Gene Summary

Gene:PBRM1; polybromo 1
Aliases: PB1, BAF180
Summary:This locus encodes a subunit of ATP-dependent chromatin-remodeling complexes. The encoded protein has been identified as in integral component of complexes necessary for ligand-dependent transcriptional activation by nuclear hormone receptors. Mutations at this locus have been associated with primary clear cell renal cell carcinoma. [provided by RefSeq, Feb 2012]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:protein polybromo-1
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: PBRM1 (cancer-related)

Farnaby W, Koegl M, Roy MJ, et al.
BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design.
Nat Chem Biol. 2019; 15(7):672-680 [PubMed] Article available free on PMC after 10/12/2019 Related Publications
Targeting subunits of BAF/PBAF chromatin remodeling complexes has been proposed as an approach to exploit cancer vulnerabilities. Here, we develop proteolysis targeting chimera (PROTAC) degraders of the BAF ATPase subunits SMARCA2 and SMARCA4 using a bromodomain ligand and recruitment of the E3 ubiquitin ligase VHL. High-resolution ternary complex crystal structures and biophysical investigation guided rational and efficient optimization toward ACBI1, a potent and cooperative degrader of SMARCA2, SMARCA4 and PBRM1. ACBI1 induced anti-proliferative effects and cell death caused by SMARCA2 depletion in SMARCA4 mutant cancer cells, and in acute myeloid leukemia cells dependent on SMARCA4 ATPase activity. These findings exemplify a successful biophysics- and structure-based PROTAC design approach to degrade high profile drug targets, and pave the way toward new therapeutics for the treatment of tumors sensitive to the loss of BAF complex ATPases.

Chen J, Chen J, He F, et al.
Design of a Targeted Sequencing Assay to Detect Rare Mutations in Circulating Tumor DNA.
Genet Test Mol Biomarkers. 2019; 23(4):264-269 [PubMed] Related Publications
BACKGROUND: Qualitative and quantitative detection of circulating tumor DNA (ctDNA) is a liquid biopsy technology used for early cancer diagnosis. However, the plasma ctDNA content is extremely low, so it is difficult to detect somatic mutations of tumors using conventional sequencing methods. Target region sequencing (TRS) technology, through enrichment of the target genomic region followed by next generation sequencing, overcomes this challenge and has been widely used in ctDNA sequencing.
METHODS: We designed a ctDNA sequencing panel to capture 128 tumor genes, and tested the performance of the panel by running TRS for ctDNA of a clear cell renal cell carcinoma (ccRCC) patient and 12 breast cancer patients.
RESULTS: TRS using the new ctDNA panel at more than 500 × coverage depth achieved almost the same accuracy as traditional whole-exome sequencing (WES). PBRM1 p.L641V was detected in the plasma sample of the ccRCC patient with an allele frequency of 0.2%. The ctDNA of 12 breast cancer patients was sequenced at a depth of 500-fold, achieving 99.89% coverage; 34 genes were detected with mutations, including the drug target genes BRCA2, PTEN, TP53, APC, KDR, and NOTCH2.
CONCLUSIONS: This TRS new ctDNA panel can be used to detect mutations in cell-free DNA from multiple types of cancer.

Huang Y, Wang J, Jia P, et al.
Clonal architectures predict clinical outcome in clear cell renal cell carcinoma.
Nat Commun. 2019; 10(1):1245 [PubMed] Article available free on PMC after 10/12/2019 Related Publications
The genetic landscape of clear cell renal cell carcinoma (ccRCC) had been investigated extensively but its evolution patterns remained unclear. Here we analyze the clonal architectures of 473 patients from three different populations. We find that the mutational signatures vary substantially across different populations and evolution stages. The evolution patterns of ccRCC have great inter-patient heterogeneities, with del(3p) being regarded as the common earliest event followed by three early departure points: VHL and PBRM1 mutations, del(14q) and other somatic copy number alterations (SCNAs) including amp(7), del(1p) and del(6q). We identify three prognostic subtypes of ccRCC with distinct clonal architectures and immune infiltrates: long-lived patients, enriched with VHL but depleted of BAP1 mutations, have high levels of Th17 and CD8

Bihr S, Ohashi R, Moore AL, et al.
Expression and Mutation Patterns of PBRM1, BAP1 and SETD2 Mirror Specific Evolutionary Subtypes in Clear Cell Renal Cell Carcinoma.
Neoplasia. 2019; 21(2):247-256 [PubMed] Article available free on PMC after 10/12/2019 Related Publications
Bi-allelic inactivation of the VHL gene on chromosome 3p is the characteristic feature in most clear cell renal cell carcinomas (ccRCC). Frequent gene alterations were also identified in SETD2, BAP1 and PBRM1, all of which are situated on chromosome 3p and encode histone/chromatin regulators. The relationship between gene mutation, loss of protein expression and the correlations with clinicopathological parameters is important for the understanding of renal cancer progression. We analyzed PBRM1 and BAP1 protein expression as well as the tri-methylation state of H3K36 as a surrogate marker for SETD2 activity in more than 700 RCC samples. In ccRCC loss of nuclear PBRM1 (68%), BAP1 (40%) and H3K36me3 (47%) expression was significantly correlated with each other, advanced tumor stage, poor tumor differentiation (P < .0001 each), and necrosis (P < .005) Targeted next generation sequencing of 83 ccRCC samples demonstrated a significant association of genetic mutations in PBRM1, BAP1, and SETD2 with absence of PBRM1, BAP1, and HEK36me3 protein expression (P < .05, each). By assigning the protein expression patterns to evolutionary subtypes, we revealed similar clinical phenotypes as suggested by TRACERx Renal. Given their important contribution to tumor suppression, we conclude that combined functional inactivation of PBRM1, BAP1, SETD2 and pVHL is critical for ccRCC progression.

