The incidence of renal cell carcinoma (RCC) has more than doubled in the UK since the late 1970s. Much of this increase may be explained by the rise in the incidental radiological detection of asymptomatic small renal masses, but >25% of patients have metastatic disease at diagnosis. Of the patients who undergo surgery with curative intent one third will subsequently develop metastatic disease. Therefore, half of all patients will have advanced disease, which is associated with a five-year survival of only 5%. An improved understanding of the factors that drive metastatic disease and treatment resistance is fundamental for improving these outcomes. We have previously revealed extensive intra-tumour heterogeneity present within RCC demonstrating that genetically distinct, physically and temporally separated subclones evolving in a branched pattern contribute to the make-up of the tumour as a whole.
This type of heterogeneity appears to play a central role in tumour evolution, progression and treatment resistance and is also a significant hurdle for precision medicine, not least through the effect of tumour sampling bias on prognostic and predictive markers development. The principal objectives of TRACERx Renal are to define drivers and intratumour heterogeneity in RCC and determine the relationship between heterogeneity and disease stage, clinical outcome and treatment response. Additional objectives include the identification of drivers of metastatic progression and drug response, or resistance and establishing the utility of cell-free tumour DNA in patients’ blood and urine as a predictive biomarker in RCC. Finally TRACERx Renal will asses the impact of the genomic landscape upon anti-tumour T cell responses, especially in the context of immunotherapy.
THE TEAM
Chief Clinical Investigator:
Dr Samra Turajlic – Consultant Medical Oncologist, Royal Marsden Hospital (RMH)
Chief Scientific Investigators:
Dr Samra Turajlic- Clinician Scientist, Francis Crick Institute (FCI)
Professor Charles Swanton- Consultant Medical Oncologist and Group Leader, FCI and UCL Cancer Institute (CI)
Dr Sergio Quezada – Group Leader, UCL CI
Scientific Co-Investigators
Stuart Horswell, Bioinfomatician, FCI
Hang Xu, Post-doctoral Fellow, FCI
Andrew Rowan, Principal Scientific Officer, FCI
Tim Chambers, Senior Scientific Officer, FCI
Clinical Co-investigators
Mr Tim O’Brien, Consultant Surgeon, Guy’s and St Thomas’ (GSST)
Mr David Nicol, Consultant Surgeon, RMH
Mr Ben Challacombe, Consultant Surgeon, GSST
Archana Fernando, Consultant Surgeon, GSST
Dr Steve Hazell, Consultant Pathologits, RMH
Dr Ashish Chandra, Consultant Pathologist, GSST
Dr James Larkin Consultant Medical Oncologist, RMH
Professor Martin Gore Consultant Medical Oncologist, RMH
Dr Lisa Pickering, Consultant Medical Oncologist, RMH
Dr Lavinia Spain Clinical Research Fellow
Dr Andrew Furness Clinical Research Fellow
Dr Kroopa Joshi Clinical Research Fellow
Dr Joanna Lynch, Clinical Research Fellow
Dr Sarah Rudman Consultant Medical Oncologist, Guy’s and St Thomas (GSST)
Dr Simon Chowdhury, Consultant Medical Oncologist, GSST
Miss Karen Harrison-Phipps, Consultant Surgeon, GSST
Dr Mary Varia, Consultant Pathologist, GSST
Dr Catherine Horsfield, Consultant Pathologist, GSST
Dr Alex Polson, Consultant Pathologist, GSST
