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Genomic and epigenomic impact of oncogenic mutation in the PIK3CA gene

Lau, Evelyn Keet Wai; (2021) Genomic and epigenomic impact of oncogenic mutation in the PIK3CA gene. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

PIK3CA encodes the p110 alpha phosphoinositide 3-kinase (PI3K) catalytic subunit. PIK3CA is frequently mutated or amplified in cancer, with PIK3CA mutation often being an early clonal event in breast adenocarcinoma, occurring before whole genome-doubling. PI3K/Akt activation is normally linked to transient cellular signalling events. We speculate that sustained oncogenic PI3K activation may also induce genomic and epigenomic effects. The overall aim of this thesis was to explore such impact of PIK3CA-H1047R, the most commonly found PIK3CA mutation in breast cancer, using primary mouse embryonic fibroblasts (MEFs) and the human non-transformed mammary epithelial MCF10A cell line as model systems. Previous findings and work in this thesis demonstrate that acute induction of Pik3ca-H1047R mutation in primary MEFs promotes cellular tolerance to genome-doubling and the development of aneuploidy. Long-term culture of Pik3ca-H1047R-transformed tetraploid MEF clones contained a greater number of copy number alterations (CNAs) than diploid MEF clones and displayed a distinct recurrent CNA pattern. It was then determined if this also occurred in MCF10A cells, using inducible and isogenic cell models. Short-term PIK3CA activation by inducible PIK3CA-H1047R expression in MCF10A did not induce tetraploidisation or aneuploidy but showed a tendency in conferring tolerance to chemically-induced tetraploidisation. Prolonged culture of isogenic PIK3CA wild-type and mutant lines revealed more widespread genomic heterogeneity in the latter, including specific recurrent CNAs. The potential impact of PIK3CA-H1047R on epigenetic alterations was also explored, focusing on early DNA methylation alterations. Interestingly, both DNA methyltransferases DNMT1 and DNMT3A, as well as multiple key components of the PI3K/Akt signalling cascade, were found to be differentially methylated upon PIK3CA-H1047R activation. The data shown in this thesis indicate that PIK3CA-H1047R mutation has: (1) the capacity to drive genome evolution and (2) a previously unappreciated acute impact on the epigenetic landscape. The combined effect of these genetic and epigenetic alterations may provide plasticity to support and drive cancer evolution.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Genomic and epigenomic impact of oncogenic mutation in the PIK3CA gene
Event: UCL (University College London)
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
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/10124314
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