Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution

Rosalie Fisher, Stuart Horswell, Andrew Rowan, Maximilian P. Salm, Elza C. de Bruin, Sakshi Gulati, Nicholas McGranahan, Mark Stares, Marco Gerlinger, Ignacio Varela, Andrew Crockford, Francesco Favero, Virginie Quidville, Fabrice André, Carolina Navas, Eva Grönroos, David Nicol, Steve Hazell, David Hrouda, Tim O’BrienNik Matthews, Ben Phillimore, Sharmin Begum, Adam Rabinowitz, Jennifer Biggs, Paul A. Bates, Neil Q. McDonald, Gordon Stamp, Bradley Spencer-Dene, James J. Hsieh, Jianing Xu, Lisa Pickering, Martin Gore, James Larkin, Charles Swanton

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    Background : Genomic analysis of multi-focal renal cell carcinomas from an individual with a germline VHL mutation offers a unique opportunity to study tumor evolution. Results : We perform whole exome sequencing on four clear cell renal cell carcinomas removed from both kidneys of a patient with a germline VHL mutation. We report that tumors arising in this context are clonally independent and harbour distinct secondary events exemplified by loss of chromosome 3p, despite an identical genetic background and tissue microenvironment. We propose that divergent mutational and copy number anomalies are contingent upon the nature of 3p loss of heterozygosity occurring early in tumorigenesis. However, despite distinct 3p events, genomic, proteomic and immunohistochemical analyses reveal evidence for convergence upon the PI3K-AKT-mTOR signaling pathway. Four germline tumors in this young patient, and in a second, older patient with VHL syndrome demonstrate minimal intra-tumor heterogeneity and mutational burden, and evaluable tumors appear to follow a linear evolutionary route, compared to tumors from patients with sporadic clear cell renal cell carcinoma. Conclusions : In tumors developing from a germline VHL mutation, the evolutionary principles of contingency and convergence in tumor development are complementary. In this small set of patients with early stage VHL-associated tumors, there is reduced mutation burden and limited evidence of intra-tumor heterogeneity.
    Original languageEnglish
    Article number433
    JournalGenome Biology (Online Edition)
    Issue number8
    Number of pages15
    Publication statusPublished - 2014

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    This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.


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