 25–49. Arrows indicate β-catenin residues mutated in our cohort of 88 pediatric medulloblastoma. Residues in red are regulatory phosphorylated residues. The bottom line shows the novel p.Ser37del β-catenin variant (ΔS37) found. Amino acids are denoted using the one-letter code. (<b>B</b>): The plot showing the identity and number of <span class="html-italic">CTNNB1</span> mutations found in pediatric medulloblastoma. Data are from Saint Jude pecan database.</p> "> Figure 4
<p>Hematoxylin-eosin staining of tumor specimen. Histological sections display tumoral (<b>A</b>): Hematoxylin-eosin stain, 40× magnification and no reticulin net enhancement (<b>B</b>): Reticulin stain, 100× magnification. No anaplastic or large cell changes are noticeable. (<b>C</b>): Hematoxylin-eosin, 200× magnification and (<b>D</b>): Hematoxylin-eosin, 400× magnification.</p> "> Figure 5
<p>Immunostaining of tumor specimen. The immunoprofile shows patchy nuclear staining for β-catenin (<b>A</b>): 400× magnification, diffuse nuclear stain for YAP1 (<b>B</b>): 100× magnification and OTX2 (<b>C</b>): 200× magnification, and negative staining for GAB1 (<b>D</b>): 200× magnification and p53 (<b>E</b>): 200× magnification.</p> "> Figure 6
<p>Functional characterization of the novel β-catenin variant c.109-111del (p.Ser37del). (<b>A</b>): Top panel. Immunoblot of endogenous β-catenin (φ), and recombinant β-catenin wild-type (WT) and S33C and ΔS37 variants. U2OS cells were transfected with empty vector (φ) or with plasmids containing the indicated β-catenin variants. Cell lysates were resolved on 4–10% SDS-PAGE under reducing conditions followed by immunoblot using anti-β-catenin antibody. Anti-α-tubulin was used to monitor protein loading. Bottom panel. Plot showing β-catenin/α-tubulin ratio, in arbitrary units (AU), from quantified immunoblot bands from two independent experiments ± SD. (<b>B</b>): Transcriptional activity of β-catenin variants. SEAP-normalized TCF/LEF-driven luciferase activity of β-catenin from U2OS transfected cells, as described in top panel. Luminescence is shown in arbitrary units (AU), from three independent experiments. Statistically significant results (<span class="html-italic">p</span> ˂ 0.05) are marked with *.</p> ">
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Tumor Material
2.2. Histology and Immunohistochemistry
2.3. Fluorescence In Situ Hybridization
2.4. Tumor DNA Isolation and Mutational Analyses of the CTNNB1 Gene
2.5. Plasmids and Cell Culture
2.6. Protein Eextracts, Immunoblot Analysis, and Antibodies
2.7. Luciferase Reporter Assay
2.8. Statistical Analysis
3. Results
3.1. Histological and Molecular Subgroups of the Pediatric MB Cohort
3.2. CTNNB1 Mutation Analysis
3.3. Clinical, Pathological and Molecular Characteristics of the Tumor with the Novel β-Catenin Variant c.109-111del (p.Ser37del)
3.4. Functional Characterization of the Novel β-Catenin Variant c.109-111del (p.Ser37del)
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Amino Acid Position 1 | Mutation 2 | This Study | Number of MB Cases 3 PeCan COSMIC BioPortal | Mutation Type | ||
---|---|---|---|---|---|---|
32 | c.94G>A/p.(Asp32Asn)/D32N c.94G>T/p.(Asp32Tyr)/D32Y c.94G>C/p.(Asp32His)/D32H c.95A>C/p.(Asp32Ala)/D32A c.95A>G/p.(Asp32Gly)/D32G c.95A>T/p.(Asp32Val)/D32V | - 1 - - 1 - | - 2 - 1 2 - | 29 34 4 2 7 10 | 1 - - 1 2 - | Substitution-Missense Substitution-Missense Substitution-Missense Substitution-Missense Substitution-Missense Substitution-Missense |
33 | c.97_114del/p.(S33_G38del)/ΔS33-G38 c.97T>G/p.(Ser33Ala)/S33A c.97T>C/p.(Ser33Pro)/S33P c.98C>G/p.(Ser33Cys)/S33C c.98C>T/p.(Ser33Phe)/S33F c.98C>A/p.(Ser33Tyr)/S33Y | - - - 1 2 2 | 1 2 1 5 6 3 | - 3 5 45 40 22 | 1 - - 4 6 2 | Deletion-In frame Substitution-Missense Substitution-Missense Substitution-Missense Substitution-Missense Substitution-Missense |
34 | c.100G>A/p.(Gly34Arg)/G34R c.101G>A/p.(Gly34Glu)/G34E c.101G>T/p.(Gly34Val)/G34V | 1 - - | 4 2 1 | 25 17 6 | 5 1 1 | Substitution-Missense Substitution-Missense Substitution-Missense |
35 | ?/p.(Ile35Lys)/I35K c.104T>G/p.(Ile35Ser)/I35S | - - | 1 - | 1 1 | - - | Substitution-Missense Substitution-Missense |
37 | c.109_111del/p.(Ser37del)/ΔS37 c.109T>C/p.(Ser37Pro)/S37P c.110C>G/p.(Ser37Cys)/S37C c.110C>T/p.(Ser37Phe)/S37F c.110C>A/p.(Ser37Tyr)/S37Y | 1 - - - - | - 1 1 3 2 | - 6 10 17 10 | - 1 1 1 1 | Deletion-In frame Substitution-Missense Substitution-Missense Substitution-Missense Substitution-Missense |
40 | c.119C>G/p.(Thr40Ser)/T40S | - | - | 1 | - | Substitution-Missense |
41 | c.121A>G/p.(Thr41Ala)/T41A | - | 1 | 2 | 1 | Substitution-Missense |
45 | c.134C>T/p.(Ser45Phe)/S45F | - | - | 2 | - | Substitution-Missense |
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Alaña, L.; Nunes-Xavier, C.E.; Zaldumbide, L.; Martin-Guerrero, I.; Mosteiro, L.; Alba-Pavón, P.; Villate, O.; García-Obregón, S.; González-García, H.; Herraiz, R.; et al. Identification and Functional Analysis of a Novel CTNNB1 Mutation in Pediatric Medulloblastoma. Cancers 2022, 14, 421. https://doi.org/10.3390/cancers14020421
Alaña L, Nunes-Xavier CE, Zaldumbide L, Martin-Guerrero I, Mosteiro L, Alba-Pavón P, Villate O, García-Obregón S, González-García H, Herraiz R, et al. Identification and Functional Analysis of a Novel CTNNB1 Mutation in Pediatric Medulloblastoma. Cancers. 2022; 14(2):421. https://doi.org/10.3390/cancers14020421
Chicago/Turabian StyleAlaña, Lide, Caroline E. Nunes-Xavier, Laura Zaldumbide, Idoia Martin-Guerrero, Lorena Mosteiro, Piedad Alba-Pavón, Olatz Villate, Susana García-Obregón, Hermenegildo González-García, Raquel Herraiz, and et al. 2022. "Identification and Functional Analysis of a Novel CTNNB1 Mutation in Pediatric Medulloblastoma" Cancers 14, no. 2: 421. https://doi.org/10.3390/cancers14020421