Meisenberg C, Pinder SI, Hopkins SR, et al.
Repression of Transcription at DNA Breaks Requires Cohesin throughout Interphase and Prevents Genome Instability.
Mol Cell. 2019; 73(2):212-223.e7 [PubMed] Article available free on PMC after 10/12/2019 Related Publications
Cohesin subunits are frequently mutated in cancer, but how they function as tumor suppressors is unknown. Cohesin mediates sister chromatid cohesion, but this is not always perturbed in cancer cells. Here, we identify a previously unknown role for cohesin. We find that cohesin is required to repress transcription at DNA double-strand breaks (DSBs). Notably, cohesin represses transcription at DSBs throughout interphase, indicating that this is distinct from its known role in mediating DNA repair through sister chromatid cohesion. We identified a cancer-associated SA2 mutation that supports sister chromatid cohesion but is unable to repress transcription at DSBs. We further show that failure to repress transcription at DSBs leads to large-scale genome rearrangements. Cancer samples lacking SA2 display mutational patterns consistent with loss of this pathway. These findings uncover a new function for cohesin that provides insights into its frequent loss in cancer.

Voss MH, Reising A, Cheng Y, et al.
Genomically annotated risk model for advanced renal-cell carcinoma: a retrospective cohort study.
Lancet Oncol. 2018; 19(12):1688-1698 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: The Memorial Sloan Kettering Cancer Center (MSKCC) risk model is an established prognostic tool for metastatic renal-cell carcinoma that integrates clinical and laboratory data, but is agnostic to tumour genomics. Several mutations, including BAP1 and PBRM1, have prognostic value in renal-cell carcinoma. Using two independent clinical trial datasets of patients with metastatic renal-cell carcinoma, we aimed to study whether the addition of the mutation status for several candidate prognostic genes to the MSKCC model could improve the model's prognostic performance.
METHODS: In this retrospective cohort study, we used available formalin-fixed paraffin-embedded tumour tissue and clinical outcome data from patients with metastatic renal-cell carcinoma assigned to treatment with tyrosine kinase inhibitors in the COMPARZ trial (training cohort; n=357) and RECORD-3 trial (validation cohort; n=258). Eligible patients in both trials were treatment-naive; had histologically confirmed, advanced, or metastatic renal-cell carcinoma; and a Karnofsky performance status score of at least 70. For each cohort, data from patients in all treatment groups (sunitinib and pazopanib in the training cohort, and everolimus and sunitinib in the validation cohort) were pooled for this analysis. In the training cohort, tumour tissue was used to evaluate somatic mutations by next-generation sequencing, and the association between cancer-specific outcomes (overall survival, progression-free survival, and overall response) and the mutation status of six genes of interest (BAP1, PBRM1, TP53, TERT, KDM5C, and SETD2) was tested. Only those genes with prognostic value in this setting were added to the MSKCC risk model to create a genomically annotated version. The validation cohort was used to independently test the prognostic value of the annotated model compared with the original MSKCC risk model.
FINDINGS: 357 (32%) of 1110 patients assigned to protocol treatment in the COMPARZ study between August, 2008, and September, 2011, were evaluable for mutation status and clinical outcomes in the training cohort. The independent validation cohort included 258 (55%) of 471 evaluable patients, enrolled between October, 2009, and June, 2011, on the RECORD-3 study. In the training cohort, the presence of any mutation in BAP1 or TP53, or both, and absence of any mutation in PBRM1 were prognostic in terms of overall survival (TP53
INTERPRETATION: The mutation status of BAP1, PBRM1, and TP53 has independent prognostic value in patients with advanced or metastatic renal-cell carcinoma treated with first-line tyrosine kinase inhibitors. Improved stratification of patients across risk groups by use of a genomically annotated model including the mutational status of these three genes warrants further investigation in prospective trials and could be of use as a model to stratify patients with metastatic renal-cell carcinoma in clinical trials.
FUNDING: Novartis Pharmaceuticals Corporation, MSKCC Support Grant/Core Grant, and the J Randall & Kathleen L MacDonald Research Fund.

Sarcognato S, Gringeri E, Fassan M, et al.
Prognostic role of BAP-1 and PBRM-1 expression in intrahepatic cholangiocarcinoma.
Virchows Arch. 2019; 474(1):29-37 [PubMed] Related Publications
Intrahepatic cholangiocarcinoma (ICC) has universally poor outcome, mainly due to its late clinical presentation. Identification of specific biomarkers and development of effective treatment are still urgently required. Mutations in PBRM-1 and BAP-1 genes, and the expression of S100P have been related to survival in ICC. miR-31 seems also to play important regulatory functions in ICC and it directly regulates BAP-1 expression in lung cancer. In this study, tissue expression of BAP-1, PBRM-1, S100P, and miR-31 was investigated in ICC and correlated with clinical-pathological features. Sixty-one consecutive patients who underwent curative hepatic resection for ICC were enrolled. None received any therapy prior to surgery. Immunostaining for BAP-1, PBRM-1, and S100P, and in situ hybridization for miR-31 were performed, using tissue microarray slides. A strong retained expression of BAP-1 and PBRM-1 was associated with a reduced overall (p = 0.04 and p = 0.002, respectively) and disease-free survival (p = 0.05 and p = 0.02, respectively). An overexpression of S100P was related to a reduced overall survival (p = 0.005). The multivariate analyses identified the presence of perineural invasion and the retained PBRM-1 expression as independent predictors of worse overall [p = 0.02, hazard ratio (HR) = 2.25 (1.16-4.39) and p = 0.001, HR = 3.13 (1.56-6.28), respectively] and disease-free survivals [p = 0.03, HR = 2.43 (1.09-5.4) and p = 0.03, HR = 2.51 (1.11-5.67), respectively]. An overexpression of S100P was predictive of a worse overall survival [p = 0.02, HR = 1.66 (1.08-2.55)]. High levels of miR-31 were significantly associated to a low expression of BAP-1 protein (p = 0.03). In ICC, a retained expression of BAP-1 and PBRM-1, and an overexpression of S100P are related to a poor prognosis.

