Journal articles: 'Pbrm1'

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Mota, Sara T. S., Lara Vecchi, Mariana A. P. Zóia, Fabrícia M. Oliveira, Douglas A. Alves, Bruno C. Dornelas, Stephania M. Bezerra, et al. "New Insights into the Role of Polybromo-1 in Prostate Cancer." International Journal of Molecular Sciences 20, no. 12 (June 12, 2019): 2852. http://dx.doi.org/10.3390/ijms20122852.

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The human protein Polybromo-1 (PBMR1/BAF180) is a component of the SWI/SNF chromatin-remodeling complex that has been reported to be deregulated in tumors. However, its role in prostate cancer (PCa) is largely unknown. In this study, we described the PBRM1 transcriptional levels and the protein expression/localization in tissues of PCa patients and in prostatic cell lines. Increased PBRM1 mRNA levels were found in PCa samples, when compared to benign disease, and were correlated with higher Gleason score. We also verified that only the nuclear localization of PBRM1 protein is correlated with a more aggressive disease and high Prostate-Specific Antigen (PSA) levels in tissue microarrays. Intriguing expression patterns of mRNA and protein were identified in the cell lines. Although PBRM1 protein was restricted to the nuclei, in tumor cell lines in non-neoplastic cells, it was also present in vesicular-like structures that were dispersed within the cytoplasm. We knocked-down PBRM1 in the castration-resistant PCa (CRPC) cell line PC-3 and we verified that PBRM1 promotes the expression of several markers of aggressiveness, including EpCAM, TGF-β, and N-Cadherin. Therefore, our data supported the hypothesis that PBRM1 displays a pivotal role in the promotion and maintenance of the malignant behavior of PCa, especially in CRPC.

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Dizman, Nazli, Paulo Gustavo Bergerot, Cristiane Decat Bergerot, Joann Hsu, and Sumanta K. Pal. "Duration of treatment (DOT) with targeted therapies (TT) or immunotherapy (IO) in PBRM1 mutated metastatic renal cell carcinoma (mRCC)." Journal of Clinical Oncology 37, no. 7_suppl (March 1, 2019): 622. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.622.

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622 Background: Current evidence indicates improved outcome with IO in mRCC patients (pts) with PBRM1 loss of function mutations (Miao et al., Nature, 2018). We seek to demonstrate an association between PBRM1 mutation and treatment duration with IO and TT in a retrospective cohort. Methods: Consecutive patients with mRCC who had genomic profiling in the course of routine clinical care were identified from an institutional database. GP assessments included testing either tissue or blood with 1 of the 3 CLIA certified commercial panels (Foundation Medicine, Cambridge, MA; Ashion Analytics, Phoenix, AZ; Guardant Health, Redwood City, CA). Information regarding systemic treatment was collected. Median DOT with first targeted therapy and first immunotherapy received was calculated for each patient. DOT was compared across treatment groups in PBRM1+ and PBRM1- patients. Only PBRM1 mutations with functional significance documented in COSMIC were considered. Results: Among 104 pts (72:32 M:F) with mRCC, 82 pts received TT, 35 pts received IO, and 45 pts received both. GP was performed in blood and tissue in 84 and 63 pts, respective, and 25 pts (24%) with PBRM1 mutations were identified. Among PBRM1+ pts, median DOT was 8.8 months (95% CI, 7.6-9.6) mos and 2.3 mos (95% CI, 1.7 – 2.8) mos with TT and IO, respectively (p=0.049). Among PBRM1- pts, median DOT was 5.5 mos and 2.8 mos with TT and IO, respectively (p=0.544). There were 11 PBRM1+ pts and 34 PBRM- pts who received both TT and IO. The ratio of DOT on IO to DOT on TT (DOTIO/TT) was higher in PBRM1- pts than PBRM1+ pts (0.76 versus 0.37 respectively, p=0.014). Conclusions: We failed to replicate the results from Miao et al, suggesting clinical benefit with IO in PBRM1 mutated patients. PBRM1 mutation did appear to predict benefit with TT versus IO. Although limited by sample size, the contrasting results of the current study with literature highlight the importance of clinical validation in a large and prospective setting.

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Shmakova, Alena, Mark Frost, Michael Batie, Niall S. Kenneth, and Sonia Rocha. "PBRM1 Cooperates with YTHDF2 to Control HIF-1α Protein Translation." Cells 10, no. 6 (June 8, 2021): 1425. http://dx.doi.org/10.3390/cells10061425.

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PBRM1, a component of the chromatin remodeller SWI/SNF, is often deleted or mutated in human cancers, most prominently in renal cancers. Core components of the SWI/SNF complex have been shown to be important for the cellular response to hypoxia. Here, we investigated how PBRM1 controls HIF-1α activity. We found that PBRM1 is required for HIF-1α transcriptional activity and protein levels. Mechanistically, PBRM1 is important for HIF-1α mRNA translation, as absence of PBRM1 results in reduced actively translating HIF-1α mRNA. Interestingly, we found that PBRM1, but not BRG1, interacts with the m6A reader protein YTHDF2. HIF-1α mRNA is m6A-modified, bound by PBRM1 and YTHDF2. PBRM1 is necessary for YTHDF2 binding to HIF-1α mRNA and reduction of YTHDF2 results in reduced HIF-1α protein expression in cells. Our results identify a SWI/SNF-independent function for PBRM1, interacting with HIF-1α mRNA and the epitranscriptome machinery. Furthermore, our results suggest that the epitranscriptome-associated proteins play a role in the control of hypoxia signalling pathways.

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Fay, Andre Poisl, Guillermo de Velasco, Kathryn P. Gray, Thai Huu Ho, Jiaxi Song, Payal Kapur, Laurence Albiges, et al. "The impact of PBRM1 and BAP1 expression on outcomes of patients with metastatic renal cell carcinoma (mRCC) treated with VEGF-targeted therapy (TT)." Journal of Clinical Oncology 34, no. 2_suppl (January 10, 2016): 616. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.616.

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616 Background: Polybromo-1 (PBRM1) and BRCA1 associated protein-1 (BAP1) are genes commonly mutated in clear cell RCC (ccRCC) and have been associated with clinical outcome. This work aims to evaluate the impact of PBRM1 and BAP1 expression by IHC in mRCC patients treated with VEGF-TT. Methods: PBRM1 and BAP1 expression was evaluated by IHC in a TMA including 146 mRCC patients. PBRM1 and BAP1 IHC scores were dichotomized as a binary variable: negative (-) or positive (+) (weak positivity was excluded). The associations of PBRM1 or BAP1 expression with baseline clinico-pathological characteristics were evaluated, as well as with overall survival (OS) and time to treatment failure (TTF) usingCox proportional hazards models. Results: Out of 146 patients, 116 and 109 samples had available results for PBRM1 and BAP1 staining, respectively. Overall, 90% (n = 131) patients had ccRCC. 70/116 samples (60%) were PBRM1- and 26/109 patients (24%) were BAP1-. Only 12% (n = 13) of patients had simultaneous negative PBRM1 and BAP1. While there was no association between PBRM1 expression status and clinical factors, BAP1- samples were associated with poor IMDC prognostic risk score (p = 0.004) and higher Fuhrman grade (p = 0.012). PBRM1+ patients showed a trend towards an increased risk of death and a shorter TTF compared to PBRM1- patients (OS: HR = 1.38, 95%CI: 0.92-2.07, p = 0.1; TTF: HR = 1.39, 95%CI: 0.94-2.06, p = 0.1). BAP1 expression was not independently associated with OS or TTF. Conclusions: Loss of PBRM1, but not BAP1 expression showed a trend towards longer TTF and OS in mRCC patients treated with VEGF-TT.

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Pal, Sumanta K., Russell Madison, Jon Chung, Neeraj Agarwal, Paulo Gustavo Bergerot, Dominick Bosse, Ethan Sokol, et al. "Comparison of tumor mutational burden (TMB) in PBRM1/BAP1-based subsets of advanced renal cell carcinoma (aRCC)." Journal of Clinical Oncology 36, no. 6_suppl (February 20, 2018): 634. http://dx.doi.org/10.1200/jco.2018.36.6_suppl.634.

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634 Background: Using IHC, Joseph et al (J Urol 2016) propose that 40.1%, 48.6%, 8.7% and 1.8% of patients (pts) can be characterized as PBRM1+BAP1+, PRBM1-BAP1+, PBRM1+BAP1- and PBRM1-BAP1-, respectively. We sought to confirm consistency of the frequency of genomic alterations (GAs) and IHC data and to compare TMB across subsets. Methods: DNA was extracted from 40 microns of FFPE sections from pts with aRCC. Comprehensive genomic profiling (CGP) was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 688X for up to 315 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. TMB was determined on 1.2 million Mb of sequenced DNA; results are reported in subsets segregated by presence or absence of PBRM1 and BAP1 alteration. Results: 648 consecutive pts (459:189 M:F) with clear cell RCC (ccRCC) were assessed with a median age of 58, and 368 consecutive pts (254:114 M:F) with non-clear cell RCC (nccRCC) were assessed with a median age of 57. Mutations in BAP1 and PBRM1 were found more frequently in ccRCC vs nccRCC (P < 0.05 for both). In pts with ccRCC, average TMB was highest in pts with co-occurring PBRM1 and BAP1 GAs (4.87 muts/Mb), and lowest in pts lacking both GAs (2.77 muts/Mb) (P < 0.05). TMB was similar across PBRM1/BAP1-based subsets amongst pts with nccRCC. Conclusions: As anticipated, the frequency of PBRM1/BAP1-mutated subsets by CGP is inversely related to the frequency of subsets with PBRM1/BAP1 loss by IHC from previous reports. In addition to these confirmatory findings, this large series identifies that pts with dual PBRM1/ BAP1 GAs (associated with the worst prognosis) had the highest TMB. [Table: see text]

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Williams, E., P. Brastianos, S. Santagata, D. Cahill, S. Ramkissoon, and T. Juratli. "P04.09 Frequent inactivating mutations of PBRM1 in meningioma with papillary features." Neuro-Oncology 23, Supplement_2 (September 1, 2021): ii20. http://dx.doi.org/10.1093/neuonc/noab180.066.

