BAP1-Mutated Clear Cell Renal Cell Carcinoma
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Abstract Objectives While aberrations in the VHL gene and chromosome 3p resulting in clear cell renal cell carcinoma (CCRCC) are well established, we know that additional mutations in chromatin remodeling genes PBRM1, SETD2, and BRCA1-associated protein 1 (BAP1) contribute to pathogenesis in some cases. Given the known aggressive clinical behavior of BAP1-mutated CCRCC, we sought to define the pathologic phenotype of BAP1-mutated CCRCC. Methods We identified 14 cases of molecularly proven BAP1-mutated CCRCC and investigated their clinicopathologic features. Results BAP1-mutated CCRCC frequently showed papillary, tubulopapillary, or expanded nested architecture; demonstrated granular to diffusely eosinophilic cytoplasm with prominent eosinophilic globules; and contained high-grade nuclei. This morphology demonstrates significant overlap with Xp11 translocation renal cell carcinoma (RCC). Immunohistochemistry notably demonstrates loss of BAP1 expression in almost all tumors, in addition to strong p504S expression. A conventional CCRCC component was frequently present adjacent to the characteristic BAP1 areas and showed retained BAP1 expression and only patchy p504S. Approximately two-thirds of BAP1-mutated CCRCCs were stage pT3, renal vein invasion was common, and 50% developed metastases. Conclusions Herein, we describe the histologic and immunohistochemical findings in BAP1-mutated CCRCC, which has important implications for utilization of molecular testing, prognosis, future therapeutics, and distinction from other RCC subtypes such as Xp11 translocation RCC.Keywords:
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TFE3
Renal cell carcinoma (RCC) associated with Xp11.2 translocation/TFE3 gene fusion (Xp11.2 RCC) is a rare subtype of RCC which is delineated as a distinct entity in the 2004 World Health Organization renal tumor classification.
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Renal cell carcinoma (RCC) is the most frequent kidney solid tumor, the clear cell RCC (ccRCC) being the major histological subtype. The probability of recurrence and the clinical behavior of ccRCC will greatly depend on the different clinical and histopathological features, already incorporated to different scoring systems, and on the genomic landscape of the tumor. In this sense, ccRCC has for a long time been known to be associated to the biallelic inactivation of Von Hippel-Lindau (VHL) gene which causes aberrant hypoxia inducible factor (HIF) accumulation. Recently, next generation-sequencing technologies have provided the bases for an in-depth molecular characterization of ccRCC, identifying additional recurrently mutated genes, such as PBRM1 (≈40–50%), SETD2 (≈12%), or BAP1 (≈10%). PBRM1, the second most common mutated gene in ccRCC after VHL, is a component of the SWI/SNF chromatin remodeling complex. Different studies have investigated the biological consequences and the potential role of PBRM1 alterations in RCC prognosis and as a drug response modulator, although some results are contradictory. In the present article, we review the current evidence on PBRM1 as potential prognostic and predictive marker in both localized and metastatic RCC.
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Renal clear cell carcinoma (ccRCC) is the most typical pathological type of renal carcinoma (RCC), accounting for about 75%. The pathogenesis of ccRCC is a complex process in which multiple factors or multiple gene variations act together and affect each other. With the deepening research of ccRCC and the development of next-generation sequencing, genomics has been recognized and widely used in cancer research. At present, the mutant gene map of renal clear cell carcinoma has been obtained by high-throughput targeted sequencing, in which the mutant gene BAP1 is a typical tumor suppressor gene. Studies have found that the mutation of BAP1 is closely related to the development and progression of ccRCC. BAP1 mutation is ubiquitous in ccRCC, and has attracted more and more scholars' research interest. Fruitful research results have been obtained, which is of great significance for the early diagnosis and targeted therapy of ccRCC. BAP1 may play a protective role in the development of CCRCC, and its mutation is a marker of poor prognosis in CCRCC. The pathogenesis, proliferation, biological activity, clinical stage and prognosis of renal clear cell carcinoma are all related to the expression and function of BAP1. BAP1 plays an important role in the development of renal clear cell carcinoma.
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Abstract Objectives While aberrations in the VHL gene and chromosome 3p resulting in clear cell renal cell carcinoma (CCRCC) are well established, we know that additional mutations in chromatin remodeling genes PBRM1, SETD2, and BRCA1-associated protein 1 (BAP1) contribute to pathogenesis in some cases. Given the known aggressive clinical behavior of BAP1-mutated CCRCC, we sought to define the pathologic phenotype of BAP1-mutated CCRCC. Methods We identified 14 cases of molecularly proven BAP1-mutated CCRCC and investigated their clinicopathologic features. Results BAP1-mutated CCRCC frequently showed papillary, tubulopapillary, or expanded nested architecture; demonstrated granular to diffusely eosinophilic cytoplasm with prominent eosinophilic globules; and contained high-grade nuclei. This morphology demonstrates significant overlap with Xp11 translocation renal cell carcinoma (RCC). Immunohistochemistry notably demonstrates loss of BAP1 expression in almost all tumors, in addition to strong p504S expression. A conventional CCRCC component was frequently present adjacent to the characteristic BAP1 areas and showed retained BAP1 expression and only patchy p504S. Approximately two-thirds of BAP1-mutated CCRCCs were stage pT3, renal vein invasion was common, and 50% developed metastases. Conclusions Herein, we describe the histologic and immunohistochemical findings in BAP1-mutated CCRCC, which has important implications for utilization of molecular testing, prognosis, future therapeutics, and distinction from other RCC subtypes such as Xp11 translocation RCC.