Prof Gordon Stamp, Consultant Pathologist, The London Clinic
Dr Marie O’Donnell, Consultant Pathologist, Edinburgh
Prof William Drake, Consultant Endocrinologist, Bart’s
Dr Peter Hill, Consultant Nephrologist, Imperial College
Prof David Hrouda, Consultant Surgeon, Imperial
Dr Eric Mayer, Consultant Surgeon, Imperial
Mr Jonathon Olsburgh, Consultant Surgeon, GSST
Mr Gordon Kooiman, Consultant Surgeons, King’s
Mr Kevin O’Connor, Consultant Surgeons (Edinburgh)
Mr Grant Stewart, Consultant Surgeon, Cambridge
Mr Michael Aithcison, Consultant Surgeon, The Royal Free Hospital (RFH)
Miss Maxine Tran, Consultant Surgeon, RFH
Dr Nicos Fotiadis, Consultant Radiologist, RMH
Dr Hema Verma, Consultant Radiologist, GSST
Collaborators:
Dr Jose Ignacio Lopez, Consultant Pathologist, Universidad del Pais Vasco, Spain
Dr Zoltan Szallasi, Denmark
Dr Peter Campbell, The Sanger Institute
RELEVANT PUBLICATIONS
Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal. Samra Turajlic, Hang Xu, Kevin Litchfield, Andrew Rowan,Stuart Horswell, Tim Chambers, Tim O’Brien, Jose I. Lopez, Thomas B.K. Watkins, David Nicol, Mark Stares, Ben Challacombe, Steve Hazell, Ashish Chandra, Thomas J. Mitchell, Lewis Au, Claudia Eichler-Jonsson, Faiz Jabbar, Aspasia Soultati, Simon Chowdhury, Sarah Rudman, Joanna Lynch, Archana Fernando, Gordon Stamp, Emma Nye, Aengus Stewart, Wei Xing, Jonathan C. Smith, Mickael Escudero, Adam Huffman, Nik Matthews, Greg Elgar, Ben Phillimore, Marta Costa, Sharmin Begum, Sophia Ward, Max Salm, Stefan Boeing, Rosalie Fisher, Lavinia Spain, Carolina Navas, Eva Groonroos, Sebastijan Hobor, Sarkhara Sharma, Ismaeel Aurangzeb, Sharanpreet Lall, Alexander Polson, Mary Varia, Catherine Horsfield, Nicos Fotiadis, Lisa Pickering, Roland F. Schwarz, Bruno Silva, Javier Herrero, Nick M. Luscombe, Mariam Jamal-Hanjani, Rachel Rosenthal, Nicolai J. Birkbak, Gareth A. Wilson, Orsolya Pipek, Dezso Ribli, Marcin Krzystanek, Istvan Csabai, Zoltan Szallasi, Martin Gore, Nicholas McGranahan, Peter Van Loo, Peter Campbell, James Larkin, Charles Swanton and the TRACERx Renal Consortium, 2018 Apr 12
Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal. Samra Turajlic, Hang Xu, Kevin Litchfield, Andrew Rowan, Tim Chambers, Jose I. Lopez, David Nicol, Tim O’Brien, James Larkin, Stuart Horswell, Mark Stares, Lewis Au, Mariam Jamal-Hanjani, Ben Challacombe, Ashish Chandra, Steve Hazell, Claudia Eichler-Jonsson, Aspasia Soultati, Simon Chowdhury, Sarah Rudman, Joanna Lynch, Archana Fernando, Gordon Stamp, Emma Nye, Faiz Jabbar, Lavinia Spain, Sharanpreet Lall, Rosa Guarch, Mary Falzon, Ian Proctor, Lisa Pickering, Martin Gore, Thomas B.K. Watkins, Sophia Ward, Aengus Stewart, Renzo DiNatale, Maria F. Becerra, Ed Reznik, James J. Hsieh, Todd A. Richmond, George F. Mayhew, Samantha M. Hill, Catherine D. McNally, Carol Jones, Heidi Rosenbaum, Stacey Stanislaw, Daniel L. Burgess, Nelson R. Alexander, Charles Swanton, and PEACE, the TRACERx Renal Consortium, 2018 April 12
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, Stephane Oudard, Nicholas McGranahan, Istvan Csabai, Martin Gore, P. Andrew Futreal, James Larkin, Andy G. Lynch, Zoltan Szallasi, Charles Swanton, Peter J. Campbell, and the TRACERx Renal Consortium
Metastasis as an evolutionary process. Turajlic S, Swanton C. Science. 2016 Apr 8;352(6282):169-75.
