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

Role of secondary mismatch repair (MMR) frameshifts in the evolution of microsatellite instable (MSI) colorectal cancer

Kayhanian, Hamzeh; (2021) Role of secondary mismatch repair (MMR) frameshifts in the evolution of microsatellite instable (MSI) colorectal cancer. Doctoral thesis (Ph.D), UCL (University College London). Green open access

[thumbnail of Kayhanian_10136836_Thesis_sig_removed.pdf]
Preview
Text
Kayhanian_10136836_Thesis_sig_removed.pdf

Download (8MB) | Preview

Abstract

Mismatch repair deficient (MMRd) cancers face a delicate balance. Whilst hypermutation fuels adaptive evolution, it also comes at the cost of immunogenic neoantigens and other deleterious mutations. How MMRd cancers navigate the costs versus benefits of hypermutation is unknown. By visualising the clonal architecture of MMRd colorectal cancer in situ I show that the mismatch repair system unfolds in reversible steps to adapt cellular mutability to immune selection. Mechanistically microsatellite instability unmasks two hypermutable homopolymers in the mismatch repair genes MSH6 and MSH3. Spontaneous frameshift mutation and reversion at these homopolymers allows them to act as a molecular switch, regulating expression of MutSα and MutSß respectively. Frameshift switching at these homopolymer sites modulates the rate and spectrum of mutations across the genome. In this manner stochastic mutation bursts combined with stringent immune selection, drive continuous adaptation. This work is supported by a bespoke clonally resolved exome sequencing dataset, validated using two large publicly available genomic datasets and tested in a mathematical model of mutation rate switching. In summary, this work identifies that adaptive mutability associates with increased immune escape and intratumour heterogeneity during mismatch repair deficient cancer evolution. Knowledge of this mechanism of adaptation may inform strategies to target resistance evolution in cancer treatment.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Role of secondary mismatch repair (MMR) frameshifts in the evolution of microsatellite instable (MSI) colorectal cancer
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
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 Pathology
URI: https://discovery.ucl.ac.uk/id/eprint/10136836
Downloads since deposit
29Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item