Cancer evolution, immune evasion and metastasis
ZOOM LINK https://zoom.us/j/95490025190?pwd=cFV5Nkd2bFR3SEkzTE9JeFV1WTlwZz09
Evidence supports complex subclonal relationships in solid tumours, manifested as intratumour heterogeneity. Parallel evolution of subclones, with distinct somatic events occurring in the same gene, signal transduction pathway or protein complex, suggests constraints to tumour evolution that might be therapeutically exploitable. Data from TRACERx, a longitudinal lung cancer evolution study will be presented. Drivers of tumour heterogeneity change during the disease course and contribute to the temporally distinct origins of lung cancer driver events. APOBEC driven mutagenesis appears to be enriched in subclones in multiple tumour types. Oncogene, tumour suppressor gene and drug induced DNA replication stress are found to drive APOBEC mutagenesis. Phylogenetic tracking detects minimal residual disease and clonal evolution of disease from primary to metastatic sites, presenting opportunities for drug development
On-going chromosomal instability, manifested as Mirrored Subclonal Allelic Imbalance (MSAI) is found to be a major driver of intratumour heterogeneity across cancer types, contributing to parallel evolution and selection. Subclonal driver events, evidence of ongoing selection within subclones, combined with genome instability driving cell-to-cell variation is likely to limit the efficacy of targeted monotherapies, suggesting a need for new approaches to drug development and integration of cancer immunotherapeutic approaches. Multiple adaptive mechanisms to neo-antigen evolution have been found in TRACERx highlighting cancer chromosomal instability driving immune evasion and HLA loss and loss of clonal neo-antigens as well as epigenetic repression of neo-antigens. The clonal neo-antigenic architecture may act as a tumour vulnerability to mitigate resistance and treatment failure.
Date: 12 March 2021, 14:00 (Friday, 8th week, Hilary 2021)
Venue: Via Zoom
Speaker: Prof Charles Swanton (The Francis Crick Institute, London)
Organising department: Sir William Dunn School of Pathology
Organiser: Melissa Wright (Sir William Dunn School of Pathology)
Organiser contact email address: melissa.wright@path.ox.ac.uk
Host: Dr Ulrike Gruneberg (University of Oxford, Sir William Dunn School of Pathology )
Part of: Dunn School of Pathology Departmental Seminars
Booking required?: Not required
Audience: Members of the University only
Editor: Melissa Wright