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Abstract BACKGROUND Papillary meningiomas (PM) are rare WHO grade III tumors that are associated with frequent recurrences and metastatic disease in spite of surgery and radiation. Due to their low incidence and scarcity of tumor tissues available for genomic analyses, the genetic alterations associated with PM remain unclear. MATERIAL AND METHODS We mined data collected as part of our clinical comprehensive genomic profiling (CGP) initiative which has to date analyzed 8 PM (>50% papillary morphology) and 22 meningiomas with focal papillary features (10–50%) amongst over 500 additional meningiomas of other subtypes. The samples were analyzed in a CAP/CLIA-accredited laboratory (Foundation Medicine, Cambridge, MA). GCP was performed on hybridization-captured, adaptor ligation-based libraries to a mean coverage depth of >650x for 236 or 315 genes plus the introns from 19 or 28 genes frequently involved in cancer. RESULTS In our cohort of 8 PMs, we identified three cases with inactivation of PBRM1; two cases with a truncating mutation in PBRM1 and one with homozygous deletion of PBRM1. Of the 22 meningiomas with only focal papillary features, 8 cases were PBRM1-mutant. Thus, 11 of 30 cases (36.7%) with at least focal (>10%) papillary morphology had inactivation of PBRM1.In the entire cohort of 562 meningiomas, we identified five additional cases with inactivating alterations in PBRM1 that did not display overt papillary morphology in the H&E sections available for analysis. Thus, 11 of 16 PBRM1-mutant cases (69%) occurred in meningioma with papillary histologic features as opposed to 19 of 546 wild-type cases (3.5%), supporting a significant association between papillary features and PBRM1 mutation (p<0.0001). The majority of PBRM1-mutant meningiomas occurred in female patients (n=10/16, 62.5%), and median age was 51 years. Most cases were located supratentorially (n=10). CONCLUSION We identified the tumor suppressor gene PBRM1 as a recurrently altered gene in meningiomas with papillary histomorphology. Further investigational studies are needed to assess outcomes of PBRM1-mutant meningioma and to determine whether mutation is an independent negative prognostic biomarker.

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Joseph, Richard Wayne, Payal Kapur, Daniel Serie, Jeanette Eckel-Passow, Thai Huu Ho, James Brugarolas, and Alexander S. Parker. "Loss of BAP1 and PBRM1 protein expression and its association with clear cell renal cell carcinoma-specific survival." Journal of Clinical Oncology 32, no. 4_suppl (February 1, 2014): 414. http://dx.doi.org/10.1200/jco.2014.32.4_suppl.414.

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414 Background: While mutations in PBRM1 (~40%) and BAP1(~10%) are associated with clinical outcomes and pathologic features in clear cell renal cell carcinoma (ccRCC), the impact of protein expression of these genes remains unknown. Herein, we quantify PBRM1/BAP1 protein expression in a large cohort of patients with localized ccRCC and associate expression with cancer-specific survival (CSS) and pathologic features. Methods: We utilized the Mayo Clinic Renal Registry and identified 1,416 patients who underwent nephrectomy to treat clinically localized ccRCC between 1/3/1990 and 4/14/2009. We used immunohistochemistry (IHC) to detect PBRM1/BAP1 expression, and a central pathologist blinded to the outcomes scored tumors as either positive or negative. Tumors with heterogeneous or equivocal staining were excluded from this analysis. We generated Cox proportional hazard regression models for associations with ccRCC-SS, and we employed Mann-Whitney U tests for associations with pathologic features. Results: Of the 1,416 samples, 1,232 (87%) were PBRM1/BAP1 positive or negative, 163 (11%) had heterogeneous staining, and 21 (1%) could not be assessed. The distribution and association of PBRM1/BAP1 phenotypes with clinical outcomes are listed in the table below. PBRM1+/BAP1+ tumors have the best CSS, and PBRM1-/BAP1- have the worst. In addition, PBRM1/BAP1 expression strongly associated with the tumor size, stage, grade, and tumor necrosis (p<0.0001). Conclusions: This study is the first and largest to quantify PRBM1/BAP1 protein expression in ccRCC tumors. We were able to quantify PBRM1/BAP1 through IHC in the vast majority of tumors (87%), and PRBM1/BAP1 expression strongly associates with both CSS and pathologic tumor characteristics. Our data confirms our previous findings of the importance of PRBM1/BAP1 in the molecular pathogenesis of ccRCC. [Table: see text]

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Zimmer, Kai, Florian Kocher, Gerold Untergasser, Alberto Puccini, Joanne Xiu, Dominik Wolf, Gilbert Spizzo, et al. "Identification and prognostic impact of PBRM1 mutations in biliary tract cancers: Results of a comprehensive molecular profiling study." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 4022. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.4022.

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4022 Background: The prognosis of biliary tract cancers (BTC) remains dismal and novel treatment strategies are needed to improve survival. Polybromo-1 ( PBRM1) is a subunit of the PBF chromatin-remodeling complex and preclinical studies suggest induction of synthetic lethality by PARP inhibitors in PBRM1-mutated cancers. Therefore, we aimed to describe the molecular landscape in BTC harboring PBRM1 mutations. Methods: 1,848 BTC samples were included in this study. Specimens were analyzed using NextGen DNA sequencing (NextSeq, 592 gene panel or NovaSeq, whole-exome sequencing), whole-transcriptome RNA sequencing (NovaSeq) and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). Pathway gene enrichment analyses were done using GSEA (Subramaniam 2015, PNAS). Immune cell fraction was calculated by QuantiSeq (Finotello 2019, Genome Medicine). Survival was calculated from time of tissue collection to last contact using Kaplan-Meier estimates. Results: PBRM1 mutations were identified in 8.1% (n = 150) of BTC tumors and were more prevalent in intrahepatic BTC (9.9%) than in gallbladder cancer (6%, p = 0.0141) and in extrahepatic BTC (4.5%, p = 0.008). In PBRM1-mutated tumors, we found a higher rate of MSI-H/dMMR (8.7% vs. 2.1%, p < 0.0001) and a higher median TMB (4 vs. 3 mt/MB, p < 0.0001). When compared to PBRM1-wildtype cancers higher rates of co-mutations in chromatin-remodeling genes (e.g. ARID1A, 31% vs. 16% , p < 0.0001) and DNA damage repair pathway (e.g. ATRX, 4.4% vs. 0.3%, p < 0.0001) were detected. Within PBRM1-mutated tumors, a significant higher frequency of infiltrating M1 macrophages was observed (p < 0.0001). Gene set enrichment analysis revealed that genes associated with tumor inflammation (e.g. HLA-DRA, HLA-DRB1, IFNGR1) were enriched in PBRM1-mutated tumors (NES = 2.02, FDR = 1.3%, p < 0.0001). Overall survival analysis showed that PBRM1 mutations were associated with a favorable outcome (HR 1.502, 95% CI [1.013-2.227], p = 0.041). This relationship was also present in MSS subgroup (HR: 1.667, [1.026-2.71], p = 0.037). Conclusions: This is the largest and most extensive molecular profiling study focusing on PBRM1-mutated BTC. Co-mutations in chromatin-remodelling and DNA damage repair genes might set the stage for clinical testing of PARP inhibitors in PBRM1-mutated BTC. Moreover, a distinct tumor microenvironment characterized by high M1 macrophages infiltration and an enrichment of inflammatory genes suggest a potential benefit of immunotherapy.

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Hakimi, A. Ari, Yasser Ged, Jessica Flynn, Douglas R. Hoen, Renzo G. Di Natale, Kyle A. Blum, Vladimir Makarov, et al. "The impact of PBRM1 mutations on overall survival in greater than 2,100 patients treated with immune checkpoint blockade (ICB)." Journal of Clinical Oncology 37, no. 7_suppl (March 1, 2019): 666. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.666.

