Integrative Genomic Mapping and Visualization From Curated Public Datasets Reveals Germline RB1 Variant Diversity in...

Area of Science:

• Genetics
• Oncology
• Bioinformatics

Background:

• Retinoblastoma (RB) is a pediatric eye cancer primarily caused by mutations in the RB1 gene.
• Understanding the spectrum and distribution of RB1 variants is crucial for diagnosis and treatment.
• Existing RB1 variant data is dispersed across multiple databases and publications, hindering comprehensive analysis.

Purpose of the Study:

• To consolidate and refine disease-causing RB1 variants associated with retinoblastoma (RB).
• To develop an integrated, visual tool (PANORAMA) for exploring RB1 variants at gene and protein levels.
• To facilitate variant interpretation and comparison across different cohorts.

Main Methods:

• RB1 variants were compiled from the Leiden Open Variation Database, published studies (2014-2025), and the Catalogue of Somatic Mutations in Cancer.
• Variants were reannotated using Human Genome Variation Society (HGVS) nomenclature and mapped to GRCh38.
• The PANORAMA tool was developed using Python with Dash and Plotly for interactive visualization.

Main Results:

• 3004 RB1 variants (1943 germline, 797 somatic, 264 unknown) were analyzed after standardization and mapping.
• Truncating germline variants constituted over 80% of the total, with missense variants at 9.2%.
• Germline variant density varied by exon, with specific domains enriched for nonsense and missense mutations; 81.2% of variants with known laterality were bilateral.

Conclusions:

• This work establishes a unified resource for RB1 variants, enhancing the understanding of genetic alterations in retinoblastoma.
• The PANORAMA tool provides a platform for exploratory analysis, aiding in variant interpretation and cohort comparison.
• Identifying domain-specific patterns of genetic disruption in RB1 contributes to a deeper insight into RB pathogenesis.