Liao L, Liu ZZ, Langbein L, et al.
Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer.
Elife. 2018; 7 [PubMed] Article available free on PMC after 01/12/2019 Related Publications

Chen X, Zhou Z, Hannan R, et al.
Reliable gene mutation prediction in clear cell renal cell carcinoma through multi-classifier multi-objective radiogenomics model.
Phys Med Biol. 2018; 63(21):215008 [PubMed] Article available free on PMC after 24/10/2019 Related Publications
Genetic studies have identified associations between gene mutations and clear cell renal cell carcinoma (ccRCC). Since the complete gene mutational landscape cannot be characterized through biopsy and sequencing assays for each patient, non-invasive tools are needed to determine the mutation status for tumors. Radiogenomics may be an attractive alternative tool to identify disease genomics by analyzing amounts of features extracted from medical images. Most current radiogenomics predictive models are built based on a single classifier and trained through a single objective. However, since many classifiers are available, selecting an optimal model is challenging. On the other hand, a single objective may not be a good measure to guide model training. We proposed a new multi-classifier multi-objective (MCMO) radiogenomics predictive model. To obtain more reliable prediction results, similarity-based sensitivity and specificity were defined and considered as the two objective functions simultaneously during training. To take advantage of different classifiers, the evidential reasoning (ER) approach was used for fusing the output of each classifier. Additionally, a new similarity-based multi-objective optimization algorithm (SMO) was developed for training the MCMO to predict ccRCC related gene mutations (VHL, PBRM1 and BAP1) using quantitative CT features. Using the proposed MCMO model, we achieved a predictive area under the receiver operating characteristic curve (AUC) over 0.85 for VHL, PBRM1 and BAP1 genes with balanced sensitivity and specificity. Furthermore, MCMO outperformed all the individual classifiers, and yielded more reliable results than other optimization algorithms and commonly used fusion strategies.

Hamieh L, Choueiri TK, Ogórek B, et al.
Mechanisms of acquired resistance to rapalogs in metastatic renal cell carcinoma.
PLoS Genet. 2018; 14(9):e1007679 [PubMed] Article available free on PMC after 24/10/2019 Related Publications
The mechanistic target of rapamycin (mTOR) is an established therapeutic target in renal cell carcinoma (RCC). Mechanisms of secondary resistance to rapalog therapy in RCC have not been studied previously. We identified six patients with metastatic RCC who initially responded to mTOR inhibitor therapy and then progressed, and had pre-treatment and post-treatment tumor samples available for analysis. We performed deep whole exome sequencing on the paired tumor samples and a blood sample. Sequence data was analyzed using Mutect, CapSeg, Absolute, and Phylogic to identify mutations, copy number changes, and their changes over time. We also performed in vitro functional assays on PBRM1 in RCC cell lines. Five patients had clear cell and one had chromophobe RCC. 434 somatic mutations in 416 genes were identified in the 12 tumor samples. 201 (46%) of mutations were clonal in both samples while 129 (30%) were acquired in the post-treatment samples. Tumor heterogeneity or sampling issues are likely to account for some mutations that were acquired in the post-treatment samples. Three samples had mutations in TSC1; one in PTEN; and none in MTOR. PBRM1 was the only gene in which mutations were acquired in more than one post-treatment sample. We examined the effect of PBRM1 loss in multiple RCC cell lines, and could not identify any effect on rapalog sensitivity in in vitro culture assays. We conclude that mTOR pathway gene mutations did not contribute to rapalog resistance development in these six patients with advanced RCC. Furthermore, mechanisms of resistance to rapalogs in RCC remain unclear and our results suggest that PBRM1 loss may contribute to sensitivity through complex transcriptional effects.

Saeed K, Ojamies P, Pellinen T, et al.
Clonal heterogeneity influences drug responsiveness in renal cancer assessed by ex vivo drug testing of multiple patient-derived cancer cells.
Int J Cancer. 2019; 144(6):1356-1366 [PubMed] Related Publications
Renal cell cancer (RCC) has become a prototype example of the extensive intratumor heterogeneity and clonal evolution of human cancers. However, there is little direct evidence on how the genetic heterogeneity impacts on drug response profiles of the cancer cells. Our goal was to determine how genomic clonal evolution impacts drug responses. Finding from our study could help to define the challenge that clonal evolution poses on cancer therapy. We established multiple patient-derived cells (PDCs) from different tumor regions of four RCC patients, verified their clonal relationship to each other and to the uncultured tumor tissue by genome sequencing. Furthermore, comprehensive drug-sensitivity testing with 460 oncological drugs was performed on all PDC clones. The PDCs retained many cancer-specific copy number alterations and mutations in driver genes such as VHL, PBRM1, PIK3C2A, KMD5C and TSC2 genes. The drug testing highlighted vulnerability in the PDCs toward approved RCC drugs, such as the mTOR-inhibitor temsirolimus, but also novel sensitivities were uncovered. The individual PDC clones from different tumor regions in a patient showed distinct drug-response profiles, suggesting that genomic heterogeneity contributes to the variability in drug responses. Studies of multiple PDCs from a patient with cancer are informative for elucidating cancer heterogeneity and for the determination on how the genomic evolution is manifested in cancer drug responsiveness. This approach could facilitate tailoring of drugs and drug combinations to individual patients.

Mitchell TJ, Rossi SH, Klatte T, Stewart GD
Genomics and clinical correlates of renal cell carcinoma.
World J Urol. 2018; 36(12):1899-1911 [PubMed] Article available free on PMC after 24/10/2019 Related Publications
PURPOSE: Clear cell, papillary cell, and chromophobe renal cell carcinomas (RCCs) have now been well characterised thanks to large collaborative projects such as The Cancer Genome Atlas (TCGA). Not only has knowledge of the genomic landscape helped inform the development of new drugs, it also promises to fine tune prognostication.
METHODS: A literature review was performed summarising the current knowledge on the genetic basis of RCC.
RESULTS: The Von Hippel-Lindau (VHL) tumour suppressor gene undergoes bi-allelic knockout in the vast majority of clear cell RCCs. The next most prevalent aberrations include a cohort of chromatin-modifying genes with diverse roles including PBRM1, SETD2, BAP1, and KMD5C. The most common non-clear cell renal cancers have also undergone genomic profiling and are characterised by distinct genomic landscapes. Many recurrent mutations have prognostic value and show promise in aiding decisions regarding treatment stratification. Intra-tumour heterogeneity appears to hamper the clinical applicability of sparsely sampled tumours. Ways to abrogate heterogeneity will be required to optimise the genomic classification of tumours.
CONCLUSION: The somatic mutational landscape of the more common renal cancers is well known. Correlation with outcome needs to be more comprehensively furnished, particularly for small renal masses, rarer non-clear cell renal cancers, and for all tumours undergoing targeted therapy.

