TY - JOUR
T1 - The architecture of clonal expansions in morphologically normal tissue from cancerous and non-cancerous prostates
AU - CRUK-ICGC Prostate Cancer Group
AU - Buhigas, Claudia
AU - Warren, Anne Y.
AU - Leung, Wing Kit
AU - Whitaker, Hayley C.
AU - Luxton, Hayley J.
AU - Hawkins, Steve
AU - Kay, Jonathan
AU - Butler, Adam
AU - Xu, Yaobo
AU - Woodcock, Dan J.
AU - Merson, Sue
AU - Frame, Fiona M.
AU - Sahli, Atef
AU - Abascal, Federico
AU - Gihawi, Abraham
AU - Lambert, Adam
AU - Thompson, Alan
AU - Futreal, Andrew
AU - Menzies, Andrew
AU - Baddage, Anne
AU - Ng, Anthony
AU - Sahil, Atef
AU - Kremeyer, Barbara
AU - Al-Lazikani, Bissan
AU - Massie, Charlie
AU - Greenman, Christopher
AU - Ogden, Christopher
AU - Verrill, Clare
AU - Fisher, Cyril
AU - Berney, Dan
AU - Burns, Dan
AU - Leongamornlert, Daniel
AU - Jones, David
AU - Nicol, David
AU - Cahill, Declan
AU - Easton, Douglas
AU - Rowe, Edward
AU - Riabchenko, Ekaterina
AU - Bancroft, Elizabeth
AU - Mayer, Erik
AU - Anokian, Ezequiel
AU - Hamdy, Freddie
AU - Park, Gahee
AU - Pelvender, Gill
AU - Leeman, Gregory
AU - Gundem, Gunes
AU - Zhang, Hongwei
AU - Mills, Ian G.
AU - Zhang, Jingjing
AU - Van Loo, Peter
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
KW - Benign prostatic hyperplasia
KW - Clonal expansions
KW - Field effect
KW - Genomics
KW - Mutational signatures
KW - Normal tissue
KW - Prostate cancer
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U2 - 10.1186/s12943-022-01644-3
DO - 10.1186/s12943-022-01644-3
M3 - Article
C2 - 36131292
AN - SCOPUS:85138312858
SN - 1476-4598
VL - 21
JO - Molecular cancer
JF - Molecular cancer
IS - 1
M1 - 183
ER -