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

Relevant Publications

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

RenalFunders