Abstract
Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases. A multi-center prospective study and two validation cohorts of matched primary metastasis biopsies from 100 patients with clear-cell renal cell carcinoma provides a comprehensive picture of the genetic underpinnings and the evolutionary patterns of metastasis.
Original language | English |
---|---|
Pages (from-to) | 581-594.e12 |
Journal | Cell |
Volume | 173 |
Issue number | 3 |
DOIs | |
State | Published - Apr 19 2018 |
Keywords
- chromosome instability
- cytoreductive nephrectomy
- evolution of metastasis
- loss of 9p
- metastasectomy
- metastasis
- oligometastasis
- renal cell cancer
- solitary metastasis
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Tracking Cancer Evolution Reveals Constrained Routes to Metastases : TRACERx Renal. / PEACE; the TRACERx Renal Consortium.
In: Cell, Vol. 173, No. 3, 19.04.2018, p. 581-594.e12.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Tracking Cancer Evolution Reveals Constrained Routes to Metastases
T2 - TRACERx Renal
AU - PEACE
AU - the TRACERx Renal Consortium
AU - Turajlic, Samra
AU - Xu, Hang
AU - Litchfield, Kevin
AU - Rowan, Andrew
AU - Chambers, Tim
AU - Lopez, Jose I.
AU - Nicol, David
AU - O'Brien, Tim
AU - Larkin, James
AU - Horswell, Stuart
AU - Stares, Mark
AU - Au, Lewis
AU - Jamal-Hanjani, Mariam
AU - Challacombe, Ben
AU - Chandra, Ashish
AU - Hazell, Steve
AU - Eichler-Jonsson, Claudia
AU - Soultati, Aspasia
AU - Chowdhury, Simon
AU - Rudman, Sarah
AU - Lynch, Joanna
AU - Fernando, Archana
AU - Stamp, Gordon
AU - Nye, Emma
AU - Jabbar, Faiz
AU - Spain, Lavinia
AU - Lall, Sharanpreet
AU - Guarch, Rosa
AU - Falzon, Mary
AU - Proctor, Ian
AU - Pickering, Lisa
AU - Gore, Martin
AU - Watkins, Thomas B.K.
AU - Ward, Sophia
AU - Stewart, Aengus
AU - DiNatale, Renzo
AU - Becerra, Maria F.
AU - Reznik, Ed
AU - Hsieh, James J.
AU - Richmond, Todd A.
AU - Mayhew, George F.
AU - Hill, Samantha M.
AU - McNally, Catherine D.
AU - Jones, Carol
AU - Rosenbaum, Heidi
AU - Stanislaw, Stacey
AU - Burgess, Daniel L.
AU - Alexander, Nelson R.
AU - Swanton, Charles
N1 - Funding Information: S.T. and H.X. are funded by Cancer Research UK (CRUK) (C50947/A18176). S.T., T.C., J.L., and M.G. are funded by the NIH Research (NIHR) Biomedical Research Centre (BRC) at the Royal Marsden Hospital and Institute of Cancer Research (A109). J.I.L. is funded by the Ministerio de Economía y Competitividad (MINECO, SAF2016-79847-R). M.S., A.S., J.L., R.F., L.A., and L.S. are funded by the Royal Marsden Cancer Charity. K.L. is funded by UK Medical Research Council (MR/P014712/1). N.M. receives funding from CRUK, Rosetrees, and the NIHR BRC at University College London Hospitals. C.S is Royal Society Napier Research Professor. C.S. is funded by Cancer Research UK (TRACERx and CRUK Cancer Immunotherapy Catalyst Network), the CRUK Lung Cancer Centre of Excellence, Stand Up 2 Cancer (SU2C), the Rosetrees and Stoneygate Trusts, NovoNordisk Foundation (ID 16584), the Breast Cancer Research Foundation (BCRF), the European Research Council (THESEUS), Marie Curie Network PloidyNet, the NIHR BRC at University College London Hospitals, and the CRUK University College London Experimental Cancer Medicine Centre. The work presented in this manuscript was funded by Cancer Research UK (grant reference number C50947/A18176), Ventana Medical Systems (grant reference numbers 10467 and 10530), the Kidney Cancer Fund of The Royal Marsden Cancer Charity, NIHR BRC at the Royal Marsden Hospital and Institute of Cancer Research (grant reference number A109), and the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001202), the UK Medical Research Council (FC001202), and the Wellcome Trust (FC001202). In particular, we acknowledge the support of the Advanced Sequencing Facility and the High-Performance Computing at the Francis Crick Institute. This project was enabled through access to the MRC eMedLab Medical Bioinformatics infrastructure, supported by the Medical Research Council (grant number MR/L016311/1). Funding Information: S.T. and H.X. are funded by Cancer Research UK (CRUK) ( C50947/A18176 ). S.T., T.C., J.L., and M.G. are funded by the NIH Research (NIHR) Biomedical Research Centre (BRC) at the Royal Marsden Hospital and Institute of Cancer Research ( A109 ). J.I.L. is funded by the Ministerio de Economía y Competitividad (MINECO, SAF2016-79847-R ). M.S., A.S., J.L., R.F., L.A., and L.S. are funded by the Royal Marsden Cancer Charity . K.L. is funded by UK Medical Research Counci l ( MR/P014712/1 ). N.M. receives funding from