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666 Background: PBRM1 is the second most commonly mutated gene in clear cell renal cell carcinoma (ccRCC). We have previously shown favorable outcomes in PBRM1-mutated ccRCC tumors treated with vascular endothelial growth factor (VEGF) inhibitors. Recent data suggested PBRM1 mutations may sensitize ccRCC and non RCC malignancies to ICB therapy. We queried the impact of PBRM1 loss on overall survival (OS) across 2,152 patients treated with ICB. Methods: PBRM1 mutations were assessed in metastatic ccRCC patients who received first line (n = 82) or second line (n = 61) ICB or ICB/VEGF combinations. Additionally, 41 cohorts of non-RCC malignancies treated with ICB and combination (n = 2,009) were analyzed. Mutations were assessed by next generation targeted sequencing using archival tissue. Association of mutation status and overall survival (OS) was tested by multivariate Cox regression analysis (MVA) and adjusted for tumor mutation burden (TMB), copy number alterations (CNA), loss of function(LOF) mutations (non RCC cohort) and IMDC risk (for ccRCC patients). Results: PBRM1 mutations were not associated with improved OS in ICB the entire ccRCC cohort (HR 1.37; CI 0.79-2.4; p = 0.265), the first line (p = 0.624) or second line setting (p = 0.39) or as combination with VEGF inhibitors (p = 0.2). Several RCC subgroups were investigated (see Table at bottom). In the non-RCC cohorts (n = 2,009) PBRM1 mutations were not significantly associated with OS on univariate analysis (HR = 0.73, p = 0.22 for LOF and HR = 0.84,p = 0.34 for non LOF), and remained insignificant after adjusting for TMB, total CNA, and drug class (CTLA4, PD-1/PDL-1 and combinations) (HR = 1.07, p = 0.78 for LOF and HR = 1.08,p = 0.67 for non LOF). Conclusions: Neither in ccRCC nor in the pan-cancer cohort did PBRM1 mutations appear to be associated with improved overall survival with ICB therapy.[Table: see text]

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Brugarolas, James, Payal Kapur, Samuel Pena-Llopis, Alana Christie, and Xian-Jin Xie. "Toward a molecular genetic classification of clear cell renal cell carcinoma." Journal of Clinical Oncology 31, no. 6_suppl (February 20, 2013): 341. http://dx.doi.org/10.1200/jco.2013.31.6_suppl.341.

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341 Background: Clear cell renal cell carcinoma (ccRCC) displays a variety of clinical behaviors. However, the molecular underpinnings are unknown. We discovered that BAP1 is mutated in approximately 15% of ccRCC and that BAP1 and PBRM1mutations are largely mutually exclusive. Herein, we investigate the clinicopathological significance of these molecular subtypes. Methods: Tumors from 145 patients with primary ccRCC were sequenced for PBRM1 and BAP1. Tumors were classified into BAP1-mutated and those exclusively mutated for PBRM1. Tumors were evaluated for pathologic features, gene expression and associated outcomes. A second independent cohort (n=327) from The Cancer Genome Atlas (TCGA) was used for validation. Results: When compared to PBRM1-mutant tumors, BAP1-mutant tumors were associated with aggressive pathological features including high Fuhrman grade and tumor necrosis. BAP1-mutant and PBRM1-mutant tumors exhibited distinct gene expression signatures. The median overall survival (OS) was shorter for patients with BAP1-mutant tumors (4.6 years; 95% CI, 2.1-7.2), than for patients with PBRM1-mutant tumors (10.6 years; 95% CI, 9.8-11.5), corresponding to a hazard ratio (HR) of 2.7 (95% CI, 0.99-7.6, p = 0.044). A similar HR was observed in the independent dataset from the TCGA (2.8; 95% CI, 1.4-5.9; p = 0.004). The BAP1-mutant group could be further subdivided into tumors with mutations exclusively in BAP1 and those with mutations in both BAP1 and PBRM1. Double mutant tumors constituted a minority (n = 4; in TCGA), and were associated with the shortest OS (HR, 10; 95% CI, 3.2-33.6). Conclusions: Our findings reveal novel biological subgroups of ccRCC with distinct clinical outcomes, a high-risk BAP1-mutant group and a favorable PBRM1-mutant group. These data establish the basis for a molecular subclassification of ccRCC that could influence treatment decisions in the future.

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Dias Carneiro, André Paternò Castello, Fernando Sabino Marques Monteiro, and Andrey Soares. "PBRM1 Mutations as a Predictive Biomarker for Immunotherapy in Metastatic Renal Cell Carcinoma: A Systematic Review." Kidney Cancer 5, no. 2 (June 16, 2021): 79–92. http://dx.doi.org/10.3233/kca-210111.

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INTRODUCTION: Genomic features linked to prediction of response to immunotherapy in metastatic renal cell carcinoma (mRCC) are still lacking. Protein polybromo-1 (PBRM1) mutations have been studied as a potential biomarker of clinical benefit, with conflicting published data so far. MATERIAL AND METHODS: This systematic review was guided by the standards of the PRISMA statement to identify studies involving mRCC, immunotherapy and mutations in PBRM1. The main objective was to assess the relationship between PBRM1 mutations and response to immune checkpoint inhibitors (ICI) in patients with mRCC. RESULTS: After an initial search that identified 422 studies, 8 studies met the eligibility criteria and were selected for the final analysis. Data are included from 2 trials in the first-line treatment setting, and 6 trials in second- or later treatment lines evaluating the relationship between the presence of PBRM1 mutations and clinical benefit (CB) with ICI treatment. Regarding the first-line treatment setting, the analysis of both studies failed to show any CB in patients with PBRM1 mutations treated with ICI. However, for the second- and later treatment lines, the results were mixed. CONCLUSIONS: PBRM1 mutations may be a potential genomic biomarker to predict response to ICI treatment in patients with mRCC, mainly in second- and later treatment lines, but the existence of conflicting data in the literature highlights an important bias in the studies and the need for additional clinical validation in large, prospective trials.

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Karki, Menuka, Rahul K. Jangid, Ramakrishnan Anish, Riyad N. H. Seervai, Jean-Philippe Bertocchio, Takashi Hotta, Pavlos Msaouel, et al. "A cytoskeletal function for PBRM1 reading methylated microtubules." Science Advances 7, no. 14 (April 2021): eabf2866. http://dx.doi.org/10.1126/sciadv.abf2866.

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Epigenetic effectors “read” marks “written” on chromatin to regulate function and fidelity of the genome. Here, we show that this coordinated read-write activity of the epigenetic machinery extends to the cytoskeleton, with PBRM1 in the PBAF chromatin remodeling complex reading microtubule methyl marks written by the SETD2 histone methyltransferase. PBRM1 binds SETD2 methyl marks via BAH domains, recruiting PBAF components to the mitotic spindle. This read-write activity was required for normal mitosis: Loss of SETD2 methylation or pathogenic BAH domain mutations disrupt PBRM1 microtubule binding and PBAF recruitment and cause genomic instability. These data reveal PBRM1 functions beyond chromatin remodeling with domains that allow it to integrate chromatin and cytoskeletal activity via its acetyl-binding BD and methyl-binding BAH domains, respectively. Conserved coordinated activity of the epigenetic machinery on the cytoskeleton opens a previously unknown window into how chromatin remodeler defects can drive disease via both epigenetic and cytoskeletal dysfunction.

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Voss, Martin Henner, Fengshen Kuo, David Chen, Mahtab Marker, Parul Patel, Almedina Redzematovic, Nadeem Riaz, et al. "Integrated biomarker analysis for 412 renal cell cancer (RCC) patients (pts) treated on the phase 3 COMPARZ trial: Correlating common mutation events in PBRM1 and BAP1 with angiogenesis expression signatures and outcomes on tyrosine kinase inhibitor (TKI) therapy." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 4523. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.4523.

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4523 Background: In RCC biology mutations in PBRM1 and BAP1are largely non-overlapping and collectively affect >50% of pts. How and through which mechanism they influence disease kinetics is poorly understood. Sunitinib and pazopanib inhibit angiogenesis, a key driver in RCC. We analyzed mutation status and gene expression signatures in a large cohort of pts receiving first-line sunitinib or pazopanib on the COMPARZ trial. Methods: RNA and DNA were extracted from archival tissue. PBRM1 and BAP1mutation status was determined via a custom exon-targeted platform. Transcriptome analysis was done using Affymetrix GeneChip HTA 2.0. We computed a 43 gene angiogenesis expression score with previously reported dynamic response to VEGF-directed therapy in xenograft models (Masiero, Cancer Cell 2013). DNA and RNA findings were correlated with clinical outcomes using parametric and non-parametric tests. Results: 412 pts contributed tumor RNA, 377 pts DNA; 362 pts both. PBRM1 and BAP1 were mutated (MT) in 44% and 15% of pts, respectively. Presence of PBRM1mutations correlated with superior PFS (p=0.008) and OS (p=0.004) on log-rank test, and PBRM1 mutation rate was higher in pts with objective response than those with progression (Fisher’s Exact, p=0.012). In contrast, pts with MT BAP1 had inferior OS compared to those whose were wild type (WT) (log-rank, p=0.012). Across all 412 pts angiogenesis score associated favorably with outcome on uni and multivariate analyses (Cox proportional hazard regression, OS p<0.001 and PFS p<0.005); scores were higher in 123 pts with objective response than 81 pts with progression as best response (Mann-Whitney, p=0.009). Angiogenesis scores were higher in PBRM1 MT vs WT patients (Mann-Whitney, p<0.001), but lower in BAP1 MT vs WT patients (p<0.001). Conclusions: PBRM1 and BAP1 mutations appear to have opposite effects in advanced RCC. Loss of PBRM1 enhances the pro-angiogenic microenvironment of RCC with favorable effects on response to TKI; BAP1 loss associates with decreased angiogenic signaling and adverse outcome to TKI. Clinical trial information: NCT00720941.

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Hagiwara, Masayuki, Atsushi Fushimi, Nami Yamashita, Atrayee Bhattacharya, Hasan Rajabi, Mark D. Long, Yota Yasumizu, Mototsugu Oya, Song Liu, and Donald Kufe. "MUC1-C activates the PBAF chromatin remodeling complex in integrating redox balance with progression of human prostate cancer stem cells." Oncogene 40, no. 30 (June 23, 2021): 4930–40. http://dx.doi.org/10.1038/s41388-021-01899-y.

