A major research project led by Professor Dean Fennell at the University of Leicester has uncovered vital new information about the genetic evolution of mesothelioma, offering promising implications for diagnosis, prognosis, and treatment. Funded by Mesothelioma UK, the study explored how the clonal architecture of mesothelioma tumours influences patient outcomes and response to therapies.
Study Overview: The research team conducted a comprehensive multiomic analysis—combining genomic, transcriptomic, and immunofluorescence data—to investigate how mesothelioma evolves at the cellular level. By analysing tumour samples from 277 patients, they were able to map the genetic landscape and identify patterns of tumour growth and immune response.
Key Findings:
- Genomic Instability as a Prognostic Marker: Tumours with a “branched” evolutionary pattern showed higher genomic instability and were associated with poorer survival outcomes. In contrast, “linear” tumours were more genomically stable and linked to better prognosis.
- MTAP as a Clinical Indicator: The study identified MTAP as a key marker of genomic instability. MTAP-positive tumours were more aggressive and are now being used in clinical practice as a prognostic indicator. MTAP is also a predictive marker for PRMT5 inhibition, which will be targeted in the upcoming SELECT clinical trial.
- Immune Response Differences: Linearly evolving tumours showed greater infiltration of CD8 T cells and activation of inflammatory pathways, suggesting they may respond better to immunotherapy. Branched tumours, while having more neoantigens, were dominated by NK cells and showed signs of higher proliferation.
- Tumour Volume Matters: Larger tumours were found to have higher genomic instability and lower immune cell infiltration, indicating that patients with smaller tumours may benefit more from early immunotherapy intervention.
Clinical Impact: This is the first study to comprehensively link genomic instability with clinical outcomes in mesothelioma. The findings are already influencing clinical practice and will inform future trials, including SELECT and NERO. The research also highlights the potential of using genomic profiling to personalise treatment strategies and improve survival rates.
Dissemination and Next Steps: The team will present their findings at ESMO (Berlin) and IMIG (Philadelphia) in late 2025. Manuscripts are in preparation for submission to high-impact journals.
This research marks a significant step forward in understanding mesothelioma biology and opens new avenues for targeted, personalised treatment.
