Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx renal

Thomas J. Mitchell; Samra Turajlic; Andrew Rowan; David Nicol; James H.R. Farmery; Tim O’Brien; Inigo Martincorena; Patrick Tarpey; Nicos Angelopoulos; Lucy R. Yates; Adam P. Butler; Keiran Raine; Grant D. Stewart; Ben Challacombe; Archana Fernando; Jose I. Lopez; Steve Hazell; Ashish Chandra; Simon Chowdhury; Sarah Rudman; Aspasia Soultati; Gordon Stamp; Nicos Fotiadis; Lisa Pickering; Lewis Au; Lavinia Spain; Joanna Lynch; Mark Stares; Jon Teague; Francesco Maura; David C. Wedge; Stuart Horswell; Tim Chambers; Kevin Litchfield; Hang Xu; Aengus Stewart; Reza Elaidi; Stéphane Oudard; Nicholas McGranahan; Istvan Csabai; Martin Gore; P. Andrew Futreal; James Larkin; Andy G. Lynch; Zoltan Szallasi; Charles Swanton; Peter J. Campbell

doi:10.1016/j.cell.2018.02.020

Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx renal

Thomas J. Mitchell, Samra Turajlic, Andrew Rowan, David Nicol, James H.R. Farmery, Tim O’Brien, Inigo Martincorena, Patrick Tarpey, Nicos Angelopoulos, Lucy R. Yates, Adam P. Butler, Keiran Raine, Grant D. Stewart, Ben Challacombe, Archana Fernando, Jose I. Lopez, Steve Hazell, Ashish Chandra, Simon Chowdhury, Sarah RudmanAspasia Soultati, Gordon Stamp, Nicos Fotiadis, Lisa Pickering, Lewis Au, Lavinia Spain, Joanna Lynch, Mark Stares, Jon Teague, Francesco Maura, David C. Wedge, Stuart Horswell, Tim Chambers, Kevin Litchfield, Hang Xu, Aengus Stewart, Reza Elaidi, Stéphane Oudard, Nicholas McGranahan, Istvan Csabai, Martin Gore, P. Andrew Futreal, James Larkin, Andy G. Lynch, Zoltan Szallasi, Charles Swanton, Peter J. Campbell

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

Abstract

Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5′ UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor’s most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention.

Original language	English
Article number	e17
Pages (from-to)	611-623
Number of pages	13
Journal	Cell
Volume	173
Issue number	3
Early online date	12 Apr 2018
DOIs	https://doi.org/10.1016/j.cell.2018.02.020
Publication status	Published - 19 Apr 2018

Keywords

Clear cell renal cell carcinoma
Cancer evolution
Chromothripsis

UN SDGs

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

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10.1016/j.cell.2018.02.020Licence: CC BY

Mitchell_2018_Cell_TRACERx_CC
Crown Copyright © 2018 Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Final published version, 7.08 MBLicence: CC BY

Andy Lynch
- andy.lynchst-andrews.acuk
- School of Medicine - Professor of Statistics in Bioscience
- School of Mathematics and Statistics - Professor
- Sir James Mackenzie Institute for Early Diagnosis
- St Andrews Bioinformatics Unit
- Cellular Medicine Division
Person: Academic

Cite this

Mitchell, T. J., Turajlic, S., Rowan, A., Nicol, D., Farmery, J. H. R., O’Brien, T., Martincorena, I., Tarpey, P., Angelopoulos, N., Yates, L. R., Butler, A. P., Raine, K., Stewart, G. D., Challacombe, B., Fernando, A., Lopez, J. I., Hazell, S., Chandra, A., Chowdhury, S., ... Campbell, P. J. (2018). Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx renal. Cell, 173(3), 611-623. Article e17. https://doi.org/10.1016/j.cell.2018.02.020

@article{8094009dab744752b246baadc90ee410,

title = "Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx renal",

abstract = "Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5′ UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor{\textquoteright}s most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention.",

keywords = "Clear cell renal cell carcinoma, Cancer evolution, Chromothripsis",

author = "Mitchell, {Thomas J.} and Samra Turajlic and Andrew Rowan and David Nicol and Farmery, {James H.R.} and Tim O{\textquoteright}Brien and Inigo Martincorena and Patrick Tarpey and Nicos Angelopoulos and Yates, {Lucy R.} and Butler, {Adam P.} and Keiran Raine and Stewart, {Grant D.} and Ben Challacombe and Archana Fernando and Lopez, {Jose I.} and Steve Hazell and Ashish Chandra and Simon Chowdhury and Sarah Rudman and Aspasia Soultati and Gordon Stamp and Nicos Fotiadis and Lisa Pickering and Lewis Au and Lavinia Spain and Joanna Lynch and Mark Stares and Jon Teague and Francesco Maura and Wedge, {David C.} and Stuart Horswell and Tim Chambers and Kevin Litchfield and Hang Xu and Aengus Stewart and Reza Elaidi and St{\'e}phane Oudard and Nicholas McGranahan and Istvan Csabai and Martin Gore and Futreal, {P. Andrew} and James Larkin and Lynch, {Andy G.} and Zoltan Szallasi and Charles Swanton and Campbell, {Peter J.}",

