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

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

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

journal contribution

posted on 2020-09-07, 11:12 authored by Thomas J Mitchell, Samra Turajlic, Andrew Rowan, David Nicol, James HR 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, TRACERx Renal Consortium

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.