PBRM1 and BAP1 as Novel Targets for Renal Cell Carcinoma

作者：James Brugarolas · 发表于：The Cancer Journal · 年份：2013 · DOI：10.1097/ppo.0b013e3182a102d1 · 被引用次数：132 · 研究领域：Renal cell carcinoma treatment、Renal and related cancers、Cancer Genomics and Diagnostics

Technological advances in genome sequencing have led to the identification of novel driver genes mutated in renal cancer. Hitherto, 1 gene was known to be frequently mutated in renal cell carcinoma of clear cell type (ccRCC), the von Hippel-Lindau (VHL) gene. VHL was identified by positional cloning as the gene responsible for a familial syndrome with renal cancer predisposition, von Hippel-Lindau. Subsequently, VHL was found to be inactivated in approximately 90% of sporadic ccRCC. The discovery of VHL, together with the elucidation of its function, transformed the treatment of ccRCC leading to the introduction of 5 new drugs into the clinic. However, no other familial ccRCC predisposing genes are frequently mutated in sporadic ccRCC. With the development of massively parallel sequencing, a plethora of somatically mutated genes has been identified. Most genes are mutated at low frequencies, but 3 genes are mutated in more than 10% of ccRCC, PBRM1 (mutated in ~50%), BAP1 (~15%), and SETD2 (~15%). Like VHL, all 3 genes are 2-hit tumor suppressor genes. Furthermore, these 3 genes are within a 50-Mb region on the short arm of chromosome 3p that encompasses VHL and is deleted in ~90% of ccRCC. We discovered that PBRM1 mutations tend to anticorrelate with BAP1 mutations in ccRCC and that PBRM1- and BAP1-mutated tumors exhibit different biology and are associated with markedly different outcomes. This established the foundation for the first molecular genetic classification of spor...