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AbstractThe polybromo-associated PBAF (SWI/SNF) chromatin remodeling complex, which includes PBRM1, ARID2, and BRD7, regulates cell differentiation and genomic integrity. MUC1-C is an oncogenic protein that drives lineage plasticity in prostate cancer (PC) progression. The present work demonstrates that MUC1-C induces PBRM1, ARID2, and BRD7 expression by the previously unrecognized E2F1-mediated activation of their respective promoters. The functional significance of the MUC1-C→PBAF pathway is supported by demonstrating involvement of MUC1-C in associating with nuclear PBAF and driving the NRF2 antioxidant gene transcriptome in PC cells. Mechanistically, MUC1-C forms a complex with NRF2 and PBRM1 on the NRF2 target SLC7A11 gene that encodes the xCT cystine-glutamate antiporter, increases chromatin accessibility and induces SLC7A11/xCT expression. We also show that MUC1-C and PBRM1 are necessary for induction of other NRF2 target genes, including G6PD and PGD that regulate the pentose phosphate pathway. Our results further demonstrate that MUC1-C integrates activation of PBRM1 with the regulation of antioxidant genes, ROS levels, pluripotency factor expression and the cancer stem cell (CSC) state. These findings reveal a role for MUC1-C in regulating PBAF, redox balance and lineage plasticity of PC CSC progression. Our findings also uncover involvement of MUC1-C in integrating the PBAF and BAF pathways in cancer.

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Shreders, Amanda, Richard Wayne Joseph, Daniel Serie, Payal Kapur, Thai Huu Ho, Jeanette Eckel-Passow, James Brugarolas, and Alexander S. Parker. "High concordance of BAP1 and PBRM1 expression in patient-matched primary and metastatic ccRCC tumors." Journal of Clinical Oncology 33, no. 7_suppl (March 1, 2015): 507. http://dx.doi.org/10.1200/jco.2015.33.7_suppl.507.

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507 Background: Clear cell renal cell carcinoma (ccRCC) is a well-described molecularly heterogeneous tumor. Herein, we assessed the concordance of two of the most commonly mutated genes in ccRCC, PBRM1 (~50%), and BAP1 (~15%), in patient-matched primary and metastatic tumors. Methods: One pathologist (PK) assessed PBRM1 and BAP1 protein expression using immunohistochemistry (IHC) in 99 patients with a primary and at least one metastatic ccRCC tumor available for analysis. All available metastatic tumors were analyzed. Results: A total of 99 patients (48 M0 and 51 M1) had both a primary tumor and at least one metastatic tumor available for analysis. There were a total of 158 metastases with one patient having up to 7 metastases available for analysis. The concordance between primary and patient-matched metastasis was 87% for PBRM1 and 99% for BAP1. We observed a similar concordance between patients with M0 versus M1 disease. Conclusions: While ccRCC is molecularly heterogeneous, PRBM1, and BAP1 are largely concordant between primary and metastatic lesions suggesting that PBRM1 and BAP1 are genetically truncal events in the molecular pathogenesis of ccRCC.

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Yasri, Sora, and Viroj Wiwanitkit. "Polybromo-1 loss in cholangiocarcinoma development: Expressional analysis." International Journal of Molecular and Immuno Oncology 3, no. 2 (July 25, 2018): 64. http://dx.doi.org/10.18203/issn.2456-3994.intjmolimmunooncol20183229.

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Dear editor, the cholangiocarcinoma is a deadly hepatobiliary cancer. It results in high fatality in affected persons in endemic Southeast Asia. The patient usually manifests at large stage of cancer and has severe obstructive jaundice. The underlying genetic pathophysiology of cholangiocarcinoma is very interesting. As a cancer, the mutation can be expected (such as KRAS mutation). In a recent publication by Luchini et al., the loss of Polybromo-1 (PBRM1) was observed during the development of cholangiocarcinoma. The similar finding was also reported by another Japanese scientist group. Here, the authors use the standard gene ontology technique to assess the effect of PBRM1 loss comparing to the naïve case. The protocol for gene ontology analysis is the same as previously gene ontology analysis studied. According to analysis, the identified main affected function due to PBRM1 loss is “regulation of chromatin association.” This implies that loss of PMB1 during cholangiocarcinoma development is the important pathobiological process that promotes the abnormal cell division and might stimulate the cancer development. In fact, the loss of PBRM1 is proposed as an important predictor for poor outcome in several cancers such as renal cancer.

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Carril-Ajuria, Lucía, María Santos, Juan María Roldán-Romero, Cristina Rodriguez-Antona, and Guillermo de Velasco. "Prognostic and Predictive Value of PBRM1 in Clear Cell Renal Cell Carcinoma." Cancers 12, no. 1 (December 19, 2019): 16. http://dx.doi.org/10.3390/cancers12010016.

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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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Sidaway, Peter. "Bap1 and Pbrm1 determine tumour grade." Nature Reviews Urology 14, no. 7 (May 31, 2017): 391. http://dx.doi.org/10.1038/nrurol.2017.84.

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Klimentova, E. A., I. R. Gilyazova, A. A. Izmailov, I. M. Sultanov, M. A. Bermisheva, V. N. Pavlov, and E. K. Khusnutdinova. "Identification of alterations in the nucleotide sequence of the chromatin remodeling gene PBRM1 in clear cell renal cell carcinoma patients." Vavilov Journal of Genetics and Breeding 22, no. 7 (November 9, 2018): 873–77. http://dx.doi.org/10.18699/vj18.428.

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Kidney cancer is a heterogeneous group of malignant tumors, the vast majority of which are renal cell carcinomas (RCC) of various morphological types, of which the most common is the clear cell renal cell carcinoma (ccRCC). Particular attention in the carcinogenesis of the ccRCC is given to a number of tumor suppressor genes located on the short arm of the third chromosome. One of these genes, which are inactivated in the case of ccRCC is the PBRM1 gene encoding the PBAF SWI/SNF subunit of the chromatin remodeling complex, BAF180. The PBRM1 gene is located on the short arm of the third chromosome in the 3p21 region near the von Hippel-Lindau gene (VHL), the mutation in which is the main event in the occurrence of ccRCC. The aim of our investigation is identification of changes in the nucleotide sequence of the PBRM1 tumor suppressor gene in patients with ccRCC. 210 pairs of DNA samples isolated from ccRCC tissue were studied. Analysis of changes in the nucleotide sequence of DNA was carried out by HRM analysis and direct sequencing. In the PBRM1 gene, two somatic mutations were found (c.233G>A (p.D45N) in exon 2, c.1675-1676delTC in exon 15) which were not described previously, and one known polymorphic variant rs17264436 (in exon 23). The frequency of detected mutations was 0.95 % of cases. Analysis of the allelic association for the polymorphic locus rs17264436 showed a statistically significant increase in the risk of developing advanced kidney cancer in carriers of allele rs17264436*A, which can be used in the development of prognostic marker panels. Perhaps the low frequency of mutations in the samples we studied is due to the fact that the inactivation of the PBRM1 gene takes place in other ways, and may also be due to the ethno-specificity of the studied group of patients.

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Miura, Yuji, Naoko Inoshita, Yukinori Ozaki, Yuko Tanabe, Koichi Suyama, Masaomi Ikeda, Toshikazu Okaneya, and Toshimi Takano. "The loss of BAP1 protein expression in the first recurrence site of metastasis to predict prognosis." Journal of Clinical Oncology 34, no. 2_suppl (January 10, 2016): 599. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.599.

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599 Background: It is well known that the loss of BAP1 protein expression in primary site of clear cell type renal cell carcinoma (ccRCC) is prognostic marker. However, the existence of intratumoral heterogeneity in primary site of ccRCC makes it difficult to assess accurate prognosis. The aim of this study is to investigate the heterogeneity of BAP1 expression in metastatic sites and to evaluate the possibility as a prognostic marker. Methods: We collected samples of both primary and matched metastatic sites of the first recurrence in 41 metastatic ccRCC patients. Immunohistochemistry (IHC) for BAP1 and PBRM1 protein expression were performed on at least two tissue microarray (TMA) sections from primary site and at least one TMA sections from metastatic sites. We retrospectively analyzed the association of the IHC with clinical outcomes. Results: 41 primary and metastatic sites were available for this analysis. The most of metastatic sites were lung (68.3%) and lymph node (12.2%). BAP1 protein expression-positive, -negative and -heterogeneity in primary/metastatic sites were 29/29 (70.7/70.7%), 8/11 (19.5/26.8%) and 4/1 (9.8/2.4%), respectively. PBRM1 protein expression-positive, -negative and -heterogeneity in primary/metastatic site were 22/27 (53.7/65.9%), 9/11 (21.9/26.8%) and 10/3 (24.4/7.3%), respectively. The concordance between primary and metastatic site for BAP1 and PBRM1 protein expression was 82.9 and 63.4%, respectively. Median overall survival (OS) from the first recurrence of metastasis in patients with BAP1-positive and -negative in metastatic sites was 97 and 51 months, respectively (p = 0.0275). Median OS from the first recurrence of metastasis in patients with PBRM1-positive and -negative in metastatic sites was 82 and 58 months, respectively (p = 0.44). Conclusions: There is more intratumoral heterogeneity for BAP1 and PBRM1 in primary site than metastatic sites of ccRCC. The loss of BAP1 protein expression by IHC in metastatic sites predicts poor clinical outcome.

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Dizman, Nazli, Yung Lyou, Nicholas Salgia, Paulo Gustavo Bergerot, JoAnn Hsu, Daniel Enriquez, Tyler Izatt, Jeffrey M. Trent, Sara Byron, and Sumanta Pal. "Correlates of clinical benefit from immunotherapy and targeted therapy in metastatic renal cell carcinoma: comprehensive genomic and transcriptomic analysis." Journal for ImmunoTherapy of Cancer 8, no. 2 (July 2020): e000953. http://dx.doi.org/10.1136/jitc-2020-000953.

