UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Mechanisms of cancer evolution and drivers of tumour heterogeneity

McGranahan, NL; (2015) Mechanisms of cancer evolution and drivers of tumour heterogeneity. Doctoral thesis , UCL (University College London). Green open access

[thumbnail of McGranahan_Final_submission_thesis.pdf.REDACTED.pdf]
Preview
Text
McGranahan_Final_submission_thesis.pdf.REDACTED.pdf

Download (28MB) | Preview

Abstract

Cancer drug resistance is almost inevitable in the majority of patients with advanced metastatic tumours. Intra-tumour heterogeneity, facilitating rapid tumour evolution, is a main cause of resistance to cancer therapies. In this thesis, I explore how cancer genome sequencing data can shed light intratumour heterogeneity and the processes shaping cancer genome evolution over space and time. Multi-region and single-sample sequencing data was harnessed to temporally and clonally dissect mutations across 10 major cancer-types. The existence of branched tumour evolution and widespread heterogeneity was demonstrated. Although mutations in known cancer genes typically occurred early in cancer evolution, subclonal ‘actionable’ mutations, including BRAF (V600E), IDH1 (R132H), PIK3CA (E545K), and EGFR (L858R), were also identified. Temporal dissection of mutational signatures revealed that APOBEC-mediated mutagenesis is frequently a late event in cancer evolution and plays a key role in the acquisition of subclonal driver mutations. Copy number analysis suggested that genome doubling is prevalent across tumour types and that it frequently occurs early in tumour evolution in colorectal cancer. A cancer cell-line system was used to demonstrate that rare cells that survive genome-doubling display increased tolerance to chromosome aberrations and a genome-doubling event was found to be independently predictive of reduced relapse-free survival in two independent cohorts. Finally, the clinical impact of intra-tumour heterogeneity was explored in the context of cancer neo-antigens and immune-modulation. The number of clonal neoantigens was associated with survival outcome in lung adenocarcinoma patients and T cells reactive to clonal neo-antigens were identified. Sensitivity to anti-PD-1 therapy was dependent on neo-antigen clonal burden and intra-tumour heterogeneity. Thus, immunotherapeutic strategies targeting clonal neo-antigens in combination with checkpoint-blockade may provide a tractable approach to tackling lung adenocarcinomas. This thesis demonstrates how analyses of genomic data can shed light on the biology and clinical relevance of cancer evolution and intra-tumour heterogeneity.

Type: Thesis (Doctoral)
Title: Mechanisms of cancer evolution and drivers of tumour heterogeneity
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Third party copyright material has been removed from ethesis.
Keywords: cancer evolution, cancer genomics, intra-tumour heterogeneity
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/1473445
Downloads since deposit
893Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item