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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Tumor patterns and cancer risk in carriers of TP53 exonic germline variants that alter mRNA splicing
Deborah Schönegger1, Emilie Montellier1, Sandrine Blanchet1
1University Grenoble Alpes, Inserm 1209, CNRS 5309, Institute for Advanced Biosciences, Grenoble, France.
Abstract:
Abnormal RNA splicing is an underrecognized driver of pathogenicity in germline TP53 - the cause of Li-Fraumeni syndrome (LFS). We re-evaluated exonic single-nucleotide variants (SNVs) that yield missense or synonymous changes for spliceogenic effects by integrating SpliceAI prediction, in-vitro minigene assays, and analysis of tumor RNA-seq from TCGA, and assessed genotype-phenotype correlations using clinical data from multiple databases and national registries. We identified 58 spliceogenic exonic SNVs (SE-SNVs) across the TP53 gene (40 missense, 18 synonymous). Experimental validation confirmed aberrant splicing for 15 out of 17 tested variants, most often through cryptic splice-site activation that introduced frameshifts and premature termination. Clinically, carriers of SE-SNVs previously considered as mild or of low-pathogenicity by protein-based assays showed earlier onset and LFS-signature cancers, indicating that splicing disruption can override amino-acid effects. The recurrent c.375 G > A (p.(Thr125 = )) showed heterogeneous effect: with both childhood/adolescent and adult onset, consistent with partial, variable retention of canonical splicing. These data reveal a substantial burden of spliceogenic pathogenicity in TP53 and strong support integrating splicing prediction, functional validation, and transcript-level evidence into variant interpretation and risk stratification in LFS.
Insights
Abnormal RNA splicing in the TP53 gene drives Li-Fraumeni syndrome (LFS) pathogenicity. Our study identifies numerous spliceogenic variants, revealing splicing
Area of Science:
- Genetics and Genomics
- Molecular Biology
- Cancer Research
Background:
- Germline TP53 variants are the primary cause of Li-Fraumeni syndrome (LFS).
- Abnormal RNA splicing is an emerging, underrecognized mechanism of pathogenicity in genetic disorders.
- The contribution of spliceogenic variants in TP53 to LFS pathogenesis requires further elucidation.
Purpose of the Study:
- To comprehensively identify and characterize spliceogenic exonic single-nucleotide variants (SE-SNVs) in the TP53 gene.
- To experimentally validate the splicing effects of identified TP53 SE-SNVs.
- To correlate TP53 SE-SNV genotypes with Li-Fraumeni syndrome clinical phenotypes, including cancer onset and type.
Main Methods:
- Integration of SpliceAI predictions with in vitro minigene assays for spliceogenicity assessment.
- Analysis of tumor RNA sequencing data from The Cancer Genome Atlas (TCGA) to confirm aberrant splicing.
- Genotype-phenotype correlation using clinical data from multiple national registries and databases.
Main Results:
- Identification of 58 spliceogenic exonic SNVs (SE-SNVs) in TP53, including 40 missense and 18 synonymous variants.
- Experimental validation confirmed aberrant splicing for 15 of 17 tested variants, primarily via cryptic splice-site activation leading to frameshifts and premature termination.
- SE-SNV carriers exhibited earlier cancer onset and LFS-signature cancers, suggesting splicing disruption can override predicted protein-level effects.
Conclusions:
- Abnormal RNA splicing represents a significant pathogenic mechanism in germline TP53, contributing substantially to Li-Fraumeni syndrome.
- Integrating splicing prediction tools, functional assays, and transcript-level evidence is crucial for accurate variant interpretation and risk stratification in LFS.
- Splicing alterations in TP53 can lead to earlier disease onset and distinct cancer profiles, highlighting the importance of transcript-focused analysis in genetic variant assessment.
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