Why TP53 Matters More Than We Thought
TP53 is the most frequently altered tumour suppressor gene in human cancer.
Yet for all its clinical relevance, our understanding of how different classes of TP53 mutations behave across different tumour types, at different disease stages; has remained incomplete. Standard genomic testing often reports a TP53 mutation without fully characterising its functional consequences, its co-mutation patterns, or its implications for treatment selection.
Our team set out to change that: at real-world scale.
The Largest TP53 Study of Its Kind in Our Dataset
In what represents one of the most comprehensive real-world analyses of TP53 alterations in our dataset, we performed comprehensive genomic profiling on 1,187 patients with advanced solid tumours:- 827 using ctDNA and 360 using tissue-derived DNA (tDNA) across breast (BC), colorectal (CRC), and lung (LC) cancers.
Sequencing was conducted using our OncoIndx 1080-gene hybrid-capture NGS assay, interrogating SNVs, small indels, structural variations, and genome-wide metrics including Tumour Mutation Burden (TMB) and Homologous Recombination Deficiency (HRD) scores.
Striking Findings Across Tumour Types
Our analysis revealed tumour-type-specific patterns that have direct clinical implications:
- TP53 mutations were detected in 50.5% of all cases:- with the highest prevalence in CRC (57.33%), followed by BC (53%) and LC (45%)
- Missense variants accounted for 65.8% of all mTP53, including recurrent GOF hotspots at R175, R248, R273, and G245 with G245 being most prominent in CRC
- GOF mutations were significantly associated with higher TMB across the cohort- a finding with direct implications for immunotherapy eligibility
- In breast cancer, mTP53 was associated with low HRD scores, demonstrating lineage-specific genomic behaviour distinct from other tumour types
- GOF mTP53 tumours showed high PD-L1 expression compared to LOF mTP53 tumours- a critical insight for checkpoint inhibitor selection
- Co-mutation analysis revealed important lineage-specific associations: TP53-KRAS in CRC, TP53-EGFR/TP53-KRAS in LC, and TP53-PIK3CA in BC
- GOF mTP53 tumours in lung cancer showed enrichment for liver and brain metastases and were associated with worse prognosis
Why This Matters for Oncologists
This large real-world dataset reveals that not all TP53 mutations are equal. The class of TP53 mutation; whether gain-of-function or loss-of-function carries distinct genomic, prognostic, and therapeutic implications that vary significantly across tumour lineages. Understanding these distinctions allows oncologists to move beyond simply detecting a TP53 mutation to truly understanding what it means for that specific patient’s treatment journey.
This is the depth of insight that our multi-omic platform is built to deliver.
Late-Breaking Research presented at the AACR Annual Meeting 2026, San Diego, CA | April 17–22, 2026 | #AACR26
Presented by Atul Bharde et al | April 20, 2026 | Session LBPO.CL02: Late-Breaking Clinical Research