Gao X, Jegede O, Gray C, et al.
Comprehensive Genomic Profiling of Metastatic Tumors in a Phase 2 Biomarker Study of Everolimus in Advanced Renal Cell Carcinoma.
Clin Genitourin Cancer. 2018; 16(5):341-348 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
INTRODUCTION: Genomic events leading to activation of mechanistic target of rapamycin (mTOR) are common in renal cell carcinoma (RCC). Everolimus is an allosteric mTOR inhibitor with efficacy in metastatic RCC. We characterized the genomic profile of RCC tumors from metastatic sites and assessed whether particular alterations correlate with clinical response to everolimus.
PATIENTS AND METHODS: An open-label, single-arm phase 2 biomarker study of everolimus 10 mg daily was conducted in metastatic RCC patients. Needle biopsy or metastasectomy was performed on metastatic tumors before everolimus initiation. Next-generation sequencing was performed using a targeted hybrid capture panel detecting alterations within exons and key introns of ≥ 300 cancer-associated genes. Disease assessments were obtained every 8 weeks using standard radiographic modalities and evaluated by Response Evaluation Criteria in Solid Tumors criteria.
RESULTS: Objective response was seen in 1 (4.2%) of 24 patients. Two patients (8.3%) had stable disease lasting > 6 months. Median (90% confidence interval) overall and progression-free survival were 20.1 (8.6, NA) and 3.8 (2.4, 5.4) months, respectively. Next-generation sequencing was successful on 18 pretreatment specimens and 3 on-treatment specimens. Alterations in the phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin (PI3K-AKT-mTOR) pathway were identified in 8 (44%) of 18 pretreatment samples. An mTOR E2419D mutation was identified in the patient who experienced partial response. Alterations in VHL, PBRM1, SETD2, KDM5C, and ATM were common in the RCC metastases before initiation of everolimus.
CONCLUSION: Nearly half of heavily pretreated RCC metastases may harbor mutations in components of the PI3K-AKT-mTOR pathway. Commonly mutated genes in primary RCC were also altered at a high frequency in RCC metastases.

Du M, Thompson J, Fisher H, et al.
Genomic alterations of plasma cell-free DNAs in small cell lung cancer and their clinical relevance.
Lung Cancer. 2018; 120:113-121 [PubMed] Related Publications
OBJECTIVES: To identify genomic variations in cell-free DNA (cfDNA) and evaluate their clinical utility in small cell lung cancer (SCLC).
MATERIALS AND METHODS: We performed whole genome sequencing using plasma cfDNAs derived from 24 SCLC patients for copy number variation (CNV) analysis, and targeted sequencing using 17 pairs of plasma cfDNA and their matched gDNA for mutation analysis. We defined somatic mutations by comparing cfDNA to its matched gDNA with 5% variant alleles as the cutoff for mutation calls. We applied Kaplan-Meier to correlate the genomic alterations with overall survival (OS) and progression-free survival (PFS).
RESULTS: We observed widespread somatic copy-number alterations and mutations, including amplification of MYC at 8q24, FGF10 at 5p13, SOX2 at 3q26 and FGFR1 at 8p12, as well as deletion of TP53 at 17p13, RASSF1 at 3p21.3, RB1 at 13q14.2, FHIT at 3p14, and PTEN at 10q23. The most frequent mutations were genes involved in chromatin regulation (KMT2D, ARID1A, SETBP1 and PBRM1), PI3K/MTOR pathway(MTOR,PIK13G), Notch1 signalling pathway (NOTCH1), and DNA repair related gene ATRX. Kaplan-Meier analysis revealed poor OS and PFS in patients with somatic mutations in gene SETBP1 (P = 0.0061/0.0264, HR = 4.785/3.841, 95% CI = 2.014-28.25/1.286-16.58) and PBRM1 (P = 0.0276/0.0286, HR = 3.532/3.506, 95% CI = 1.275 to 25.34/1.26-24.87). Poor OS was also associated with somatic mutations in ATRX (P = 0.0099, HR = 4.024, 95% CI = 1.926-42.95), EP300 (P = 0.025/0.0622, HR = 3.382/2.891, 95% CI = 1.448-27.76/1.013-17.29), while poor PFS was associated with ATM mutation (P = 0.0038, HR = 4.604, 95% CI = 2.211-40.93). The mutation index produced by summing up the number of mutations in the five genes was significantly associated with the poor OS/PFS (P = 0.0185/0.0294) after adjusting the effect of the stage.
CONCLUSIONS: Our result supports blood plasma as a promising sample source for the genomic analysis in SCLC patients whose tumor tissues are scarcely available and demonstrates potential clinical utilities of cfDNA-based liquid biopsy for clinical management of this deadly disease.