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BackgroundThe clinical significance of tumor-specific genomic alterations in metastatic renal cell carcinoma (mRCC) is emerging, with several studies suggesting an association between PBRM1 mutations and response with immunotherapy (IO). We sought to determine genomic predictors of differential response to vascular endothelial growth factor–tyrosine kinase inhibitors (VEGF-TKIs) and IO.MethodsConsecutive patients who underwent genomic profiling were identified; patients receiving either VEGF-TKIs or IO were included. Clinical tumor-normal whole exome sequencing and tumor whole transcriptome sequencing test were performed using a Clinical Laboratory Improvement Amendments (CLIA)-certified assay (Ashion Analytics; Phoenix, Arizona, USA). Genomic findings were compared between patients with clinical benefit (CB; complete/partial response or stable disease for >6 months) and no clinical benefit (NCB) in VEGF-TKI-treated patient cohort and IO-treated patient cohort.Results91 patients received genomic profiling and 58 patients received VEGF-TKI and/or IO therapy. 17 received sequenced treatment involving both VEGF-TKI and IO, resulting in 32 patients in the IO cohort and 43 patients in the VEGF-TKI cohort. The most commonly used IO and VEGF-TKIs were nivolumab (66%) and sunitinib (40%). The most frequently detected alterations in the overall cohort were in VHL (64%), PBRM1 (38%), SETD2 (24%), KDM5C (17%) and TERT (12%). TERT promoter mutations were associated with NCB in the IO cohort (p=0.038); transcriptomic analysis revealed multiple differentially regulated pathways downstream of TERT. TERT promoter mutations and PBRM1 mutations were found to be mutually exclusive. While PBRM1 mutations were more prevalent in patients with CB with IO and VEGF-TKIs, no statistically significant association was found.ConclusionsOur analysis found that TERT promoter mutations may be a negative predictor of outcome with IO and are mutually exclusive with PBRM1 loss-of-function mutations.

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Menasche, Bridget L., Eric M. Davis, Shifeng Wang, Yan Ouyang, Suzhao Li, Haijia Yu, and Jingshi Shen. "PBRM1 and the glycosylphosphatidylinositol biosynthetic pathway promote tumor killing mediated by MHC-unrestricted cytotoxic lymphocytes." Science Advances 6, no. 48 (November 2020): eabc3243. http://dx.doi.org/10.1126/sciadv.abc3243.

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Major histocompatibility complex (MHC)–unrestricted cytotoxic lymphocytes (CLs) such as natural killer (NK) cells can detect and destroy tumor and virus-infected cells resistant to T cell–mediated killing. Here, we performed genome-wide genetic screens to identify tumor-intrinsic genes regulating killing by MHC-unrestricted CLs. A group of genes identified in our screens encode enzymes for the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor, which is not involved in tumor response to T cell–mediated cytotoxicity. Another gene identified in the screens was PBRM1, which encodes a subunit of the PBAF form of the SWI/SNF chromatin-remodeling complex. PBRM1 mutations in tumor cells cause resistance to MHC-unrestricted killing, in contrast to their sensitizing effects on T cell–mediated killing. PBRM1 and the GPI biosynthetic pathway regulate the ligands of NK cell receptors in tumor cells and promote cytolytic granule secretion in CLs. The regulators identified in this work represent potential targets for cancer immunotherapy.

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Panwalkar, Pooja, Drew Pratt, Chan Chung, Derek Dang, Paul Le, Daniel Martinez, Jill M. Bayliss, et al. "SWI/SNF complex heterogeneity is related to polyphenotypic differentiation, prognosis, and immune response in rhabdoid tumors." Neuro-Oncology 22, no. 6 (February 12, 2020): 785–96. http://dx.doi.org/10.1093/neuonc/noaa004.

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Abstract Background Rhabdoid tumors (RTs) arise within (atypical teratoid/rhabdoid tumor [AT/RT]) or outside the brain (extra [e]CNS-RT) and are driven mainly by inactivation of the SWItch/sucrose nonfermentable (SWI/SNF) complex subunit SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1). A pathognomonic hallmark of RTs is heterogeneous multilineage differentiation, including anomalous neuronal differentiation in some eCNS-RTs. Because remodeling of the SWI/SNF complex regulates differentiation, we hypothesized that SWI/SNF Brahma-associated factors (BAF) and polybromo-associated BAF (PBAF) complex heterogeneity are related to both multilineage differentiation and clinical outcome. Methods We performed an integrated analysis of SWI/SNF complex alterations in the developing kidney and cerebellum (most common regions of RT origin) in comparison to eCNS-RT (n = 14) and AT/RT (n = 25) tumors. RT samples were interrogated using immunohistochemistry, DNA methylation, and gene expression analyses. Results The SWI/SNF BAF paralogs actin-like protein (ACTL)6A and ACTL6B were expressed in a mutually exclusive manner in the developing cerebellum and kidney. In contrast, a subset of eCNS-RTs lost mutual exclusivity and coexpressed both subunits. These tumors showed aberrant DNA methylation of genes that regulate neuronal and renal development and demonstrated immunohistochemical evidence of neuronal differentiation. In addition, low expression of the PBAF subunit polybromo-1 (PBRM1) identified a group of AT/RTs in younger children with better overall prognosis. PBRM1-low AT/RT and eCNS-RTs showed altered DNA methylation and gene expression in immune-related genes. PBRM1 knockdown resulted in lowering immunosuppressive cytokines, and PBRM1 levels in tumor samples showed an inverse relationship with cluster of differentiation (CD)8 cytotoxic T-cell infiltration. Conclusions Heterogeneity in SWI/SNF BAF (ACTL6A/ACTL6B) and PBAF (PBRM1) subunits is related to histogenesis, contributes to the immune microenvironment and prognosis in RTs, and may inform opportunities to develop immunotherapies.

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Otto, Grant. "PBRM1 loss promotes tumour response to immunotherapy." Nature Reviews Nephrology 14, no. 3 (January 22, 2018): 142. http://dx.doi.org/10.1038/nrneph.2018.7.

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Otto, Grant. "PBRM1 loss promotes tumour response to immunotherapy." Nature Reviews Clinical Oncology 15, no. 3 (January 23, 2018): 134–35. http://dx.doi.org/10.1038/nrclinonc.2018.12.

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Porter, Elizabeth G., Alisha Dhiman, Basudev Chowdhury, Benjamin C. Carter, Hang Lin, Jane C. Stewart, Majid Kazemian, Michael K. Wendt, and Emily C. Dykhuizen. "PBRM1 Regulates Stress Response in Epithelial Cells." iScience 15 (May 2019): 196–210. http://dx.doi.org/10.1016/j.isci.2019.04.027.

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Hakimi, A. Ari, Irina Ostrovnaya, Martin Henner Voss, Robert John Motzer, Paul Russo, Victor E. Reuter, and James Hsieh. "Association of mutations in chromatin modifiers with poor survival in clear cell renal cell carcinoma: Analysis of the Cancer Genome Atlas Project." Journal of Clinical Oncology 31, no. 6_suppl (February 20, 2013): 360. http://dx.doi.org/10.1200/jco.2013.31.6_suppl.360.

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360 Background: We have previously shown that mutations in the epigenetic modifiers PBRM1, BAP1, SETD2 and KDM5C are associated with adverse tumor characteristics and, in some cases, worse cancer specific survival in clear cell renal cell carcinoma (ccRCC). We analyzed publically available data from the Cancer Genome Atlas Project (TCGA), to assess the impact of mutations in these genes on cancer-specific survival. Methods: We analayzed the genomic and clinical data from the TCGA cohort of 424 patients with primary ccRCC. The Kaplan-Meier method was used to estimate the survival probabilities, and log-rank test was used to test the univariate association between mutation status and overall survival. Cancer specific survival (CSS) was analyzed using the competing risk method. Multivariate Cox proportional hazard regression and competing risk models were also fitted to adjust for the validated Mayo Clinic SSIGN prognostic score. Results: Mutations in these epigenetic modifiers are frequent (PBRM1, 33.7%; SETD2, 11.6%; BAP1, 9.7%, KDM5C, 5.7%). BAP1 (p=0.002, HR 2.21 [1.34-3.62]), SETD2 (p=0.036, HR 1.68 [1.03-2.72]) and KDM5C (p=0.016, HR 2.18 [1.16-4.11]) are associated with worse CSS by competing risk. When adjusting for the prognostic SSIGN score, only mutations in KDM5C remain significant (p<0.0001 HR 4.03 [2.1-7.9]). On the contrary, PBRM1 mutations, the second most common gene mutations of ccRCC, have no impact on CSS. Conclusions: BAP1, SETD2 and KDM5C mutations are associated with worse CSS, suggesting their roles in disease progression. PBRM1 mutations do not impact CSS, implicating its principal role in the tumor initiation. Future efforts should focus on therapeutic interventions and further clinical, pathologic and molecular interrogation of this novel class of tumor suppressors.

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Hsieh, James, David Chen, Patricia Wang, Yingbei Chen, Mahtab Marker, Parul Patel, Michael Chevinsky, et al. "Differential overall survival (OS) results in RECORD-3 study based on three distinct mRCC molecular subgroups classified by BAP1 and/or PBRM1 mutations." Journal of Clinical Oncology 34, no. 2_suppl (January 10, 2016): 561. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.561.

