Abstract

Abstract 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. 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. 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. Multiple adaptive mechanisms to neo-antigen evolution have been found in TRACERx that emphasise the role of cancer chromosomal instability driving immune evasion and HLA/MHC 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, targeting multiple clonal neo-antigens present in each tumour to mitigate resistance and treatment failure. Citation Format: Charles Swanton. Cancer evolution, immune evasion and metastasis [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr IA16.

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