@article{10902/9687,
year = {2014},
url = {http://hdl.handle.net/10902/9687},
abstract = {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},
publisher = {Genome Biology 2014, 15:433},
title = {Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution},
author = {Fisher, Rosalie and Horswell, Stuart and Rowan, Andrew and Salm, Maximilian P and Bruin, Elza C de and Gulati, Sakshi and McGranahan, Nicholas and Stares, Mark and Gerlinger, Marco and Varela Egocheaga, Ignacio and Crockford, Andrew and Favero, Francesco and Quidville, Virginie and Andre, Fabrice and Navas, Carolina and Grönroos, Eva and Nicol, David and Hazell, Steve and Hrouda, David and O`Brian, Tim and Matthews, Nik and Phillimore, Ben and Begum, Sharmin and Rabinowitz, Adam and Biggs, Jennifer and Bates, Paul A and McDonald, Neil Q and Stamp, Gordon and Spencer-Dene, Bradley and Hsieh, James J and Xu, Jianing and Pickering, Lisa and Gore, Martin and Larkin, James and Swanton, Charles},
}