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561 Background: PBRM1 and BAP1, both of which encode chromatin modulating proteins, have recently been identified as frequently mutated tumor suppressor genes in RCC. However, their correlation with outcomes of targeted therapies is unknown. We explored correlations between overall survival (OS) and mutations in archival tumor samples from RECORD-3, a randomized phase 2 trial comparing first-line everolimus (EVE) then sunitinib (SUN) to first-line SUN then EVE at progression in 471 treatment-naïve mRCC patients (J Clin Oncol 2014; 32:2764). Methods: Somatic mutations in exons of 341 cancer related genes were identified by a next generation sequencing (NGS) assay (MSK IMPACT). Association between genotypes and OS was assessed by Cox PH models and log-rank tests. Results: DNA of 258 archival tumor and 181 matched germline samples was successfully analyzed (median coverage 530X). Three molecular subgroups Gr1 (BAP1 MT [mutant], PBRM1 WT [wild-type]/MT; 17.4%), Gr2 (PBRM1 MT, BAP1 WT; 38.4%), and Gr3 (PBRM1 WT, BAP1 WT; 44.2%) with different OS outcomes after sequential EVE-SUN or SUN-EVE were identified (Table). In the sequential EVE-SUN arm, median OS (months) was shortest with Gr1 (9.8; 95% CI, 7.8–20.0), longest with Gr2 (39.6; 95% CI, 31.7–not estimable), and intermediate with Gr3 (18.1; 13.7–30.0), whereas in the SUN-EVE arm there was no significant difference among groups. When comparing OS between treatment sequences within molecular groups, a trend suggested differences for EVE-SUN vs SUN-EVE in Gr1 (HR 1.5), Gr2 (0.8), and Gr3 (1.2), although comparisons were not statistically significant. Conclusions: Our results suggest that these genotypes may represent distinct RCC molecular subtypes with potentially different predictive/prognostic values on targeted therapies. Different treatment sequences may be considered depending on the genotypes. Clinical trial information: NCT00903175. [Table: see text]

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Slaughter, Mariesa J., Erin K. Shanle, Andrew W. McFadden, Emily S. Hollis, Lindsey E. Suttle, Brian D. Strahl, and Ian J. Davis. "PBRM1 bromodomains variably influence nucleosome interactions and cellular function." Journal of Biological Chemistry 293, no. 35 (July 9, 2018): 13592–603. http://dx.doi.org/10.1074/jbc.ra118.003381.

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Kessel, Adam, Summer Tran, Zachary Rivers, Andrew W. Hahn, Roberto Nussenzveig, Nityam Rathi, Benjamin Louis Maughan, Deepika Sirohi, David D. Stenehjem, and Neeraj Agarwal. "Identification of genomic aberrations associated with overall survival in metastatic clear cell renal cell carcinoma (mccRCC)." Journal of Clinical Oncology 38, no. 6_suppl (February 20, 2020): 745. http://dx.doi.org/10.1200/jco.2020.38.6_suppl.745.

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745 Background: Tumor comprehensive genomic profiling (CGP) in addition to risk stratification by IMDC criteria may aid in improving risk stratification. The objective of this study was to assess the prognostic impact of somatic mutations in addition to IMDC risk criteria. Methods: All patients with mccRCC treated with first line with VEGFR-TKI with CGP data available through a CLIA certified lab were included. Kaplan-Meier methodology and Cox proportional hazard ratios were used to test the association of overall survival with genomic alterations present in at least 7% of the population in this dataset. Genomic data were correlated with outcome by univariate analysis and subsequent multivariate testing, integrating genomic data with IMDC risk criteria. Results: A total of 58 patients met eligibly. The presence of any mutation in VHL, PBRM1, and MLL2 were prognostic in terms of overall survival (Table). The mutation status for these three prognostic genes was added to the IMDC risk model to test for the prognostic correlation. The mutations status of these 3 genes significantly correlated with overall survival (VHL: 0.32 [95% CI 0.11-0.95], PBRM1: 0.36 [0.14-0.96], and MLL2: 7.60 [1.35-24.6]) independent of the IMDC risk criteria. Conclusions: In mccRCC, VHL, PBRM1, and MLL2 mutations each predict overall survival independent of IMDC criteria. Further studies are warranted to assess alterations with low prevalence in this data set. Upon external validation, these data provide the rationale for integration of mutation status of these three genes in to the IMDC risk criteria.[Table: see text]

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Verbiest, Annelies, Benoit Beuselinck, Gabrielle Couchy, Sylvie Job, Aurelien De Reynies, Clément Meiller, Maarten Albersen, et al. "Metastatic clear cell renal cell carcinoma: Proangiogenic gene expression and outcome on sunitinib." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e16085-e16085. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e16085.

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e16085 Background: Clear cell renal cell carcinomas (ccRCC) are hypervascular tumors that respond to vascular endothelial growth factor receptor (VEGFR) inhibitors such as sunitinib. They can be divided into 4 mRNA-expression based subgroups (ccrcc 1-4) with different outcomes on sunitinib. We hypothesized that the expression of proangiogenic genes is predictive for response to sunitinib. Methods: Retrospective series of metastatic ccRCC-patients treated with sunitinib as first line targeted therapy (n = 104). We studied expression of genes involved in angiogenesis and the immune-suppressive microenvironment (qRT-PCR) and mutational status of Von Hippel Lindau and Polybromo (PBRM) 1 (sequencing) on primary tumor samples. Outcome parameters were response rate (Response Evaluation Criteria in Solid Tumors), progression free survival (PFS) and overall survival (OS). Gene expression levels were tested in multivariate analysis (MV) against the IMDC risk criteria, presence of bone metastases and sarcomatoid dedifferentiation ≥25%. Results: Expression of Hypoxia Inducible Factor (HIF) 2A, Platelet Derived Growth Factor Receptor B, VEGFC, VEGFR1 and VEGFR2 was significantly correlated with PFS on MV and expression of HIF1A, HIF2A and VEGFR2 with OS. VEGFR2-expression was also correlated with partial response (p = 0.03) and anti-correlated with early progressive disease (p = 0.008). HIF2A, VEGFA, VEGFR1, VEGFR2 and VEGFR3-expression was higher in ccrcc2-tumors compared to others. Expression of genes involved in angiogenesis and in the immune-suppressive microenvironment was not directly correlated nor anti-correlated. In tumors with a bi-allelic PBRM1-inactivation, HIF2A, VEGFA, VEGFR1 and VEGFR2-expression were higher compared to tumors with 1 or 2 functional PBRM1-alleles. This did not translate in different outcome on sunitinib. Conclusions: Tumoral expression of genes involved in the HIF-VEGF-VEGFR proangiogenic pathway, especially VEGFR2, is associated with favorable outcome on sunitinib in metastatic ccRCC. Expression of these genes was high in the molecular ccrcc2-subgroup, known to be sensitive to sunitinib. These findings could be used for patient selection in future clinical trials.

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Fay, Andre Poisl, Eliezer Mendel Van Allen, Bradley Murray, Laurence Albiges, Sabina Signoretti, Thai Huu Ho, A. Ari Hakimi, et al. "Whole-exome sequencing (WES) predicting two extreme phenotypes of response to VEGF-targeted therapies (VEGF-TT) in patients with metastatic clear cell renal cell carcinoma (mRCC)." Journal of Clinical Oncology 33, no. 7_suppl (March 1, 2015): 422. http://dx.doi.org/10.1200/jco.2015.33.7_suppl.422.

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422 Background: There is significant variability in the response to VEGF-TT in mRCC with no validated predictive biomarkers. We hypothesized that whole exome analysis might identify markers of response and resistance to VEGF-TT in mRCC. Methods: mRCC patients who received first-line sunitinib or pazopanib and were in two extreme phenotypes of response were identified. Extreme responders (ER) were defined as PR or CR for ≥3 years (n=10) and primary refractory patients (PRP) were defined as PD within the first 3 months of therapy (n=10). WES was performed in pre-treatment specimens and established Broad Institute analytical pipelines were utilized to identify point mutations and copy number alterations across the exome. ER (n=4) and PRP (n=4) who were part of TCGA project for clear-cell RCC were included in this analysis. Nonsense, missense and indel mutations in established or novel RCC genes were investigated. Results: IMDC prognostic scores were not significantly different between the two groups. VHL mutations were observed at similar frequency in ER and PRP, overall 57%. Mutations in PBRM1 were identified in 7 ER (50%) vs. 1 PRP (7%) (p=0.03). In addition, mutations in TP53 were only found in PRP (p=0.09). No other gene had mutations that were associated with either response or primary refractory disease (Table). Conclusions: In this pilot study, PBRM1 mutations were associated with extreme response to VEGF-TT. However, this was exploratory, and multivariable analysis was not performed. Analysis of additional patient samples is ongoing to confirm or refute this association. If true it suggests that epigenetic effects of PBRM1 mutation may contribute to response to VEGF-TT in mRCC. [Table: see text]

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Ross, Jeffrey S., Laurie M. Gay, Ethan Sokol, Julia Andrea Elvin, Jo-Anne Vergilio, James Suh, Shakti H. Ramkissoon, et al. "PBRM1 genomic alterations in mesothelioma: Potential predictor of immunotherapy efficacy." Journal of Clinical Oncology 36, no. 15_suppl (May 20, 2018): 8562. http://dx.doi.org/10.1200/jco.2018.36.15_suppl.8562.

