Year: 2018
Type: article
Study design: Observational Study
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.
Source: Cell
Authors: 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
Institutions: University of Cambridge, Wellcome Sanger Institute, Addenbrooke's Hospital, National Health Service, Royal Marsden NHS Foundation Trust, The Francis Crick Institute, Guy's and St Thomas' NHS Foundation Trust, University of the Basque Country, Hospital de Cruces, University of Oxford, Hôpital Européen Georges-Pompidou, Cancer Research UK, University College London, Eötvös Loránd University, The University of Texas MD Anderson Cancer Center, University of St Andrews, Harvard University, Harvard–MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Technical University of Denmark, University College London Hospitals NHS Foundation Trust
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $11,400
Funders: Prostate Cancer Foundation, Breast Cancer Research Foundation, Wellcome Trust, Francis Crick Institute, Cancer Research UK, National Institute for Health and Care Research, University of Cambridge, University College London, Rosetrees Trust, Novo Nordisk Fonden, Medical Research Council, European Research Council, Institute of Cancer Research
Awards: Somatic mutation, clonal dynamics and tumour evolution in premalignant lung disease., G115918137, G1394760774, G143899097, G1524023739, G1530421398, G182428912, G1872847433, G189782301, G2864965629, G3950410013, G4344689229, G5638595947, G5974791237, G6328017282, G640145969, G6523146432, G6838766548, G7554413032, G8538723892
OpenAlex ID: W2797702016