CRUK , Rosetrees , and the NIHR BRC at University College London Hospitals . C.S is Royal Society Napier Research Professor. C.S. is funded by Cancer Research UK (TRACERx and CRUK Cancer Immunotherapy Catalyst Network), the CRUK Lung Cancer Centre of Excellence , Stand Up 2 Cancer (SU2C) , the Rosetrees and Stoneygate Trusts, NovoNordisk Foundation ( ID 16584 ), the Breast Cancer Research Foundation (BCRF) , the European Research Council (THESEUS) , Marie Curie Network PloidyNet , the NIHR BRC at University College London Hospitals, and the CRUK University College London Experimental Cancer Medicine Centre . The work presented in this manuscript was funded by Cancer Research UK (grant reference number C50947/A18176 ), Ventana Medical Systems (grant reference numbers 10467 and 10530 ), the Kidney Cancer Fund of The Royal Marsden Cancer Charity , NIHR BRC at the Royal Marsden Hospital and Institute of Cancer Research (grant reference number A109 ), and the Francis Crick Institute , which receives its core funding from Cancer Research UK ( FC001202 ), the UK Medical Research Council ( FC001202 ), and the Wellcome Trust ( FC001202 ). In particular, we acknowledge the support of the Advanced Sequencing Facility and the High-Performance Computing at the Francis Crick Institute. This project was enabled through access to the MRC eMedLab Medical Bioinformatics infrastructure, supported by the Medical Research Council (grant number MR/L016311/1 ). Funding Information: S.T. and H.X. are funded by Cancer Research UK (CRUK) (C50947/A18176). S.T., T.C., J.L., and M.G. are funded by the NIH Research (NIHR) Biomedical Research Centre (BRC) at the Royal Marsden Hospital and Institute of Cancer Research (A109). J.I.L. is funded by the Ministerio de Econom?a y Competitividad (MINECO, SAF2016-79847-R). M.S., A.S., J.L., R.F., L.A., and L.S. are funded by the Royal Marsden Cancer Charity. K.L. is funded by UK Medical Research Council (MR/P014712/1). N.M. receives funding from CRUK, Rosetrees, and the NIHR BRC at University College London Hospitals. C.S is Royal Society Napier Research Professor. C.S. is funded by Cancer Research UK (TRACERx and CRUK Cancer Immunotherapy Catalyst Network), the CRUK Lung Cancer Centre of Excellence, Stand Up 2 Cancer (SU2C), the Rosetrees and Stoneygate Trusts, NovoNordisk Foundation (ID 16584), the Breast Cancer Research Foundation (BCRF), the European Research Council (THESEUS), Marie Curie Network PloidyNet, the NIHR BRC at University College London Hospitals, and the CRUK University College London Experimental Cancer Medicine Centre. The work presented in this manuscript was funded by Cancer Research UK (grant reference number C50947/A18176), Ventana Medical Systems (grant reference numbers 10467 and 10530), the Kidney Cancer Fund of The Royal Marsden Cancer Charity, NIHR BRC at the Royal Marsden Hospital and Institute of Cancer Research (grant reference number A109), and the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001202), the UK Medical Research Council (FC001202), and the Wellcome Trust (FC001202). In particular, we acknowledge the support of the Advanced Sequencing Facility and the High-Performance Computing at the Francis Crick Institute. This project was enabled through access to the MRC eMedLab Medical Bioinformatics infrastructure, supported by the Medical Research Council (grant number MR/L016311/1). Publisher Copyright: © 2018
PY - 2018/4/19
Y1 - 2018/4/19
N2 - Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases. A multi-center prospective study and two validation cohorts of matched primary metastasis biopsies from 100 patients with clear-cell renal cell carcinoma provides a comprehensive picture of the genetic underpinnings and the evolutionary patterns of metastasis.
AB - Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases. A multi-center prospective study and two validation cohorts of matched primary metastasis biopsies from 100 patients with clear-cell renal cell carcinoma provides a comprehensive picture of the genetic underpinnings and the evolutionary patterns of metastasis.
KW - chromosome instability
KW - cytoreductive nephrectomy
KW - evolution of metastasis
KW - loss of 9p
KW - metastasectomy
KW - metastasis
KW - oligometastasis
KW - renal cell cancer
KW - solitary metastasis
UR - http://www.scopus.com/inward/record.url?scp=85045083551&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2018.03.057
DO - 10.1016/j.cell.2018.03.057
M3 - Article
C2 - 29656895
AN - SCOPUS:85045083551
VL - 173
SP - 581-594.e12
JO - Cell
JF - Cell
SN - 0092-8674
IS - 3
ER -