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Brugarolas, James. "PBRM1 and BAP1 as Novel Targets for Renal Cell Carcinoma." Cancer Journal 19, no. 4 (2013): 324–32. http://dx.doi.org/10.1097/ppo.0b013e3182a102d1.

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Cai, Weijia, Liya Su, and Haifeng Yang. "PBRM1 suppresses tumor growth as a novel p53 acetylation reader." Molecular & Cellular Oncology 7, no. 3 (March 11, 2020): 1729680. http://dx.doi.org/10.1080/23723556.2020.1729680.

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Sarcognato, S., E. Gringeri, M. Fassan, M. Di Giunta, V. Guzzardo, U. Cillo, and M. Guido. "Prognostic role of BAP1 and PBRM1 expression in intrahepatic cholangiocarcinoma." Digestive and Liver Disease 50, no. 1 (February 2018): 39. http://dx.doi.org/10.1016/j.dld.2018.01.114.

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Venneti, Sriram, Pooja Panwalkar, Drew Pratt, Chan Chung, Derek Dang, Paul Lee, Daniel Martinez, et al. "GENE-50. SWI/SNF COMPLEX HETEROGENEITY RELATES WITH POLYPHENOTYPIC DIFFERENTIATION, PROGNOSIS AND IMMUNE RESPONSE IN RHABDOID TUMORS." Neuro-Oncology 21, Supplement_6 (November 2019): vi108. http://dx.doi.org/10.1093/neuonc/noz175.452.

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Abstract PURPOSE Rhabdoid tumors (RTs) arise within (Atypical Teratoid/Rhabdoid Tumor-AT/RT) or outside the brain (extraCNS-RT-eCNS-RT) and are driven mainly by inactivation of the SWI/SNF complex subunit SMARCB1. A pathognomonic hallmark of RTs is heterogeneity characterized by multilineage differentiation of tumor cells including anomalous neuronal differentiation in a subset of eCNS-RT. The mechanisms that regulate heterogeneity in RTs are unknown. Because remodeling of the SWI/SNF complex regulates differentiation, we hypothesized that SWI/SNF-BAF and PBAF complex heterogeneity correlates with both multilineage differentiation and clinical outcome. EXPERIMENTAL DESIGN: We performed an integrated analysis of SWI/SNF complex subunit alterations in the developing kidney and cerebellum (most common regions of origin for RT) in comparison to eCNS-RT (n=14) and AT/RT (n=25) tumors. RT samples were interrogated using immunohistochemistry, DNA methylation and gene expression analyses. RESULTS (A) The SWI/SNF-BAF paralogs ACTL6A/ACTL6B were expressed in a mutually exclusive manner in the developing cerebellum and kidney. In contrast, a subset of eCNS-RTs lost mutual exclusivity and co-expressed both subunits. These tumors showed aberrant DNA methylation of genes that regulate neuronal and renal development and demonstrated immunohistochemical evidence of neuronal differentiation. (B) Low expression of the PBAF subunit-PBRM1 identified a group of AT/RTs in younger children with better overall prognosis. PBRM1-low AT/RT and eCNS-RTs showed altered DNA methylation and gene expression in immune-related genes accompanied by increased CD8 cytotoxic T-cell infiltration. CONCLUSIONS Heterogeneity in SWI/SNF BAF (ACTL6A/ACTL6B) and PBAF (PBRM1) subunits correlates with histogenesis, contributes to the immune microenvironment and prognosis in RTs and may inform opportunities to develop immunotherapies.

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Yoshikawa, Yoshie, Mitsuru Emi, Tomoko Hashimoto-Tamaoki, Masaki Ohmuraya, Ayuko Sato, Tohru Tsujimura, Seiki Hasegawa, et al. "High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma." Proceedings of the National Academy of Sciences 113, no. 47 (November 9, 2016): 13432–37. http://dx.doi.org/10.1073/pnas.1612074113.

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We used a custom-made comparative genomic hybridization array (aCGH; average probe interval 254 bp) to screen 33 malignant mesothelioma (MM) biopsies for somatic copy number loss throughout the 3p21 region (10.7 Mb) that harbors 251 genes, including BRCA1 (breast cancer 1)-associated protein 1 (BAP1), the most commonly mutated gene in MM. We identified frequent minute biallelic deletions (<3 kb) in 46 of 251 genes: four were cancer-associated genes: SETD2 (SET domain-containing protein 2) (7 of 33), BAP1 (8 of 33), PBRM1 (polybromo 1) (3 of 33), and SMARCC1 (switch/sucrose nonfermentable- SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily c, member 1) (2 of 33). These four genes were further investigated by targeted next-generation sequencing (tNGS), which revealed sequence-level mutations causing biallelic inactivation. Combined high-density aCGH and tNGS revealed biallelic gene inactivation in SETD2 (9 of 33, 27%), BAP1 (16 of 33, 48%), PBRM1 (5 of 33, 15%), and SMARCC1 (2 of 33, 6%). The incidence of genetic alterations detected is much higher than reported in the literature because minute deletions are not detected by NGS or commercial aCGH. Many of these minute deletions were not contiguous, but rather alternated with segments showing oscillating copy number changes along the 3p21 region. In summary, we found that in MM: (i) multiple minute simultaneous biallelic deletions are frequent in chromosome 3p21, where they occur as distinct events involving multiple genes; (ii) in addition to BAP1, mutations of SETD2, PBRM1, and SMARCC1 are frequent in MM; and (iii) our results suggest that high-density aCGH combined with tNGS provides a more precise estimate of the frequency and types of genes inactivated in human cancer than approaches based exclusively on NGS strategy.

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Lee, Chung-Han, Renzo G. DiNatale, Diego Chowell, Chriag Krishna, Vladimir Makarov, Natalie Shapnik, Samuel J. Murray, et al. "Genomic biomarkers of response to lenvatinib/pembrolizumab (Len/Pembro) in patients with advanced renal cell carcinoma." Journal of Clinical Oncology 38, no. 6_suppl (February 20, 2020): 733. http://dx.doi.org/10.1200/jco.2020.38.6_suppl.733.

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733 Background: A phase 1b/2 clinical trial indicated that len/pembro shows promise in the treatment of renal cell carcinoma (RCC) in both PD-1/PD-L1 immune checkpoint blockade (ICB)-naïve and pretreated patients (NCT02501096). The combination is being further investigated in a phase 3 clinical trial in RCC (NCT02811861). Tumor antigen presentation depends on multiple factors, including HLA diversity, which can be measured by HLA evolutionary divergence (HED). HED quantitates the capacity of a patient’s HLA genotype to present different peptide antigens. This study is investigating the genomic components of tumor antigen presentation in ICB-naïve patients who have RCC and are treated with len/pembro. Methods: Whole exome sequencing (WES) was performed on pretreatment tumor-derived DNA. Somatic mutations, tumor mutation burden (TMB), neoantigen (NA) load, germline HLA zygosity and somatic loss of heterozygosity (LOH), and HED were correlated with objective response rate (ORR) and progression-free survival (PFS). An updated clinical cutoff was March 29, 2019. Results: Twenty four (80%) of 30 ICB-naïve patients underwent WES. A top-quartile cutoff was used. Increased mean HED was associated with improved PFS, while HLA homozygosity or LOH trended toward worse PFS. Loss-of-function mutations in PBRM1 (PBRM1 LOF) trended toward improved PFS. However, TMB and NA load were not correlated to PFS. No genomic biomarkers were correlated to ORR. Conclusions: Increased HLA diversity was associated with improved PFS, while decreased HLA diversity may be associated with worse PFS. PBRM1 mutation may be associated with improved PFS; however, TMB and NA load were not correlated to outcomes. These findings warrant further examination in larger datasets to rule out possible artifacts from multiple testing in a small cohort. Clinical trial information: NCT02811861. [Table: see text]

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Voss, Martin Henner, Yuan Cheng, Mahtab Marker, Fengshen Kuo, Toni K. Choueiri, James J. Hsieh, Albert Reising, Robert J. Motzer, and A. Ari Hakimi. "Incorporation of PBRM1, BAP1, TP53 mutation status into the Memorial Sloan Kettering Cancer Center (MSKCC) risk model: A genomically annotated tool to improve stratification of patients (pts) with advanced renal cell carcinoma (RCC)." Journal of Clinical Oncology 36, no. 6_suppl (February 20, 2018): 639. http://dx.doi.org/10.1200/jco.2018.36.6_suppl.639.

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639 Background: The MSKCC risk model, an established prognostic tool fo r metastatic RCC, integrates clinical + laboratory data, but is ignorant to tumor genomics. Mutations in BAP1, PBRM1, TP53, cumulatively found in over 50% of pts, have prognostic value in RCC. We sought to study the use of integrating mutation status into the MSKCC model using two large clinical trial datasets. Methods: Pts had received first line sunitinib or pazopanib on the phase III COMPARZ (training set, n = 357) or the phase II RECORD3 trial (validation set, n = 130). Genes were evaluated by next generation sequencing using archival tissue. Association of mutation status and overall survival (OS) was tested by multivariate Cox regression analysis (MVA) in the training set. An annotated model was constructed combining the original clinical variables and mutation status for the 3 genes. We compared risk group assignment and concordance index (c-index) for the original vs. new model in training and validation set. Results: Mutation status for each gene: BAP1, TP53 and PBRM1 independently correlated with OS on MVA (p≤0.0035). Comparing the original (clinical only) to the annotated (clinical + genomics) model, risk categories changed in 139 pts (39%). The C-index was improved with integration of genomic information (0.595 original model - > 0.628 new model). The independent validation cohort confirmed improvement of c-index for predicting OS with integration of genomic data (c-index 0.622 original model - > 0.641 new model). Conclusions: Mutation status for BAP1, PBRM1, and TP53 has prognostic value in pts with advanced RCC. The annotated risk model alters risk status in over 1/3 of pts and improves accuracy of estimating outcomes in patients receiving first-line therapy. Clinical trial information: NCT00720941. [Table: see text]

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Brugarolas, James. "Molecular Genetics of Clear-Cell Renal Cell Carcinoma." Journal of Clinical Oncology 32, no. 18 (June 20, 2014): 1968–76. http://dx.doi.org/10.1200/jco.2012.45.2003.

