Von Hippel-Lindau (VHL) disease is an inherited cancer syndrome attributed to germline mutations in the VHL gene. These patients develop multiple tumours in different target organs, including clear cell renal cell carcinomas (ccRCC). Molecular profiling of synchronous or metachronous tumours occurring in the same patient and in the same organ is a rare opportunity to relate evolutionary principles to tumour formation. Cancers that develop in the background of an identical germline aberration, arise in the same organ and therefore are subject to the same environmental constraints provide the opportunity to test the hypothesis proposed by Jay Gould. Gould’s view was that if the “tape of life” was rewound to the same starting point an replayed under the same conditions then the evolutionary trajectory would follow a different course every time.

We study four tumours from the same patient with VHL germline mutation and show that they arose independently and that each tumour was characterised by a completely unique set of mutations and copy number alterations. Therefore, consistent with Gould’s theory, from a common starting point there are multiple, currently unpredictable routes to tumour development.

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Fisher et al. Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution. Genome biology 15, 433 (2014)

Gould SJ: Wonderful Life: The Burgess Shale and the Nature of History. New York:Norton; 1989