Targeted exome sequencing in clear cell renal cell carcinoma tumors suggests aberrant chromatin regulation as a crucial step in ccRCC development

Abstract

Clear cell renal cell carcinomas are characterized by 3p loss, and by inactivation of Von Hippel Lindau (VHL), a tumorsuppressor gene located at 3p25. Recently, SETD2, located at 3p21, was identified as a new candidate ccRCC tumor-suppressor gene. The combined mutational frequency in ccRCC tumors of VHL and SETD2 suggests that there are still undiscovered tumor-suppressor genes on 3p. We screened all genes on 3p for mutations in 10 primary ccRCC tumors using exome-sequencing. We identified inactivating mutations in VHL, PBRM1, and BAP1. Sequencing of PBRM1 in ccRCC-derived cell lines confirmed its frequent inactivation in ccRCC. PBRM1 encodes for BAF180, the chromatin targeting subunit of the SWI/SNF complex. BAP1 encodes for BRCA1 associated protein-1, involved in histone deubiquitination. Taken together, the accumulating data suggest an important role for aberrant chromatin regulation in ccRCC development.

Inactivation of the PBRM1 tumor suppressor gene amplifies the HIF-response in VHL −/− clear cell renal carcinoma

“…As noted earlier, however, the BAF180 present in SLR26 cells is possibly defective. In contrast, apparent loss of SETD2 was found both among cell lines lacking BAF180 and among cell lines lacking BAP1, consistent with genetic studies that have identified ccRCCs with coexisting SETD2 and PBRM1 mutations and ccRCCs with coexisting SETD2 and BAP1 mutations (2,3,6,13,20,23).…”

“…VHL loss, however, is not sufficient to cause ccRCC (4,(7)(8)(9). Other cooperating genetic events in ccRCC include copy number gain of chromosome 5q, copy number loss of chromosome 14q, and intragenic mutations affecting chromatin regulatory genes such as PBRM1, BAP1, ARID1A, SETD2, KDM5C, and KDM6A; PI3K pathway genes such as PTEN, PIK3CA, TSC1, and TORC1; and redox stress genes such as KEAP1 and NFE2L2 (1,(10)(11)(12)(13)(14).…”

The clinical significance of SWI/SNF complex in pancreatic cancer.

“…Actually, it is reported that BAF180 mutation is associated with carcinogenesis of breast cancer, and BAF180 suppresses tumorigenesis through its ability to regulate p21 (40), which controls the cell cycle (41). Recent research also clarified BAF180 mutation in clear cell renal cell carcinoma (42). These results suggest the idea that BAF180-containing complexes (PBAF) suppress tumor progression, which does not contradict our present results.…”

DNA Methylation of the SLC16A3 Promoter Regulates Expression of the Human Lactate Transporter MCT4 in Renal Cancer with Consequences for Clinical Outcome

“…Accordingly, epigenetic modifications, such as DNA methylation seem to be important for gene regulation in ccRCC (14,15). Although upregulation of MCT4 by hypoxia through an HIF-1a-mediated mechanism has been showed in HeLa cell line (16), the epigenetic regulation of MCT4 in ccRCC has not yet been reported and may offer clue to novel therapeutic strategy.…”