Agaimy A, Amin MB, Gill AJ, et al.
SWI/SNF protein expression status in fumarate hydratase-deficient renal cell carcinoma: immunohistochemical analysis of 32 tumors from 28 patients.
Hum Pathol. 2018; 77:139-146 [PubMed] Related Publications
Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare, aggressive RCC type, originally described in the setting of hereditary leiomyomatosis and RCC syndrome, which is defined by germline FH gene inactivation. Inactivation of components of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex is involved in renal medullary carcinoma (SMARCB1/INI1 loss), clear cell RCC (PBRM1 loss), and subsets of dedifferentiated RCC of clear cell, chromophobe, and papillary types (loss of different SWI/SNF components). FH-RCC and SWI/SNF-deficient RCC share anaplastic nuclear features and highly aggressive course. We analyzed 32 FH-RCCs from 28 patients using 7 commercially available SWI/SNF antibodies (SMARCB1/INI1, SMARCA2, SMARCA4, SMARCC1, SMARCC2, PBRM1, and ARID1A). Variable loss of SMARCB1, ARID1A, and SMARCC1 was observed in 1 of 31, 2 of 31, and 1 of 29 evaluable cases, respectively; 3 of these 4 SWI/SNF-deficient tumors had confirmed FH mutations. No correlation of SWI/SNF loss with solid or sarcomatoid features was observed. Two tumors with SMARCB1 and ARID1A deficiency had available SWI/SNF molecular data; both lacked SMARCB1 and ARID1A mutations. The remaining 5 SWI/SNF components were intact in all cases. Especially PBRM1 seems not to be involved in the pathogenesis or progression of FH-RCC. Our data showed that a subset of FH-RCC (12%) have a variable loss of SWI/SNF complex subunits, likely as secondary genetic events. This should not be confused with SWI/SNF-deficient RCC of other types. Evaluation of FH and SWI/SNF together with comprehensive molecular genetic profiling is needed to explore possible prognostic implications of FH/SWI-SNF double deficiency and to better understand the somatic mutation landscape in high-grade RCC.

de Velasco G, Wankowicz SA, Madison R, et al.
Targeted genomic landscape of metastases compared to primary tumours in clear cell metastatic renal cell carcinoma.
Br J Cancer. 2018; 118(9):1238-1242 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: The genomic landscape of primary clear cell renal cell carcinoma (ccRCC) has been well described. However, little is known about cohort genomic alterations (GA) landscape in ccRCC metastases, or how it compares to primary tumours in aggregate. The genomic landscape of metastases may have biological, clinical, and therapeutic implications.
METHODS: We collected targeted next-generation sequencing mutation calls from two independent cohorts and described the metastases GA landscape and descriptively compared it to the GA landscape in primary tumours.
RESULTS: The cohort 1 (n = 578) consisted of 349 primary tumours and 229 metastases. Overall, the most common mutations in the metastases were VHL (66.8%), PBRM1 (41.87%), and SETD2 (24.7%). TP53 was more frequently mutated in metastases compared to primary tumours (14.85% versus 8.9%; p = 0.031). No other gene had significant difference in the cohort frequency of mutations between the metastases and primary tumours. Mutation burden was not significantly different between the metastases and primary tumours or between metastatic sites. The second cohort (n = 257) consisted of 177 primary tumours and 80 metastases. No differences in frequency of mutations or mutational burden were observed between primaries and metastases.
CONCLUSIONS: These data support the theory that ccRCC primary tumours and metastases encompass a uniform distribution of common genomic alterations tested by next-generation sequencing targeted panels. This study does not address variability between matched primary tumours and metastases or the change in genomic alterations over time and after sequential systemic therapies.

Gatalica Z, Xiu J, Swensen J, Vranic S
Comprehensive analysis of cancers of unknown primary for the biomarkers of response to immune checkpoint blockade therapy.
Eur J Cancer. 2018; 94:179-186 [PubMed] Related Publications
BACKGROUND: Cancer of unknown primary (CUP) accounts for approximately 3% of all malignancies. Avoiding immune destruction is a major cancer characteristic and therapies aimed at immune checkpoint blockade are in use for several specific cancer types. A comprehensive survey of predictive biomarkers to immune checkpoint blockade in CUP were explored in this study.
METHODS: About 389 cases of CUP were analysed for mutations in 592 genes and 52 gene fusions using a massively parallel DNA sequencing platform (next-generation sequencing [NGS]). Total mutational load (TML) and microsatellite instability (MSI) were calculated from NGS data. PD-L1 expression was explored using immunohistochemistry (with 5% cutoff value).
RESULTS: High TML was seen in 11.8% (46/389) of tumours. MSI-high (MSI-H) was detected in 7/384 (1.8%) of tumours. Tumour PD-L1 expression was detected in 80/362 CUP (22%). A small proportion of CUP cases harboured genetic alterations of negative predictive biomarkers to immune checkpoint inhibitors (predictors to hyperprogression) including MDM2 gene amplification (2%) and loss of function JAK2 gene mutations (1%). Amplifications of CD274 (PD-L1) and PDCD1LG2 (PD-L2) genes were also rare (1.4% and 0.8%, respectively). The most frequently mutated genes were TP53 (54%), KRAS (22%), ARID1A (13%), PIK3CA (9%), CDKN2A (8%), SMARCA4 (7%) and PBRM1, STK11, APC, RB1 (5%, respectively).
CONCLUSIONS: Using a multiplex testing approach, 28% of CUP carried one or more predictive biomarkers (MSI-H, PD-L1 and/or TML-H) to the immune checkpoint blockade, providing a novel option for treatment in patients with CUP.

Shi C, Pan BQ, Shi F, et al.
Sequestosome 1 protects esophageal squamous carcinoma cells from apoptosis via stabilizing SKP2 under serum starvation condition.
Oncogene. 2018; 37(24):3260-3274 [PubMed] Related Publications
Esophageal squamous cell carcinoma (ESCC) is one of the malignancies in digestive system, with a low 5-year survival rate. We previously revealed that Sequestosome 1 (SQSTM1/p62) protein levels were upregulated in ESCC tissues. However, it is unclear about the function of p62 and the underlying mechanism. Here, we used immunofluorescence and immunohistochemistry to investigate the expression of p62 in ESCC. Western blotting, quantitative RT-PCR, colony formation assay, flow cytometry, immunoprecipitation and xenograft tumor assay were used to analyze the role of p62 in vitro and vivo. Here, we showed that p62 serves as a regulator of cell apoptosis under serum starvation condition in ESCC cells. Through activating the protein kinase C iota (PKCiota)-S-phase kinase-associated protein 2 (SKP2) signaling pathway, p62 enhances cell apoptosis resistance and colony formation in vitro and tumor growth in mouse models. Through interaction with the domains PB1, p62 upregulated the expression of PKCiota and then depressed the ubiquitin-mediated proteasomal degradation of SKP2. p62-silencing combined with a PKCiota inhibitor ATM significantly enhanced cell apoptosis and inhibited cell survival. Immunohistochemical analysis revealed a positive association between the expression of p62 and SKP2 in primary ESCC tissues. And importantly, p62 presented a markedly cytoplasmic translocation in cancerous cells, including in 16 (30.76%) tumors at stage T1, as compared with its nuclear location in normal esophageal epithelial cells. In summary, p62 plays an anti-apoptotic role in ESCC cells via stabilizing SKP2 under serum starvation condition. These data suggest that p62 might be an early biomarker and a candidate therapeutic target of ESCC.

