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

Abstract

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 VHL tumor suppressor gene. Bi-allelic VHL alterations lead to inactivation of pVHL, which plays a major role by downstream activation of the hypoxia inducible factor (HIF) pathway. Somatic VHL mutations occur in 80% of sporadic ccRCC cases and the second most frequently mutated gene is polybromo 1 (PBRM1). As there is currently no data regarding PBRM1 involvement in VHL disease-associated ccRCC, the aim of the present study was to assess the PBRM1 mutational status, and PBRM1 and HIF expression in VHL disease-associated ccRCC series compared with a sporadic series. PBRM1 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 PBRM1 somatic mutations and 17.4% (n=4/23) had a loss of PBRM1 nuclear expression. In sporadic cases, 27.3% (n=6/22) showed PBRM1 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

Clear Cell Adenocarcinoma of Urethra: Clinical and Pathologic Implications and Characterization of Molecular Aberrations

“…In our study, the loss of PBRM1 expression was not validated in patient 5 with strong nuclear positivity. Gad et al [ 24 ] recently reported increased PBRM1 expression with uniform and strong nuclear staining in Von Hippel-Lindau disease-associated clear cell renal cell carcinoma and a PBRM1 mutant case showing retained protein expression. Additionally, an ARID1A W1545* nonsense mutation (c.4634G>A, p.Trp1545*) was observed.…”

Research Progress of Tumor Microenvironment Targeted Therapy for Clear Cell Renal Cell Carcinoma

“…HIF1α and HIF2α play an important role in ccRCC carcinogenesis. 16 Yang et al 17 revealed the effect of long non-coding RNALINC01234 on ccRCC. Knockout of LINC01234 inhibited the HIF-2α pathway, which led to decreased HIF-2α expression, and causing the inhibition of ccRCC cell growth and metastasis.…”

The Roles of Extracellular Vesicles in the Progression of Renal Cell Carcinoma and Their Potential for Future Clinical Application

“…HIF-1a and HIF-2a are transcription factors that bind to the hypoxia response element (HRE), activating a myriad of genes involved in hypoxia adaptation [ 66 ]. In most cases of ccRCC, pVHL is inactivated, resulting in the accumulation of HIF-1a and HIF-2a and continual activation of HIF target genes, despite normal oxygen levels [ 67 , 68 ]. One of the most common targets of HIF1 is vascular endothelial growth factor (VEGF), which induces angiogenesis.…”