Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal

T.J. Mitchell; S. Turajlic; Andrew Rowan; D. Nicol; J.H.R. Farmery; T. O'Brien; I. Martincorena; P. Tarpey; N. Angelopoulos; L.R. Yates; Adam Butler; K. Raine; Grant Stewart; B. Challacombe; Archana Fernando; Jose Lopez; S. Hazell; Ashish Chandra; Simon Chowdhury; S. Rudman; A. Soultati; G. Stamp; N. Fotiadis; Lisa Pickering; L. Au; L. Spain; Joanna Lynch; M. Stares; Jon Teague; F. Maura; D.C. Wedge; S. Horswell; Tim Chambers; K. Litchfield; Hang Xu; R. Elaidi; Aengus Stewart; S. Oudard; N. McGranahan; I. Csabai; M. Gore; P.A. Futreal; J. Larkin; Andy Lynch; Z. Szallasi; C. Swanton; Peter Campbell

doi:10.1016/j.cell.2018.02.020

Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal

T.J. Mitchell, S. Turajlic, Andrew Rowan, D. Nicol, J.H.R. Farmery, T. O'Brien, I. Martincorena, P. Tarpey, N. Angelopoulos, L.R. Yates, Adam Butler, K. Raine, Grant Stewart, B. Challacombe, Archana Fernando, Jose Lopez, S. Hazell, Ashish Chandra, Simon Chowdhury, S. RudmanA. Soultati, G. Stamp, N. Fotiadis, Lisa Pickering, L. Au, L. Spain, Joanna Lynch, M. Stares, Jon Teague, F. Maura, D.C. Wedge, S. Horswell, Tim Chambers, K. Litchfield, Hang Xu, R. Elaidi, Aengus Stewart, S. Oudard, N. McGranahan, I. Csabai, M. Gore, P.A. Futreal, J. Larkin, Andy Lynch, Z. Szallasi, C. Swanton, Peter Campbell

Division of Cancer Sciences (L5)

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
Journal	Cell
Early online date	12 Apr 2018
DOIs	https://doi.org/10.1016/j.cell.2018.02.020
Publication status	Published - 2018

Research Beacons, Institutes and Platforms

Manchester Cancer Research Centre

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

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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., Raine, K., Stewart, G., Challacombe, B., Fernando, A., Lopez, J., Hazell, S., Chandra, A., Chowdhury, S., ... Campbell, P. (2018). Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal. Cell. https://doi.org/10.1016/j.cell.2018.02.020

@article{6a2dbd9928f748cbaeee93410ce5741d,

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.",

author = "T.J. Mitchell and S. Turajlic and Andrew Rowan and D. Nicol and J.H.R. Farmery and T. O'Brien and I. Martincorena and P. Tarpey and N. Angelopoulos and L.R. Yates and Adam Butler and K. Raine and Grant Stewart and B. Challacombe and Archana Fernando and Jose Lopez and S. Hazell and Ashish Chandra and Simon Chowdhury and S. Rudman and A. Soultati and G. Stamp and N. Fotiadis and Lisa Pickering and L. Au and L. Spain and Joanna Lynch and M. Stares and Jon Teague and F. Maura and D.C. Wedge and S. Horswell and Tim Chambers and K. Litchfield and Hang Xu and R. Elaidi and Aengus Stewart and S. Oudard and N. McGranahan and I. Csabai and M. Gore and P.A. Futreal and J. Larkin and Andy Lynch and Z. Szallasi and C. Swanton and Peter Campbell",

year = "2018",

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

language = "English",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

}

Mitchell, TJ, Turajlic, S, Rowan, A, Nicol, D, Farmery, JHR, O'Brien, T, Martincorena, I, Tarpey, P, Angelopoulos, N, Yates, LR, Butler, A, Raine, K, Stewart, G, Challacombe, B, Fernando, A, Lopez, J, 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, Elaidi, R, Stewart, A, Oudard, S, McGranahan, N, Csabai, I, Gore, M, Futreal, PA, Larkin, J, Lynch, A, Szallasi, Z, Swanton, C & Campbell, P 2018, 'Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal', Cell. 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: TRACERx Renal

AU - Mitchell, T.J.

AU - Turajlic, S.

AU - Rowan, Andrew

AU - Nicol, D.

AU - Farmery, J.H.R.

AU - O'Brien, T.

AU - Martincorena, I.

AU - Tarpey, P.

AU - Angelopoulos, N.

AU - Yates, L.R.

AU - Butler, Adam

AU - Raine, K.

AU - Stewart, Grant

AU - Challacombe, B.

AU - Fernando, Archana

AU - Lopez, Jose

AU - Hazell, S.

AU - Chandra, Ashish

AU - Chowdhury, Simon

AU - Rudman, S.

AU - Soultati, A.

AU - Stamp, G.

AU - Fotiadis, N.

AU - Pickering, Lisa

AU - Au, L.

AU - Spain, L.

AU - Lynch, Joanna

AU - Stares, M.

AU - Teague, Jon

AU - Maura, F.

AU - Wedge, D.C.

AU - Horswell, S.

AU - Chambers, Tim

AU - Litchfield, K.

AU - Xu, Hang

AU - Elaidi, R.

AU - Stewart, Aengus

AU - Oudard, S.

AU - McGranahan, N.

AU - Csabai, I.

AU - Gore, M.

AU - Futreal, P.A.

AU - Larkin, J.

AU - Lynch, Andy

AU - Szallasi, Z.

AU - Swanton, C.

AU - Campbell, Peter

PY - 2018

Y1 - 2018

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.

U2 - 10.1016/j.cell.2018.02.020

DO - 10.1016/j.cell.2018.02.020

M3 - Article

SN - 0092-8674

JO - Cell

JF - Cell

ER -

Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal

Abstract

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