Akhtar M, Al-Bozom IA, Al Hussain T
Molecular and Metabolic Basis of Clear Cell Carcinoma of the Kidney.
Adv Anat Pathol. 2018; 25(3):189-196 [PubMed] Related Publications
Renal cell carcinoma (RCC) is a heterogenous group of tumors, >70% of which belong to the category of clear cell carcinoma. In recent years, crucial advances have been made in our understanding of the molecular and metabolic basis of clear cell carcinoma. This tumor manifests significant alterations in the cellular metabolism, so that the tumor cells preferentially induce the hypoxia response pathway using aerobic glycolysis, rather than the normal oxidative phosphorylation for energy. Most of the clear cell carcinomas (sporadic as well as familial) have mutations and deletions in the VHL gene located at 3p (p3.25). Normally, pVHL plays a crucial role in the proteasomal degradation of hypoxia-inducible factors (HIF)1 and HIF2. Lack of a functioning pVHL owing to genetic alterations results in stabilization and accumulation of these factors, which promotes cell growth, cell proliferation, and angiogenesis, contributing to a neoplastic phenotype. Several other genes normally located adjacent to VHL (BAP1, SETD2, PBRM1) may also be lost. These are tumor suppressor genes whose loss not only plays a role in carcinogenesis but may also influence the clinical course of these neoplasms. In addition, interaction among a variety of other genes located at several different chromosomes may also play a role in the genesis and progression of clear cell carcinoma.

Liu ZH, Lian BF, Dong QZ, et al.
Whole-exome mutational and transcriptional landscapes of combined hepatocellular cholangiocarcinoma and intrahepatic cholangiocarcinoma reveal molecular diversity.
Biochim Biophys Acta Mol Basis Dis. 2018; 1864(6 Pt B):2360-2368 [PubMed] Related Publications
BACKGROUND: Primary liver cancer (PLC) is the third largest contributor to cancer mortality in the world. PLC is a heterogeneous disease that encompasses several biologically distinct subtypes including hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular-cholangiocarcinoma (CHC). CHC is a distinct, albeit rare, subtype of PLC and is comprised of cells with histopathological features of both HCC and ICC. Several studies have focused on the mutation and expression landscapes of HCC and ICC. However, studies of CHC were rare.
OBJECTIVE: The aim of the current study was to identify genetic and gene expression alterations in the carcinogenesis and development of CHC and ICC in the Chinese population. Unraveling both similar and differing patterns among these subtypes may help to identify personalized medicine approaches that could improve patient survival.
METHODS: Whole genome sequencing (WGS), whole exome sequencing (WES) and RNA-seq were performed on 10 ICC and 10 CHC samples, matched with adjacent non-tumor liver tissue specimens. Comparative analysis was performed using HCC datasets from The Cancer Genome Atlas (TCGA).
RESULTS: Mutational and transcriptional landscapes of CHC and ICC were clearly delineated. TP53 and CTNNB1 were identified as exhibiting mutations in CHC. ARID1A, PBRM1, and IDH1 were frequently mutated in ICC. RYR3, FBN2, and KCNN3 are associated with cell migration and metastasis and might be driver genes in CHC. KCNN3 was identified as also exhibiting mutations in ICC. The ECM-receptor interaction pathway associated fibrogenic hepatic progenitor cell differentiation and liver fibrosis may play an important role in carcinogenesis of PLC. Chromatin remodeling and chromosome organization are key processes in carcinogenesis and development in PLC. P53 related pathways showed alterations in CHC and HCC. Inflammation may be a key factor involved in ICC carcinogenesis.
CONCLUSION: CHC and ICC are different subtypes of PLC. This study discusses predominantly the molecular genetic details of PLC subtypes and highlights the need for an accurate diagnosis and treatment of specific PLC subtypes to optimize patient management.

Miao D, Margolis CA, Gao W, et al.
Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma.
Science. 2018; 359(6377):801-806 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Immune checkpoint inhibitors targeting the programmed cell death 1 receptor (PD-1) improve survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). To identify genomic alterations in ccRCC that correlate with response to anti-PD-1 monotherapy, we performed whole-exome sequencing of metastatic ccRCC from 35 patients. We found that clinical benefit was associated with loss-of-function mutations in the

Pan D, Kobayashi A, Jiang P, et al.
A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing.
Science. 2018; 359(6377):770-775 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Many human cancers are resistant to immunotherapy, for reasons that are poorly understood. We used a genome-scale CRISPR-Cas9 screen to identify mechanisms of tumor cell resistance to killing by cytotoxic T cells, the central effectors of antitumor immunity. Inactivation of >100 genes-including

Espana-Agusti J, Warren A, Chew SK, et al.
Loss of PBRM1 rescues VHL dependent replication stress to promote renal carcinogenesis.
Nat Commun. 2017; 8(1):2026 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Inactivation of the VHL (Von Hippel Lindau) tumour suppressor has long been recognised as necessary for the pathogenesis of clear cell renal cancer (ccRCC); however, the molecular mechanisms underlying transformation and the requirement for additional genetic hits remain unclear. Here, we show that loss of VHL alone results in DNA replication stress and damage accumulation, effects that constrain cellular growth and transformation. By contrast, concomitant loss of the chromatin remodelling factor PBRM1 (mutated in 40% of ccRCC) rescues VHL-induced replication stress, maintaining cellular fitness and allowing proliferation. In line with these data we demonstrate that combined deletion of Vhl and Pbrm1 in the mouse kidney is sufficient for the development of fully-penetrant, multifocal carcinomas, closely mimicking human ccRCC. Our results illustrate how VHL and PBRM1 co-operate to drive renal transformation and uncover replication stress as an underlying vulnerability of all VHL mutated renal cancers that could be therapeutically exploited.