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Aim: BAP1 is frequently mutated in clear cell renal cell carcinoma (ccRCC) with a definitive role still unclear.Methods: In silico analysis of BAP1-mutant and wild-type gene enrichment and functional annotation in TCGA-KIRC dataset was performed.Target gene was studied based on functional clustering and was knowledge-based.Validation using in-house pathological sections were performed immunohistochemically.In vitro and in vivo studies on target gene were performed. Results:The TCGA ccRCC dataset included 534 ccRCC samples.BAP1 was frequently mutated and more frequently downregulated in ccRCC compared to normal kidney tissue or benign renal tumors.In the analysis between samples with BAP1 mutation (N = 33) and pan-negative (N = 33), we found that cancers with BAP1 mutation was significantly enriched for 14 pathways, of which 3 were DNA repair pathways, in which EZH2 played a role.CcRCC patients with lower BAP1 expression had poor prognosis and showed higher EZH2 expression, which also conferred worsened survival.Genetic and pharmaceutical inhibition of EZH2 not only inhibited BAP1-mutatn ccRCC cell viability and invasion but also abrogated genetic replenishing of BAP1 expression.Validation cohort encompassing 62 ccRCC samples confirmed the worsened phenotype for cases with higher EZH2 expression and significant positive correlation between expressions of EZH2 and BAP1.EZH2 inhibitor also inhibited tumor growth in xenograft mouse model with BAP1-mutated ccRCC cells with unremarkable toxicity. Conclusion:CcRCC with decreased BAP1 level has poor prognosis and is associated with higher EZH2 expression.Inhibition of EZH2 in BAP1-mutated entity holds promise for further investigation.
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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 sporadic ccRCC. Herein, I review the evidence that implicated PBRM1 and BAP1 as renal cancer driver genes, provide an update on the function of the gene products, and speculate on how mutations in these genes may be exploited therapeutically.
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4529 Background: Loss of function mutations in PBRM1 (41-50%) and BAP1(5-15%) are associated with poor outcomes for patients with clear cell renal cell carcinoma (ccRCC) tumors. However, there are no data regarding the prevalence of these mutations in other RCC subtypes (non-ccRCC). We evaluated loss of PBRM1 and BAP1 expression in ccRCC and non-ccRCC tumors using an IHC assay for which negative staining correlates with loss of function mutations. Methods: From our Registry database, we identified 311 and 105 patients treated surgically for ccRCC and non-ccRCC. We performed IHC assays to evaluate PBRM1 and BAP1 protein expression. We classified tumors as BAP1 or PBRM1 negative when tumor cells showed diffuse absence of nuclear staining. We compared loss of expression of these two proteins between ccRCC and non-ccRCC using Fisher’s exact tests. Results: Of the total cohort of 416 patients, we successfully stained BAP1 in 406 (97.5%) and PBRM1 in 372 (89.4%). Of those with successful staining, we further excluded samples with focal negative or weak positive expression of BAP1 (n=59) or PBRM1 (n=55). Thus, we were left with 186 ccRCC and 79 non-ccRCC patient samples that had both BAP1 and PBRM1 available for analysis. We observed BAP1 loss of expression in 9% (17/186) of the ccRCC tumors but only 1% (1/79) of the non-ccRCC tumors (p=0.016). Similarly, we noted loss of expression of PBRM1 in 43% (80/186) of the ccRCC tumors but only 4% (3/79) of the non-ccRCC tumors (p=0.0001). Of note, within the non-ccRCC group, we observed 0% (0/61) papillary tumors and 5% (1/18) chromophobe tumors with loss of BAP1. By comparison, 3% (2/61) of papillary tumors and 1/18 (5%) of chromophobe tumors showed loss of PBRM1 expression. Conclusions: Our data are the first to suggest that loss of function mutations in PBRM1 and BAP1 are less common in non-ccRCC tumors compared to ccRCC. If these findings are independently confirmed, they suggest that while loss of PBRM1 and BAP1 are key events in ccRCC, disruption of other pathways may support tumorigenesis in non-ccRCC subtypes. BAP1/PBRM1 Papillary Chromophobe ccRCC -/- 0 (0%) 0 (0%) 3 (2%) -/+ 0 (0%) 1 (5%) 14 (8%) +/- 2 (3%) 1 (5%) 77 (41%) +/+ 59 (97%) 16 (90%) 92 (49%) 61 18 186
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