Characterising the evolutionary dynamics of hypermutated tumours using single-cell sequencing
type: CreativeWork
description: DNA mismatch repair deficiency (MMRD) is caused by the inactivation of the mismatch repair pathway, which corrects DNA replication-associated errors. MMRD results in an elevated rate of point mutations and indels, called hypermutation, which leads to a high burden of neoantigens and increased tumour immunogenicity. As a result, hypermutated cancers show the highest response rates to immune checkpoint blockade (ICB), a type of immunotherapy that has revolutionised the treatment landscape for multiple cancer types. Yet, durable responses are only observed in a subset of patients. Therefore, advancing our understanding of the molecular mechanisms underpinning variable responses to ICB is critical. Previous clinical and preclinical studies of MMRD tumours showed that the clonality rather than the burden of mutations determines the variable responses to ICB observed in the clinic. Given that the clonality of mutations is determined by the evolutionary dynamics and patterns of intra-tumour heterogeneity, it is paramount to elucidate the clonal dynamics of MMRD tumours. Moreover, genomics analyses of MMRD tumour evolution have relied on bulk whole-genome sequencing (WGS), which is limited to infer the clonal structure and dynamics of tumours due to the impossibility of assigning mutations to subclones and limited sensitivity for subclonal mutation detection. Thus, the evolutionary trajectories and the timing of the onset of the disease remain unknown for MMRD cancers. Recently, the advent of single-cell (WGS) methodologies allowed for the assignment of mutations to individual cells, making the reconstruction of single-cell lineage histories possible. As a first contribution in my PhD, I have reconstructed the phylogenetic history of eight patient-derived organoids with MMRD at single-cell resolution using single-cell wholegenome sequencing. I found that the evolution of MMRD tumours is characterised by the accumulation of tens of thousands of clonal mutations during decade…
abstract: DNA mismatch repair deficiency (MMRD) is caused by the inactivation of the mismatch repair pathway, which corrects DNA replication-associated errors. MMRD results in an elevated rate of point mutations and indels, called hypermutation, which leads to a high burden of neoantigens and increased tumour immunogenicity. As a result, hypermutated cancers show the highest response rates to immune checkpoint blockade (ICB), a type of immunotherapy that has revolutionised the treatment landscape for multiple cancer types. Yet, durable responses are only observed in a subset of patients. Therefore, advancing our understanding of the molecular mechanisms underpinning variable responses to ICB is critical. Previous clinical and preclinical studies of MMRD tumours showed that the clonality rather than the burden of mutations determines the variable responses to ICB observed in the clinic. Given that the clonality of mutations is determined by the evolutionary dynamics and patterns of intra-tumour heterogeneity, it is paramount to elucidate the clonal dynamics of MMRD tumours. Moreover, genomics analyses of MMRD tumour evolution have relied on bulk whole-genome sequencing (WGS), which is limited to infer the clonal structure and dynamics of tumours due to the impossibility of assigning mutations to subclones and limited sensitivity for subclonal mutation detection. Thus, the evolutionary trajectories and the timing of the onset of the disease remain unknown for MMRD cancers. Recently, the advent of single-cell (WGS) methodologies allowed for the assignment of mutations to individual cells, making the reconstruction of single-cell lineage histories possible. As a first contribution in my PhD, I have reconstructed the phylogenetic history of eight patient-derived organoids with MMRD at single-cell resolution using single-cell wholegenome sequencing. I found that the evolution of MMRD tumours is characterised by the accumulation of tens of thousands of clonal mutations during decade…
author: Kalyva, Maria
language: eng
keywords: bioinformatics, cancer genomics, mismatch repair, phylogenetics, single-cell
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/d2393dab-9830-4a98-be44-f923ded034cb/download
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2024-01-30
date modified: 2026-07-22T22:23:59Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.109433