note = "The work presented in this manuscript was funded by EU FP7 (project PREDICT ID number 259303) and the Wellcome Trust and Cancer Research UK. S.T. is funded by Cancer Research UK (C50947/A18176). S.T., J.L., and M.G. receive funding from the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden Hospital and Institute of Cancer Research (A109). J.H.R.F. and A.G.L. were supported by the University of Cambridge, Cancer Research UK (C14303/A17197), and Hutchison Whampoa. K.L. is supported by a UK Medical Research Council Skills Development Fellowship Award. C.S. is funded by Cancer Research UK (TRACERx), the Rosetrees Trust, NovoNordisk Foundation (16584), EU FP7 (projects PREDICT and RESPONSIFY, ID number 259303), the Prostate Cancer Foundation, the Breast Cancer Research Foundation, the European Research Council (THESEUS), and National Institute for Health Research University College London Hospitals Biomedical Research Centre. P.J.C. has a Wellcome Trust Senior Clinical Research Fellowship (WT088340MA).",

year = "2018",

month = apr,

day = "19",

doi = "10.1016/j.cell.2018.02.020",

language = "English",

volume = "173",

pages = "611--623",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "3",

}

Mitchell, TJ, Turajlic, S, Rowan, A, Nicol, D, Farmery, JHR, O’Brien, T, Martincorena, I, Tarpey, P, Angelopoulos, N, Yates, LR, Butler, AP, Raine, K, Stewart, GD, Challacombe, B, Fernando, A, Lopez, JI, Hazell, S, Chandra, A, Chowdhury, S, Rudman, S, Soultati, A, Stamp, G, Fotiadis, N, Pickering, L, Au, L, Spain, L, Lynch, J, Stares, M, Teague, J, Maura, F, Wedge, DC, Horswell, S, Chambers, T, Litchfield, K, Xu, H, Stewart, A, Elaidi, R, Oudard, S, McGranahan, N, Csabai, I, Gore, M, Futreal, PA, Larkin, J, Lynch, AG, Szallasi, Z, Swanton, C & Campbell, PJ 2018, 'Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx renal', Cell, vol. 173, no. 3, e17, pp. 611-623. https://doi.org/10.1016/j.cell.2018.02.020

TY - JOUR

T1 - Timing the landmark events in the evolution of clear cell renal cell cancer

T2 - TRACERx renal

AU - Mitchell, Thomas J.

AU - Turajlic, Samra

AU - Rowan, Andrew

AU - Nicol, David

AU - Farmery, James H.R.

AU - O’Brien, Tim

AU - Martincorena, Inigo

AU - Tarpey, Patrick

AU - Angelopoulos, Nicos

AU - Yates, Lucy R.

AU - Butler, Adam P.

AU - Raine, Keiran

AU - Stewart, Grant D.

AU - Challacombe, Ben

AU - Fernando, Archana

AU - Lopez, Jose I.

AU - Hazell, Steve

AU - Chandra, Ashish

AU - Chowdhury, Simon

AU - Rudman, Sarah

AU - Soultati, Aspasia

AU - Stamp, Gordon

AU - Fotiadis, Nicos

AU - Pickering, Lisa

AU - Au, Lewis

AU - Spain, Lavinia

AU - Lynch, Joanna

AU - Stares, Mark

AU - Teague, Jon

AU - Maura, Francesco

AU - Wedge, David C.

AU - Horswell, Stuart

AU - Chambers, Tim

AU - Litchfield, Kevin

AU - Xu, Hang

AU - Stewart, Aengus

AU - Elaidi, Reza

AU - Oudard, Stéphane

AU - McGranahan, Nicholas

AU - Csabai, Istvan

AU - Gore, Martin

AU - Futreal, P. Andrew

AU - Larkin, James

AU - Lynch, Andy G.

AU - Szallasi, Zoltan

AU - Swanton, Charles

AU - Campbell, Peter J.

N1 - The work presented in this manuscript was funded by EU FP7 (project PREDICT ID number 259303) and the Wellcome Trust and Cancer Research UK. S.T. is funded by Cancer Research UK (C50947/A18176). S.T., J.L., and M.G. receive funding from the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden Hospital and Institute of Cancer Research (A109). J.H.R.F. and A.G.L. were supported by the University of Cambridge, Cancer Research UK (C14303/A17197), and Hutchison Whampoa. K.L. is supported by a UK Medical Research Council Skills Development Fellowship Award. C.S. is funded by Cancer Research UK (TRACERx), the Rosetrees Trust, NovoNordisk Foundation (16584), EU FP7 (projects PREDICT and RESPONSIFY, ID number 259303), the Prostate Cancer Foundation, the Breast Cancer Research Foundation, the European Research Council (THESEUS), and National Institute for Health Research University College London Hospitals Biomedical Research Centre. P.J.C. has a Wellcome Trust Senior Clinical Research Fellowship (WT088340MA).

PY - 2018/4/19

Y1 - 2018/4/19

N2 - Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5′ UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor’s most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention.

AB - Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5′ UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor’s most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention.

KW - Clear cell renal cell carcinoma

KW - Cancer evolution

KW - Chromothripsis

U2 - 10.1016/j.cell.2018.02.020

DO - 10.1016/j.cell.2018.02.020

M3 - Article

SN - 0092-8674

VL - 173

SP - 611

EP - 623

JO - Cell

JF - Cell

IS - 3

M1 - e17

ER -

Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx renal

Abstract

Keywords

UN SDGs

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