Kidney cancer. Principles and practice. Second edition. Primo N. Lara, Jr. Eric Jonasch (Editors). Springer International Publishing (2015)
von Hippel-Lindau disease is characterized by an increased risk of clear cell renal carcinoma; hemangioblastomas of the retina, spinal cord, and cerebellum; and pheochromocytoma . Pioneering studies by Bert Zbar, Marston Linehan, and Eamon Maher led to the identification of the gene that, when mutated in the germline, causes this disease (VHL) . The human VHL gene is located on 3p25 and contains three exons. VHL orthologs have now been identified in a wide variety of metazoan species. Individuals with VHL disease have inherited a defective VHL allele from one of their parents or, less commonly, have a de novo VHL mutation. The development of tumors in VHL disease is linked to inactivation of the remaining wildtype VHL allele in a susceptible cell. As such, VHL conforms to the Knudson 2-hit model. In keeping with the increased risk of clear cell renal carcinoma in VHL patients, biallelic VHL inactivation, due to somatic VHL mutations or VHL hypermethylation, is also very common in sporadic (nonhereditary) clear cell renal carcinomas . In many early studies, VHL mutations were documented in about 50 % of sporadic clear cell renal carcinomas, with another 5–20 % of tumors exhibiting VHL hypermethylation, which inhibits transcription of the VHL gene. More recent studies, using newer sequencing methods, suggest that the frequency of VHL mutations in clear cell renal carcinoma is actually much higher [4, 5]. This would explain why the vast majority of clear cell renal carcinomas have molecular signatures suggestive of VHL inactivation (see also below) .
One can infer the evolutionary history of a given tumor by determining the frequency of specific mutant alleles (and hence subclones) within that tumor by next-generation sequencing. Such studies confirm that biallelic VHL inactivation is an early “truncal” event in clear cell renal carcinoma but is not sufficient to cause this disease [7–10].
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