Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma

Abstract

We sequenced whole exomes of ten clear cell renal cell carcinomas (ccRCCs) and performed a screen of ∼1,100 genes in 88 additional ccRCCs, from which we discovered 12 previously unidentified genes mutated at elevated frequencies in ccRCC. Notably, we detected frequent mutations in the ubiquitin-mediated proteolysis pathway (UMPP), and alterations in the UMPP were significantly associated with overexpression of HIF1α and HIF2α in the tumors (P = 0.01 and 0.04, respectively). Our findings highlight the potential contribution of UMPP to ccRCC tumorigenesis through the activation of the hypoxia regulatory network.

Deubiquitylases From Genes to Organism

“…Somatic inactivating mutations have been found at high incidence in uveal melanomas, clear cell renal carcinoma, and pleural malignant mesotheliomas (1,82,86). Germline mutations have been linked to a tumor predisposition syndrome for melanocytic tumors and mesothelioma (252,274).…”

The epigenetic landscape of renal cancer

“…BAP1 encodes a deubiquitylating enzyme with multiple targets. This gene is mutated in up to 11% of patients with ccRCC 143,167,168 and 3% of patients with pRCC 5 . BAP1 is associated with multiprotein complexes that include breast cancer type 1 susceptibility protein (BRCA1) and BRCA1-associated RING domain protein 1 (BARD1).…”

Stabilization and targeting of INO80 to replication forks by BAP1 during normal DNA synthesis

“…Earlier studies have shown that BAP1 is deleted or mutated in various human cancer cell lines and that re-expression of BAP1 in H226 human non-small cell lung cancer (or mesothelioma) cells lacking BAP1 reverses their tumorigenicity [14][15][16] . Importantly, a series of recent studies has identified inactivating mutations of BAP1 in various human cancers with high frequency in pleural malignant mesothelioma (MPM), uveal melanoma and cutaneous melanoma, indicating that germline BAP1 mutations cause the tumorigenesis of these cancers [17][18][19][20][21][22][23] . A recent study reported that BAP1 disruption in mice leads to the development of myeloid neoplasia 24 .…”