Högner A, Krause H, Jandrig B, et al.
PBRM1 and VHL expression correlate in human clear cell renal cell carcinoma with differential association with patient's overall survival.
Urol Oncol. 2018; 36(3):94.e1-94.e14 [PubMed] Related Publications
OBJECTIVE: To identify the clinicopathological association of PBRM1 (Polybromo-1 gene) and VHL (von Hippel-Lindau gene) expression at mRNA and protein levels in clear cell renal cell carcinoma (ccRCC) and its role in tumor progression.
PATIENTS AND METHODS: Immunohistochemical analysis, Western blotting and qPCR analysis of PBRM1 and VHL were performed on fresh-frozen ccRCC and adjacent normal tissue obtained from 70 patients who underwent radical nephrectomy. In addition, a tissue microarray (TMA) from specimens of 326 ccRCC patients was used to evaluate the effect of loss of PBRM1 and VHL immunohistological expression on clinicopathological features as well as patient survival.
RESULTS: In frozen tissue, PBRM1 and VHL mRNA were significantly down-regulated in most ccRCC tumors (77.6%/80.6%). Simultaneous weak PBRM1 and VHL protein expression was observed in 21.4% of frozen tumors. In the TMA samples, weak PBRM1 and VHL immunohistochemical staining was observed in 60.4% of the cases and was correlated (P<0.001). The association of PBRM1 and VHL immunohistochemical expression with clinicopathological parameters depicts a variable picture: predominantly weak PBRM1 and VHL expression were significantly associated with higher Fuhrman grade (P = 0.012 and 0.024, respectively) but only weak VHL expression was associated with a higher pT stage (P = 0.023). PBRM1 expression did not affect the overall survival, whereas weak VHL expression was associated with decreased patient overall survival (P = 0.013).
CONCLUSIONS: Our data suggest that reduced expression of PBRM1 and VHL is correlated with an increased tumor aggressiveness. Low VHL expression was identified as a risk factor for worse patient overall survival, independently from PBRM1 expression pattern.

Lampis A, Carotenuto P, Vlachogiannis G, et al.
MIR21 Drives Resistance to Heat Shock Protein 90 Inhibition in Cholangiocarcinoma.
Gastroenterology. 2018; 154(4):1066-1079.e5 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND & AIMS: Cholangiocarcinomas (CCA) are resistant to chemotherapy, so new therapeutic agents are needed. We performed a screen to identify small-molecule compounds that are active against CCAs. Levels of microRNA 21 (MIR21 or miRNA21) are increased in CCAs. We investigated whether miRNA21 mediates resistance of CCA cells and organoids to HSP90 inhibitors.
METHODS: We performed a high-throughput screen of 484 small-molecule compounds to identify those that reduced viability of 6 human CCA cell lines. We tested the effects of HSP90 inhibitors on cells with disruption of the MIR21 gene, cells incubated with MIR21 inhibitors, and stable cell lines with inducible expression of MIR21. We obtained CCA biopsies from patients, cultured them as organoids (patient-derived organoids). We assessed their architecture, mutation and gene expression patterns, response to compounds in culture, and when grown as subcutaneous xenograft tumors in mice.
RESULTS: Cells with IDH1 and PBRM1 mutations had the highest level of sensitivity to histone deacetylase inhibitors. HSP90 inhibitors were effective in all cell lines, irrespective of mutations. Sensitivity of cells to HSP90 inhibitors correlated inversely with baseline level of MIR21. Disruption of MIR21 increased cell sensitivity to HSP90 inhibitors. CCA cells that expressed transgenic MIR21 were more resistant to HSP90 inhibitors than cells transfected with control vectors; inactivation of MIR21 in these cells restored sensitivity to these agents. MIR21 was shown to target the DnaJ heat shock protein family (Hsp40) member B5 (DNAJB5). Transgenic expression of DNAJB5 in CCA cells that overexpressed MIR21 re-sensitized them to HSP90 inhibitors. Sensitivity of patient-derived organoids to HSP90 inhibitors, in culture and when grown as xenograft tumors in mice, depended on expression of miRNA21.
CONCLUSIONS: miRNA21 appears to mediate resistance of CCA cells to HSP90 inhibitors by reducing levels of DNAJB5. HSP90 inhibitors might be developed for the treatment of CCA and miRNA21 might be a marker of sensitivity to these agents.

Beuselinck B, Verbiest A, Couchy G, et al.
Pro-angiogenic gene expression is associated with better outcome on sunitinib in metastatic clear-cell renal cell carcinoma.
Acta Oncol. 2018; 57(4):498-508 [PubMed] Related Publications
OBJECTIVES: Clear-cell renal cell carcinomas (ccRCC) are characterized by hyper-vascularization and can respond to vascular endothelial growth factor receptor (VEGFR) inhibitors such as sunitinib. We aimed to study the predictive value of the expression of genes in the hypoxia induced factor (HIF) - vascular endothelial growth factor (VEGF) - VEGFR-pro-angiogenic pathway in metastatic ccRCC (m-ccRCC) patients treated with sunitinib and the correlation between the expression of these genes and the molecular ccrcc-classification, the expression of genes involved in the immune-suppressive microenvironment and Von Hippel-Lindau (VHL) - and Polybromo-1 (PBRM1) - mutational status.
MATERIAL AND METHODS: m-ccRCC patients treated with sunitinib as first-line targeted therapy were included. Gene expression was studied in the primary nephrectomy sample by qRT-PCR, VHL- and PBRM1-mutational status by sequencing. Response rate by RECIST, progression-free survival (PFS) and overall survival (OS) were study endpoints.
RESULTS: One hundred and four patients were included. On multivariate-analysis, HIF2A-, platelet derived growth factor receptor beta (PDGFRB)-, VEGFC-, VEGFR1- and VEGFR2-expression were correlated with PFS and HIF1A-, HIF2A-, VEGFR1- and VEGFR2-expression with OS. VEGFR2-expression showed the strongest association with outcome, being significantly correlated with all outcome parameters. HIF2A, VEGFA, VEGFR1, VEGFR2 and VEGFR3 were highly expressed in the transcriptomic ccrcc2-subtype of tumors, known to be highly sensitive to sunitinib. In the total tumor series, there was no correlation nor inverse correlation between the expression of genes involved in angiogenesis and in the immune-suppressive microenvironment. In tumors with a bi-allelic PBRM1-inactivation, HIF2A-, VEGFA-, VEGFR1- and VEGFR2-expression were higher, compared to tumors with one or two functional PBRM1-alleles.
CONCLUSIONS: Intratumoral expression of genes involved in the HIF-VEGF-VEGFR-pro-angiogenic pathway, especially VEGFR2, is associated with favorable outcome on sunitinib in m-ccRCCs. Several genes involved in this pathway are upregulated in the molecular ccrcc2-subgroup, which usually responds well to sunitinib.

