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Background Up to 80% of cases of prostate cancer present with multifocal independent tumour lesions leading to the concept of a field effect present in the normal prostate predisposing to cancer development. In the present study we applied Whole Genome DNA Sequencing (WGS) to a group of morphologically normal tissue ( n  = 51), including benign prostatic hyperplasia (BPH) and non-BPH samples, from men with and men without prostate cancer. We assess whether the observed genetic changes in morphologically normal tissue are linked to the development of cancer in the prostate. Results Single nucleotide variants ( P  = 7.0 × 10 –03 , Wilcoxon rank sum test) and small insertions and deletions (indels, P  = 8.7 × 10 –06 ) were significantly higher in morphologically normal samples, including BPH, from men with prostate cancer compared to those without. The presence of subclonal expansions under selective pressure, supported by a high level of mutations, were significantly associated with samples from men with prostate cancer ( P  = 0.035, Fisher exact test). The clonal cell fraction of normal clones was always higher than the proportion of the prostate estimated as epithelial ( P  = 5.94 × 10 –05 , paired Wilcoxon signed rank test) which, along with analysis of primary fibroblasts prepared from BPH specimens, suggests a stromal origin. Constructed phylogenies revealed lineages associated with benign tissue that were completely distinct from adjacent tumour clones, but a common lineage between BPH and non-BPH morphologically normal tissues was often observed. Compared to tumours, normal samples have significantly less single nucleotide variants ( P  = 3.72 × 10 –09 , paired Wilcoxon signed rank test), have very few rearrangements and a complete lack of copy number alterations. Conclusions Cells within regions of morphologically normal tissue (both BPH and non-BPH) can expand under selective pressure by mechanisms that are distinct from those occurring in adjacent cancer, but that are allied to the presence of cancer. Expansions, which are probably stromal in origin, are characterised by lack of recurrent driver mutations, by almost complete absence of structural variants/copy number alterations, and mutational processes similar to malignant tissue. Our findings have implications for treatment (focal therapy) and early detection approaches.

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.