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    The architecture of clonal expansions in morphologically normal tissue from cancerous and non-cancerous prostates

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    Authors
    Buhigas, C.
    Warren, A. Y.
    Leung, W. K.
    Whitaker, H. C.
    Luxton, H. J.
    Hawkins, S.
    Kay, J.
    Butler, A.
    Xu, Y.
    Woodcock, D. J.
    Merson, S.
    Frame, F. M.
    Sahli, A.
    Abascal, F.
    Martincorena, I.
    Bova, G. S.
    Foster, C. S.
    Campbell, P.
    Maitland, N. J.
    Neal, D. E.
    Massie, C. E.
    Lynch, A. G.
    Eeles, R. A.
    Cooper, C. S.
    Wedge, David C
    Brewer, D. S.
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    Affiliation
    Norwich Medical School, University of East Anglia, Norwich, Norfolk, NR4 7TJ, UK
    Issue Date
    2022
    
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    Abstract
    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.
    Citation
    Buhigas C, Warren AY, Leung WK, Whitaker HC, Luxton HJ, Hawkins S, et al. The architecture of clonal expansions in morphologically normal tissue from cancerous and non-cancerous prostates. Mol Cancer. 2022 Sep 22;21(1):183. PubMed PMID: 36131292. Pubmed Central PMCID: PMC9494848. Epub 2022/09/22. eng.
    Journal
    Molecular Cancer
    URI
    http://hdl.handle.net/10541/625682
    DOI
    10.1186/s12943-022-01644-3
    PubMed ID
    36131292
    Additional Links
    https://dx.doi.org/10.1186/s12943-022-01644-3
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1186/s12943-022-01644-3
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