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

Claudia Buhigas; Anne Y. Warren; Wing-Kit Leung; Hayley C. Whitaker; Hayley J. Luxton; Steve Hawkins; Jonathan Kay; Adam Butler; Yaobo Xu; Dan Woodcock; Sue Merson; Fiona M. Frame; Atef Sahli; Federico Abascal; CRUK-ICGC Prostate Group; Iñigo  Martincorena; G. Steven Bova; Christopher S. Foster; Peter Campbell; Norman Maitland; David E. Neal; Charlie E. Massie; Andy Lynch; Rosalind A. Eeles; Colin S. Cooper; David C. Wedge; Daniel S. Brewer

doi:10.1186/s12943-022-01644-3

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

Claudia Buhigas, Anne Y. Warren, Wing-Kit Leung, Hayley C. Whitaker, Hayley J. Luxton, Steve Hawkins, Jonathan Kay, Adam Butler, Yaobo Xu, Dan Woodcock, Sue Merson, Fiona M. Frame, Atef Sahli, Federico Abascal, CRUK-ICGC Prostate Group, Iñigo Martincorena, G. Steven Bova, Christopher S. Foster, Peter Campbell, Norman MaitlandDavid E. Neal, Charlie E. Massie, Andy Lynch, Rosalind A. Eeles, Colin S. Cooper, David C. Wedge, Daniel S. Brewer^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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 = 7.0x10^-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.

Original language	English
Article number	183
Number of pages	16
Journal	Molecular Cancer
Volume	21
DOIs	https://doi.org/10.1186/s12943-022-01644-3
Publication status	Published - 22 Sept 2022

Keywords

Prostate cancer
Clonal expansions
Genomics
Normal tissue
Benign prostatic hyperplasia
Field effect
Mutational signatures

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Additional files 1, 3-8 of The architecture of clonal expansions in morphologically normal tissue from cancerous and non-cancerous prostates
Buhigas, C. (Creator), Warren, A. Y. (Creator), Leung, W.-K. (Creator), Whitaker, H. C. (Creator), Luxton, H. J. (Creator), Hawkins, S. (Creator), Kay, J. (Creator), Butler, A. (Creator), Xu, Y. (Creator), Woodcock, D. J. (Creator), Merson, S. (Creator), Frame, F. M. (Creator), Sahli, A. (Creator), Abascal, F. (Creator), Martincorena, I. (Creator), Bova, G. S. (Creator), Foster, C. S. (Creator), Campbell, P. (Creator), Maitland, N. J. (Creator), Neal, D. E. (Creator), Massie, C. E. (Creator), Lynch, A. G. (Creator), Eeles, R. A. (Creator), Cooper, C. S. (Creator), Wedge, D. C. (Creator) & Brewer, D. S. (Creator), Figshare, 2022
DOI: 10.6084/m9.figshare.21185567.v1, https://doi.org/10.6084/m9.figshare.21185573.v1 and 5 more links, https://doi.org/10.6084/m9.figshare.21185576.v1, https://doi.org/10.6084/m9.figshare.21185579.v1, https://doi.org/10.6084/m9.figshare.21185588.v1, https://doi.org/10.6084/m9.figshare.21185591.v1, https://doi.org/10.6084/m9.figshare.21185594.v1 (show fewer)
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Cite this

Buhigas, 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., ... Brewer, D. S. (2022). The architecture of clonal expansions in morphologically normal tissue from cancerous and non-cancerous prostates. Molecular Cancer, 21, Article 183. https://doi.org/10.1186/s12943-022-01644-3

@article{105e03e5a0d442b3a6bacc5f9b5a41da,

title = "The architecture of clonal expansions in morphologically normal tissue from cancerous and non-cancerous prostates",

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 = 7.0x10-03, 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. ",

keywords = "Prostate cancer, Clonal expansions, Genomics, Normal tissue, Benign prostatic hyperplasia, Field effect, Mutational signatures",

author = "Claudia Buhigas and Warren, {Anne Y.} and Wing-Kit Leung and Whitaker, {Hayley C.} and Luxton, {Hayley J.} and Steve Hawkins and Jonathan Kay and Adam Butler and Yaobo Xu and Dan Woodcock and Sue Merson and Frame, {Fiona M.} and Atef Sahli and Federico Abascal and {CRUK-ICGC Prostate Group} and I{\~n}igo Martincorena and Bova, {G. Steven} and Foster, {Christopher S.} and Peter Campbell and Norman Maitland and Neal, {David E.} and Massie, {Charlie E.} and Andy Lynch and Eeles, {Rosalind A.} and Cooper, {Colin S.} and Wedge, {David C.} and Brewer, {Daniel S.}",

note = "Funding: This project was funded by Cancer Research UK (C5047/A29626/A22530/A17528), the Dallaglio Foundation, and Prostate Cancer UK (TLD-S15-003). ",

year = "2022",

month = sep,

day = "22",

doi = "10.1186/s12943-022-01644-3",

language = "English",

volume = "21",

journal = "Molecular Cancer",

}

Buhigas, C, Warren, AY, Leung, W-K, Whitaker, HC, Luxton, HJ, Hawkins, S, Kay, J, Butler, A, Xu, Y, Woodcock, D, Merson, S, Frame, FM, Sahli, A, Abascal, F, CRUK-ICGC Prostate Group, Martincorena, I, Bova, GS, Foster, CS, Campbell, P, Maitland, N, Neal, DE, Massie, CE, Lynch, A, Eeles, RA, Cooper, CS, Wedge, DC & Brewer, DS 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/s12943-022-01644-3

TY - JOUR

T1 - The architecture of clonal expansions in morphologically normal tissue from cancerous and non-cancerous prostates

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

AU - Merson, Sue

AU - Frame, Fiona M.

AU - Sahli, Atef

AU - Abascal, Federico

AU - CRUK-ICGC Prostate Group

AU - Martincorena, Iñigo

AU - Bova, G. Steven

AU - Foster, Christopher S.

AU - Campbell, Peter

AU - Maitland, Norman

AU - Neal, David E.

AU - Massie, Charlie E.

AU - Lynch, Andy

AU - Eeles, Rosalind A.

AU - Cooper, Colin S.

AU - Wedge, David C.

AU - Brewer, Daniel S.

N1 - Funding: This project was funded by Cancer Research UK (C5047/A29626/A22530/A17528), the Dallaglio Foundation, and Prostate Cancer UK (TLD-S15-003).

PY - 2022/9/22

Y1 - 2022/9/22

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 = 7.0x10-03, 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.

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 = 7.0x10-03, 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.

KW - Prostate cancer

KW - Clonal expansions

KW - Genomics

KW - Normal tissue

KW - Benign prostatic hyperplasia

KW - Field effect

KW - Mutational signatures

U2 - 10.1186/s12943-022-01644-3

DO - 10.1186/s12943-022-01644-3

M3 - Article

VL - 21

JO - Molecular Cancer

JF - Molecular Cancer

M1 - 183

ER -

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

Abstract

Keywords

UN SDGs

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Additional files 1, 3-8 of The architecture of clonal expansions in morphologically normal tissue from cancerous and non-cancerous prostates

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