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Background <p>Hepatoblastoma (HB) is the most common primary malignant liver tumor in children, with alterations in the Wnt/β-catenin signaling pathway implicated in up to 90% of cases. The <i>CTNNB1</i>, which codes for β-catenin protein, plays a crucial role in this pathway, but its mutation landscape across diverse populations requires further investigation.</p> Objectives <p>To analyse and characterize the genetic variations in the&#xa0;<i>CTNNB1</i> across three geographically diverse cohorts of hepatoblastoma patients and understand their potential pathogenic mechanisms.</p> Methods <p>The exome data for 54 hepatoblastoma tissue samples was subjected to quality control and alignment to GRCh38. SNVs were identified using GATK/Mutect2 and annotated using multiple databases. CTNNB1 gene variants were filtered and analyzed using cBioPortal, CONSURF 3.0, STRING database, and VarElect for comprehensive molecular and phenotypic analysis.</p> Results <p><i>CTNNB1</i> mutations were identified in 88.9% of patients, with 21 unique variants found in 24 patients post-filtering. Exon 3 was most frequently affected, with 17 unique mutations present in 91.66% of mutation-positive patients. The most common variants were c.101G &gt; T (p.Gly34Val), c.98C &gt; T (p.Ser33Phe), and c.98C &gt; A (p.Ser33Tyr). Novel mutations were identified at positions S29 and I35, while additional variations were found in exons 4, 7, 10, and 13.</p> Conclusion <p>This study identified significant <i>CTNNB1</i> genetic variations in hepatoblastoma, confirming exon 3 as a critical mutational hotspot. The findings enhance our understanding of HB pathogenesis and suggest potential therapeutic targets, particularly in the Wnt/β-catenin signaling pathway. These mutations may serve as valuable diagnostic and prognostic biomarkers for personalized treatment approaches in pediatric hepatoblastoma.</p>

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Novel CTNNB1 gene mutations reveal critical pathogenic mechanisms in pediatric hepatoblastoma

  • 期刊论文

  • 发表日期：

    2025年7月26日

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  • Sourabh Kumar,
  • Jyoti Sharma,
  • Himani Pandey,
  • Vishesh Jain,
  • Anjan Kumar Dhua,
  • Devendra Kumar Yadav,
  • Devi Lal,
  • Prabudh Goel

摘要

Background

Hepatoblastoma (HB) is the most common primary malignant liver tumor in children, with alterations in the Wnt/β-catenin signaling pathway implicated in up to 90% of cases. The CTNNB1, which codes for β-catenin protein, plays a crucial role in this pathway, but its mutation landscape across diverse populations requires further investigation.

Objectives

To analyse and characterize the genetic variations in the CTNNB1 across three geographically diverse cohorts of hepatoblastoma patients and understand their potential pathogenic mechanisms.

Methods

The exome data for 54 hepatoblastoma tissue samples was subjected to quality control and alignment to GRCh38. SNVs were identified using GATK/Mutect2 and annotated using multiple databases. CTNNB1 gene variants were filtered and analyzed using cBioPortal, CONSURF 3.0, STRING database, and VarElect for comprehensive molecular and phenotypic analysis.

Results

CTNNB1 mutations were identified in 88.9% of patients, with 21 unique variants found in 24 patients post-filtering. Exon 3 was most frequently affected, with 17 unique mutations present in 91.66% of mutation-positive patients. The most common variants were c.101G > T (p.Gly34Val), c.98C > T (p.Ser33Phe), and c.98C > A (p.Ser33Tyr). Novel mutations were identified at positions S29 and I35, while additional variations were found in exons 4, 7, 10, and 13.

Conclusion

This study identified significant CTNNB1 genetic variations in hepatoblastoma, confirming exon 3 as a critical mutational hotspot. The findings enhance our understanding of HB pathogenesis and suggest potential therapeutic targets, particularly in the Wnt/β-catenin signaling pathway. These mutations may serve as valuable diagnostic and prognostic biomarkers for personalized treatment approaches in pediatric hepatoblastoma.