Shu XS, Zhao Y, Sun Y, et al.
The epigenetic modifier PBRM1 restricts the basal activity of the innate immune system by repressing retinoic acid-inducible gene-I-like receptor signalling and is a potential prognostic biomarker for colon cancer.
J Pathol. 2018; 244(1):36-48 [PubMed] Related Publications
It has long been known that patients suffering from inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer (CRC). The innate immune system of host cells provides a first-line defence against pathogenic infection, whereas an uncontrolled inflammatory response under homeostatic conditions usually leads to pathological consequences, as exemplified by the chronic inflammation of IBD. The key molecules and pathways keeping innate immunity in check are still poorly defined. Here, we report that the chromatin remodeller polybromo-1 (PBRM1) is a repressor of innate immune signalling mediated by retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs). Knockdown of PBRM1 in colon cancer cells increased the expression of two receptor genes (RIG-I and MDA5) and upregulated interferon (IFN)-related and inflammation-related gene signatures. The innate immune signal stimulated by a double-stranded RNA viral mimic was exaggerated by PBRM1 suppression. PBRM1 cooperated with polycomb protein EZH2 to directly bind the cis-regulatory elements of RIG-I and MDA5, thereby suppressing their transcription. Moreover, upregulation of RIG-I and MDA5 is required for IFN response activation induced by PBRM1 silencing. TRIM25, a protein stimulated by the RLR pathway and IFN production, physically interacted with PBRM1 and induced PBRM1 protein destabilization by promoting its ubiquitination. These findings reveal a PBRM1-RLR regulatory circuit that can keep innate immune activity at a minimal level in resting cells, and also ensure a robust inflammatory response in the case of pathogen invasion. PBRM1 was found to be downregulated in primary tissues from patients with CRC or IBD, and its expression correlated negatively with that of RLR genes and interferon-stimulated genes in CRC samples. Lower PBRM1 expression was associated with advanced pathological grade and poorer survival of CRC patients, indicating that PBRM1 could serve as a potential prognostic biomarker for CRC. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Hopson S, Thompson MJ
BAF180: Its Roles in DNA Repair and Consequences in Cancer.
ACS Chem Biol. 2017; 12(10):2482-2490 [PubMed] Related Publications
In 2011, Varela et al. reported that the PBRM1 gene is mutated in approximately 40% of clear cell renal cell carcinoma cases. Since then, the number of studies relating PBRM1 mutations to cancers has substantially increased. BAF180 has now been linked to more than 30 types of cancers, including ccRCC, cholangiocarcinomas, esophageal squamous cell carcinoma, bladder cancer, and breast cancer. The mutations associated with BAF180 are most often truncations, which result in a loss of protein expression. This loss has been shown to adversely affect the expression of genes, likely because BAF180 is the chromatin recognition subunit of PBAF. In addition, BAF180 functions in numerous DNA repair mechanisms. Its roles in mediating DNA repair are likely the mechanism by which BAF180 acts a tumor suppressor protein. As research on this protein gains more interest, scientists will begin to piece together the complicated puzzle of the BAF180 protein and why its loss often results in cancer.

Wang H, Qu Y, Dai B, et al.
PBRM1 regulates proliferation and the cell cycle in renal cell carcinoma through a chemokine/chemokine receptor interaction pathway.
PLoS One. 2017; 12(8):e0180862 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
PBRM1 is a novel tumor suppressor gene that can inhibit cancer cell proliferation and predict the outcome of renal cell carcinoma (RCC), but its biological role needs further elucidation. We examined expression of the PBRM1 gene in RCC cell lines and the effect of PBRM1 on cell proliferation and cell cycle in RCC ACHN cells. Microarray processing and analysis was used to explore novel pathways involved in tumorigenesis related to PBRM1 knockdown. PBRM1 was expressed at high levels in RCC ACHN cells and lentivirus-mediated PBRM1 knockdown in these cells caused an increase in the proportion of cells in S phase of the cell cycle and promoted in vitro proliferation and migration. In vivo experiments showed that downregulation of PBRM1 promoted tumorigenesis in nude mice. In pathway gene chip analysis, the chemokine/chemokine receptor interaction pathway showed the greatest difference in gene expression upon PBRM1 knockdown. Protein levels of IL6ST and CCL2 were increased, whereas levels of interleukin (IL)-8, IL-6, and CXCL2 were decreased, in knockdown cells. Re-expression of IL-8 in PBRM1 knockdown ACHN cells could significantly decrease cell proliferation/migration and induced cell arrest in the G2/M phase. These findings indicate that PBRM1 alters cell cycle progression and inhibits proliferation and migration of ACHN cells through the chemokine/chemokine receptor pathway.

Mehdi A, Riazalhosseini Y
Epigenome Aberrations: Emerging Driving Factors of the Clear Cell Renal Cell Carcinoma.
Int J Mol Sci. 2017; 18(8) [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Clear cell renal cell carcinoma (ccRCC), the most common form of Kidney cancer, is characterized by frequent mutations of the von Hippel-Lindau (

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