SnapShot: Renal Cell Carcinoma. Turajlic S, Larkin J, Swanton C. Cell. 2015 Dec 3;163(6):1556-1556.e1.
Relapse models for clear cell renal carcinoma. Gulati S, Turajlic S, Larkin J, Bates PA, Swanton C. Lancet Oncol. 2015 Aug;16(8):e376-8
Ultra-deep T cell receptor sequencing reveals the complexity and intratumour heterogeneity of T cell clones in renal cell carcinomas. Gerlinger M, Quezada SA, Peggs KS, Furness AJ, Fisher R, Marafioti T, Shende VH, McGranahan N, Rowan AJ, Hazell S, Hamm D, Robins HS, Pickering L, Gore M, Nicol DL, Larkin J, Swanton C. J Pathol. 2013 Dec;231(4):424-32.
Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Gerlinger M, Horswell S, Larkin J, Rowan AJ, Salm MP, Varela I, Fisher R, McGranahan N, Matthews N, Santos CR, Martinez P, Phillimore B, Begum S, Rabinowitz A, Spencer-Dene B, Gulati S, Bates PA, Stamp G, Pickering L, Gore M, Nicol DL, Hazell S, Futreal PA, Stewart A, Swanton C. Nat Genet. 2014 Mar;46(3):225-33.
How should clinicians address intratumour heterogeneity in clear cell renal cell carcinoma? Soultati A, Stares M, Swanton C, Larkin J, Turajlic S. Curr Opin Urol. 2015 Sep;25(5):358-66.
SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair. Kanu N, Grönroos E, Martinez P, Burrell RA, Yi Goh X, Bartkova J, Maya-Mendoza A, Mistrík M, Rowan AJ, Patel H, Rabinowitz A, East P, Wilson G, Santos CR, McGranahan N, Gulati S, Gerlinger M, Birkbak NJ, Joshi T, Alexandrov LB, Stratton MR, Powles T, Matthews N, Bates PA, Stewart A, Szallasi Z, Larkin J, Bartek J, Swanton C. Oncogene. 2015 Nov 12;34(46):5699-708. Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution. Fisher R, Horswell S, Rowan A, Salm MP, de Bruin EC, Gulati S, McGranahan N, Stares M, Gerlinger M, Varela I, Crockford A, Favero F, Quidville V, André F, Navas C, Grönroos E, Nicol D, Hazell S, Hrouda D, O’Brien T, Matthews N, Phillimore B, Begum S, Rabinowitz A, Biggs J, Bates PA, McDonald NQ, Stamp G, Spencer-Dene B, Hsieh JJ, Xu J, Pickering L, Gore M, Larkin J, Swanton C. Genome Biol. 2014 Aug 27;15(8):433.
Recurrent chromosomal gains and heterogeneous driver mutations characterise papillary renalcancer evolution. Kovac M, Navas C, Horswell S, Salm M, Bardella C, Rowan A, Stares M, Castro-Giner F, Fisher R, de Bruin EC, Kovacova M, Gorman M, Makino S, Williams J, Jaeger E, Jones A, Howarth K, Larkin J, Pickering L, Gore M, Nicol DL, Hazell S, Stamp G, O’Brien T, Challacombe B, Matthews N, Phillimore B, Begum S, Rabinowitz A, Varela I, Chandra A, Horsfield C, Polson A, Tran M, Bhatt R, Terracciano L, Eppenberger-Castori S, Protheroe A, Maher E, El Bahrawy M, Fleming S, Ratcliffe P, Heinimann K,Swanton C, Tomlinson I. Nat Commun. 2015 Mar 19;6:6336.
Inter and intratumour heterogeneity: a barrier to individualized medical therapy in renal cell carcinoma? Fisher R, Larkin J, Swanton C. Front Oncol. 2012 May 18;2:49. doi: 10.3389/fonc.2012.00049.
FUNDERS
Cancer Research UK
Royal Marsden Hospital and The Institute of Cancer Research Biomedical Research Centre
Royal Marsden Cancer Charity
