Involvement of PBRM1 in VHL disease-associated clear cell renal cell carcinoma and its putative relationship with the HIF pathway.

Von Hippel-Lindau (VHL) disease is the main cause of inherited clear-cell renal cell carcinoma (ccRCC) and is caused by germline mutations in the tumor suppressor gene. Bi-allelic alterations lead to inactivation of pVHL, which plays a major role by downstream activation of the hypoxia inducible factor (HIF) pathway. Somatic mutations occur in 80% of sporadic ccRCC cases and the second most frequently mutated gene is polybromo 1 (). As there is currently no data regarding involvement in VHL disease-associated ccRCC, the aim of the present study was to assess the mutational status, and PBRM1 and HIF expression in VHL disease-associated ccRCC series compared with a sporadic series. gene was screened by Sanger sequencing for 23 VHL-disease-associated ccRCC and 22 sporadic ccRCC cases. Immunohistochemical studies were performed to detect the expression of PBRM1, HIF1 and HIF2 for all cases. In VHL-associated tumors, 13.0% (n=3/23) had somatic mutations and 17.4% (n=4/23) had a loss of PBRM1 nuclear expression. In sporadic cases, 27.3% (n=6/22) showed somatic mutations and 45.5% (n=10/22) had a loss of PBRM1 nuclear expression. Loss of PBRM1 was associated with an advanced tumor stage. HIF1-positive tumors were observed more frequently in the VHL-associated ccRCC than in the sporadic series. Furthermore, in the VHL cohort, PBRM1 expression appeared to be associated more with HIF1 than with HIF2. Given that hereditary tumors tend to be less aggressive, these results would suggest that co-expression of PBRM1 and HIF1 may have a less oncogenic role in VHL-associated ccRCC.