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Renal cell carcinoma of clear-cell type (ccRCC) is an enigmatic tumor type, characterized by frequent inactivation of the VHL gene (infrequently mutated in other tumor types), responsiveness to angiogenesis inhibitors, and resistance to both chemotherapy and conventional radiation therapy. ccRCC tumors exhibit substantial mutation heterogeneity. Recent studies using massively parallel sequencing technologies have implicated several novel driver genes. In VHL wild-type tumors, mutations were discovered in TCEB1, which encodes Elongin C, a protein that binds to VHL and is required for its function. Several additional tumor suppressor genes have been identified near the VHL gene, within a region that is frequently deleted in ccRCC on chromosome 3p: SETD2, BAP1, and PBRM1. Mutations in BAP1 and PBRM1 are largely mutually exclusive and are associated with different tumor biology and patient outcomes. In addition, the mTORC1 pathway is deregulated by mutations in MTOR, TSC1, PIK3CA, and PTEN in approximately 20% of ccRCCs. Mutations in TSC1, and possibly other genes, may predict for sensitivity to mTORC1 inhibitors. These discoveries provide insight into ccRCC development and set the foundation for the first molecular genetic classification of the disease, paving the way for subtype-specific therapies.

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Huang, Li, Yang Peng, Guangzheng Zhong, Weibin Xie, Wen Dong, Bo Wang, Xu Chen, et al. "PBRM1 suppresses bladder cancer by cyclin B1 induced cell cycle arrest." Oncotarget 6, no. 18 (April 19, 2015): 16366–78. http://dx.doi.org/10.18632/oncotarget.3879.

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Luchini, Claudio, Scott A. Robertson, Seung-Mo Hong, Matthäus Felsenstein, Robert A. Anders, Antonio Pea, Alessia Nottegar, et al. "PBRM1 loss is a late event during the development of cholangiocarcinoma." Histopathology 71, no. 3 (June 22, 2017): 375–82. http://dx.doi.org/10.1111/his.13234.

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Pawłowski, Rafal, Sarah M. Mühl, Tullio Sulser, Wilhelm Krek, Holger Moch, and Peter Schraml. "Loss of PBRM1 expression is associated with renal cell carcinoma progression." International Journal of Cancer 132, no. 2 (October 3, 2012): E11—E17. http://dx.doi.org/10.1002/ijc.27822.

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Bratslavsky, Gennady, Laurie M. Gay, Ethan Sokol, Julia Andrea Elvin, Jo-Anne Vergilio, James Suh, Shakti H. Ramkissoon, et al. "PBRM1 mutation and immunotherapy efficacy: A comprehensive genomic profiling (CGP) assessment." Journal of Clinical Oncology 36, no. 15_suppl (May 20, 2018): 12091. http://dx.doi.org/10.1200/jco.2018.36.15_suppl.12091.

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Volodin, I., V. M. Kozlova, K. I. Anoshkin, A. S. Tanas, D. V. Zaletaev, and V. V. Strelnikov. "PBRM1 is a novel candidate low-penetrance familial cancer predisposition gene." Annals of Oncology 29 (October 2018): viii666. http://dx.doi.org/10.1093/annonc/mdy303.053.

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Wang, Zhun, Shuanghe Peng, Linpei Guo, Hui Xie, Aixiang Wang, Zhiqun Shang, and Yuanjien Niu. "Prognostic and clinicopathological value of PBRM1 expression in renal cell carcinoma." Clinica Chimica Acta 486 (November 2018): 9–17. http://dx.doi.org/10.1016/j.cca.2018.07.014.

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Chabanon, Roman M., Daphné Morel, Thomas Eychenne, Léo Colmet-Daage, Ilirjana Bajrami, Nicolas Dorvault, Marlène Garrido, et al. "PBRM1 Deficiency Confers Synthetic Lethality to DNA Repair Inhibitors in Cancer." Cancer Research 81, no. 11 (June 1, 2021): 2888–902. http://dx.doi.org/10.1158/0008-5472.can-21-0628.

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Miao, Diana, Claire Margolis, Dylan Martini, Stephanie Anne Mullane, Dana Cullen, Christine Horak, Megan Wind-Rotolo, et al. "Loss-of-function of PBRM1 to predict response to anti-PD-1/PD-L1 therapy in metastatic renal cell carcinoma." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 3016. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.3016.

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3016 Background: Immune checkpoint inhibitors targeting programmed cell death-1 (PD-1) substantially improve patient survival in clear-cell renal cell carcinoma (ccRCC), but predictive biomarkers for efficacy have not yet been identified. Methods: We analyzed whole exome sequencing (WES) from a clinical trial of anti-PD-1 monotherapy (nivolumab) for ccRCC (N = 34) to discover genomic predictors of response to immune checkpoint therapy, and validated our findings in 28 ccRCC patients from 2 institutions treated with anti-PD-1 or anti-PD-L1 therapies. We defined 3 response groups: clinical benefit (CB) – complete or partial response by RECIST or stable disease with objective decrease in tumor burden and progression free survival (PFS) > 6 months - and no clinical benefit (NCB) – progressive disease with PFS < 3 months, with all other patients in intermediate benefit (IB). We further validated our findings in WES from 212 melanoma patients treated with immune checkpoint therapies in 3 published cohorts. Results: Biallelic loss of the chromatin remodeling subunit PBRM1, mutated in 34/62 (55%) patients across both cohorts and up to 41% of ccRCC overall, was the only gene mutation associated with CB in both the training (p = 0.0064; Pearson’s chi-squared) and validation cohorts (p = 0.043), and predicted both PFS and overall survival (OS) (p = 0.042 and 0.014, respectively; Kaplan-Meier). In 212 melanomas, truncating alterations in ARID2 – a closely related chromatin remodeler - were also enriched in responders after correcting for tumor mutational burden (p = 0.036), and having a truncating alteration in either PBRM1 or ARID2 significantly predicted overall survival (p = 0.022). In this ccRCC cohort, tumor mutational burden and loss of antigen presentation machinery were not associated with CB or NCB. Conclusions: Loss of chromatin remodeling subunits may impact response to immune checkpoint therapy in both ccRCC and melanoma. Further study in larger cohorts of immunotherapy-treated patients and functional characterization of ARID2 and PBRM1 in the context of the tumor-immune microenvironment will help to determine potential for further biomarker development.

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Chen, Jimin, Yanrui Zhang, Tongtong Yang, Huina Wang, Jing Guo, Xiayuan Liang, Feng Lou, Shanbo Cao, and Chuanjun Du. "Molecular profile of early-stage and advanced-stage of renal cell cancer in China." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e16071-e16071. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e16071.

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e16071 Background: The mutation spectrum has been extensively studied in Renal Cell Cancer (RCC), a heterogeneous disease. While major investigations have focused on metastatic RCC (mRCC). This study intended to explore the molecular characteristics between early-stage (stage I/Ⅱ) and advanced-stage (Ⅲ/Ⅳ) of RCC patients (pts). Methods: 36 tumor specimens were obtained from individual pts diagnosed RCC, including 22 tissues paired with blood samples. Somatic mutations were identified via targeted next generation sequencing with Acornmed panel including 808 genes associated with tumor development. Sequencing data were analyzed to call tumor specific single nucleotide variants (SNV), small insertions and deletions (InDels), copy number alterations (CNA) and chromosomal rearrangements. Clinical data of a cohort from TCGA who had RCC was collected and analyzed. Results: Among the 36 pts enrolled, 61% were early-stage group and 39% were advanced-stage group. The most frequently mutated genes in RCC were VHL (50%), PBRM1 (14%), BAP1 (11%), TP53 (11%) and PIK3CA (6%). Truncating mutations were the most frequent alterations accounting for 66% (33/50) of genetic alterations. Mutations in VHL, BAP1, PBRM1 and TP53 were shared by both early and advanced RCC. While mutations in PIK3CA, CDKN2C, EGFR, FAMCA, GRIN2A, KDM6A, SOX17, TSC1 and APC were only detected in early stage group. KNSTRN, KRAS, MYD88, NF2, ATM, PTEN and STAT5B mutations were only detected in advanced group. Among 22 plasma samples, genomic alterations were detected in 40.9% (9/22) of pts postoperatively, such as TP53, PIK3CA, PTEN, and APC. Functional annotation clustering revealed that 4/9 in these genes were tumor suppressors, which negatively regulated apoptosis. Pts with genomic alterations in TP53 (p = 0.0034), PIK3CA (p = 0.0015) or PTEN (p = 0.00017) had worse OS significantly (TCGA). Conclusions: VHL, PBRM1, BAP1 were the most important driver genes mainly detected in all stages of RCC. The heterogeneity between early and advanced-stage may be related with clinical status. Gene alterations in plasma ctDNA postoperatively should have the potential to stratify patients with different prognostic outcome.

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Journal articles on the topic 'Pbrm1'

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