Analysis of genomic alterations in morphologically normal tissue in prostate cancer patients reveals a potential role in tumour development.

Buhigas, Claudia (2020) Analysis of genomic alterations in morphologically normal tissue in prostate cancer patients reveals a potential role in tumour development. Doctoral thesis, University of East Anglia.

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Abstract

Up to 80 % of cases of prostate cancer present with multifocal tumour lesions leading to the hypothesis of a field effect present in an apparently normal prostate that predisposes it to cancer development. In this thesis we explore the development of the field effect in the prostate by analysing normal tissues.

We first applied Whole Genome DNA Sequencing (WGS) to morphologically normal tissue and benign prostatic hyperplasia (BPH) samples (n = 44) from men with and without prostate cancer. Substitutions (P =7.1x10-03, Wilcoxon rank sum test) and indels (P = 9.5x10-04) were significantly higher in morphologically normal samples, including BPH, from men with prostate cancer (median = 436) compared to those without (median = 141). Subclonal expansions under selective pressure were significantly associated with prostate cancer presence (P = 3.5x10-02, Fisher exact test). Phylogenies reveal lineages were sometimes shared between BPH and normal tissues but were completely distinct from tumour clones.

Secondly, we gathered 95 samples from previously analysed normal tissue of a prostate cancer patient and performed deep targeted sequencing (> 500X) on a panel of 98 prostate cancer associated genes. We identified hundreds of mutations and validated the majority of the mutations previously found for this patient. Some genes showed repeated mutations in specific areas of the prostate whereas others were spread across the prostate. Apart from gene MUC3A, we did not find evidence of positive selection.

Our results show that field characterisation of the human prostate is associated with selected clonal expansions in morphologically normal tissue/BPH that expand under selective pressure by mechanisms that are distinct from those occurring in adjacent cancer, but that are allied to the presence of the cancer. Expansions are characterised by lack of recurrent driver mutations, by almost complete absence of structure variants/copy number alterations and by distinct mutational processes.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User:	Chris White
Date Deposited:	08 Dec 2021 14:55
Last Modified:	08 Dec 2021 14:55
URI:	https://ueaeprints.uea.ac.uk/id/eprint/82609
DOI:

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