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dc.contributor.authorBuhigas, Claudia
dc.contributor.authorWarren, Anne Y.
dc.contributor.authorLeung, Wing-Kit
dc.contributor.authorWhitaker, Hayley C.
dc.contributor.authorLuxton, Hayley J.
dc.contributor.authorHawkins, Steve
dc.contributor.authorKay, Jonathan
dc.contributor.authorButler, Adam
dc.contributor.authorXu, Yaobo
dc.contributor.authorWoodcock, Dan
dc.contributor.authorMerson, Sue
dc.contributor.authorFrame, Fiona M.
dc.contributor.authorSahli, Atef
dc.contributor.authorAbascal, Federico
dc.contributor.authorCRUK-ICGC Prostate Group
dc.contributor.authorMartincorena, Iñigo
dc.contributor.authorBova, G. Steven
dc.contributor.authorFoster, Christopher S.
dc.contributor.authorCampbell, Peter
dc.contributor.authorMaitland, Norman
dc.contributor.authorNeal, David E.
dc.contributor.authorMassie, Charlie E.
dc.contributor.authorLynch, Andy
dc.contributor.authorEeles, Rosalind A.
dc.contributor.authorCooper, Colin S.
dc.contributor.authorWedge, David C.
dc.contributor.authorBrewer, Daniel S.
dc.date.accessioned2022-09-23T11:30:17Z
dc.date.available2022-09-23T11:30:17Z
dc.date.issued2022-09-22
dc.identifier.citationBuhigas , C , Warren , A Y , Leung , W-K , Whitaker , H C , Luxton , H J , Hawkins , S , Kay , J , Butler , A , Xu , Y , Woodcock , D , Merson , S , Frame , F M , Sahli , A , Abascal , F , CRUK-ICGC Prostate Group , Martincorena , I , Bova , G S , Foster , C S , Campbell , P , Maitland , N , Neal , D E , Massie , C E , Lynch , A , Eeles , R A , Cooper , C S , Wedge , D C & Brewer , D S 2022 , ' The architecture of clonal expansions in morphologically normal tissue from cancerous and non-cancerous prostates ' , Molecular Cancer , vol. 21 , 183 . https://doi.org/10.1186/s12943-022-01644-3en
dc.identifier.otherPURE: 280925342
dc.identifier.otherPURE UUID: 105e03e5-a0d4-42b3-a6ba-cc5f9b5a41da
dc.identifier.otherORCID: /0000-0002-7876-7338/work/119628527
dc.identifier.otherScopus: 85138312858
dc.identifier.otherWOS: 000859367700001
dc.identifier.urihttps://hdl.handle.net/10023/26063
dc.descriptionFunding: This project was funded by Cancer Research UK (C5047/A29626/A22530/A17528), the Dallaglio Foundation, and Prostate Cancer UK (TLD-S15-003).en
dc.description.abstractBackground : 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 = 7.0x10-03, Wilcoxon rank sum test) and small insertions and deletions (indels, P = 8.7x10-06) 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 = 5.94x10-05, 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 had 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 = 3.72x10-09, 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.
dc.format.extent16
dc.language.isoeng
dc.relation.ispartofMolecular Canceren
dc.rightsCopyright © The Author(s) 2022.Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence. The Creative Commons Public Domain Dedication waiver applies to the data made available in this article, unless otherwise stated in a credit line to the data.en
dc.subjectProstate canceren
dc.subjectClonal expansionsen
dc.subjectGenomicsen
dc.subjectNormal tissueen
dc.subjectBenign prostatic hyperplasiaen
dc.subjectField effecten
dc.subjectMutational signaturesen
dc.subjectQH426 Geneticsen
dc.subjectRC0254 Neoplasms. Tumors. Oncology (including Cancer)en
dc.subjectDASen
dc.subjectSDG 3 - Good Health and Well-beingen
dc.subjectMCCen
dc.subjectNCADen
dc.subject.lccQH426en
dc.subject.lccRC0254en
dc.titleThe architecture of clonal expansions in morphologically normal tissue from cancerous and non-cancerous prostatesen
dc.typeJournal articleen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews. School of Medicineen
dc.contributor.institutionUniversity of St Andrews. Statisticsen
dc.contributor.institutionUniversity of St Andrews. Sir James Mackenzie Institute for Early Diagnosisen
dc.contributor.institutionUniversity of St Andrews. St Andrews Bioinformatics Uniten
dc.contributor.institutionUniversity of St Andrews. Cellular Medicine Divisionen
dc.identifier.doihttps://doi.org/10.1186/s12943-022-01644-3
dc.description.statusPeer revieweden


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