Breast Cancer Patient Prognosis Is Determined by the Interplay between TP53 Mutation and Alternative Transcript...

Area of Science:

• Molecular Biology
• Genetics
• Oncology

Background:

• The TP53 gene locus produces multiple RNA transcripts encoding various p53 protein isoforms.
• Previous multiplex long amplicon droplet digital PCR (ddPCR) assays quantified seven of eight TP53 reference transcripts.
• Quantifying the eighth TP53 transcript, encoding ∆40p53α, was previously lacking.

Purpose of the Study:

• To develop and validate a ddPCR assay for the TP53 ∆40p53α transcript.
• To investigate the association between TP53 mutations, transcript variant expression, and patient outcomes in a New Zealand breast cancer cohort.
• To explore the prognostic significance of combining TP53 mutation status with TP53 transcript expression patterns.

Main Methods:

• Developed a novel long amplicon ddPCR assay for the TP53 ∆40p53α transcript.
• Applied multiplex long amplicon ddPCR assays to quantify eight TP53 reference transcripts.
• Performed DNA sequencing of the TP53 gene locus.
• Conducted Cox proportional hazards survival analysis to assess the interplay between TP53 mutation status, transcript variants, and patient outcomes.

Main Results:

• A high prevalence of TP53 splice site mutations was observed in the New Zealand breast cancer cohort.
• TP53 intron 4 splice site mutations correlated with overexpression of ∆133TP53 transcripts.
• A significant association was found between TP53 mutation status, TP53 transcript variant expression, and patient survival.
• Patients with no TP53 mutation and a low ratio of TP53 transcripts t2 to t1 exhibited a remarkably good prognosis.

Conclusions:

• The developed ddPCR assay enables comprehensive quantification of TP53 transcript variants.
• TP53 splice site mutations and specific transcript expression patterns are significant prognostic factors in breast cancer.
• Integrating TP53 mutation analysis with transcript expression profiling offers a novel approach to understanding TP53's role in cancer and predicting patient outcomes.