Precision oncology


Session type:

Sandesh Kc1,Thomas King2,David Mak2,Rupesh Bhatt2,Alan Doherty2,Richard Viney2,Prashant Patel2,Brian Kelly2

1University Hospital Birmingham,2UHB


Increasing 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. Emerging 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. Evidence that intratumour heterogeneity and chromosomal instability is finely tuned will be presented, to create sufficient diversity for adaptation mitigating the risks of excessive genome instability resulting in cell autonomous lethality. On-going chromosomal instability, manifested as Mirrored Subclonal Allelic Imbalance (MSAI) is found to be a major driver of intratumour heterogeneity in non-small cell lung cancer, contributing to parallel evolution and selection. The finding of 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 the need for new approaches to drug development and clinical trial design and integration of cancer immunotherapeutic approaches. The clonal neo-antigenic architecture may act as a tumour vulnerability, targeting multiple clonal neo-antigens present in each tumour to mitigate resistance and treatment failure. The role of cancer genome instability driving immune evasion and HLA/MHC loss and immune escape will be presented.