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Xiaojun Zhou - One of the best experts on this subject based on the ideXlab platform.

  • frequent co inactivation of the swi snf subunits smarcb1 smarca2 and PBRM1 in malignant rhabdoid tumours
    Histopathology, 2015
    Co-Authors: Zi-yu Wang, Li Li, Bo Yu, Zhenfeng Lu, Qin Shen, Xuan Wang, Yan-fen Wang, Yan He, Rusong Zhang, Xiaojun Zhou
    Abstract:

    Aims Malignant rhabdoid tumours (MRTs) are highly aggressive malignancies of early infancy characterized by inactivation of SMARCB1, a core member of the SWI/SNF chromatin-remodelling complex. The aim of this study was to explore the status of multiple key subunits of the SWI/SNF complex in MRTs. Methods and results We screened the key subunits of the SWI/SNF complex, including SMARCB1, SMARCA2, PBRM1, SMARCA4, and ARID1A, in four MRTs by immunohistochemistry, sequencing, and fluorescence in-situ hybridization (FISH). Complete loss of SMARCB1, SMARCA2 and PBRM1 expression and corresponding mutations in the same genes were observed in all cases. The mutations included seven missense, three same-sense, four frameshift and two truncating mutations. FISH revealed heterozygous deletion of SMARCB1 in one case, and monoploidy of chromosome 22, which harbours SMARCB1, in another case. Furthermore, trisomy of chromosome 9, which harbours SMARCA2, was observed in two cases. Abnormality of PBRM1 was not found in any case. Conclusions We report, for the first time, co-inactivation and frequent mutations of SMARCB1, SMARCA2 and PBRM1 in MRTs. Multiple subunit abnormalities of the SWI/SNF complex potentially act together to contribute to the tumorigenesis of MRTs, which provides unique insights into this disease.

  • concurrent loss of ini1 PBRM1 and brm expression in epithelioid sarcoma implications for the cocontributions of multiple swi snf complex members to pathogenesis
    Human Pathology, 2014
    Co-Authors: Li Li, Bo Yu, Zhenfeng Lu, Xiaojun Zhou
    Abstract:

    Summary The loss of INI1 (SMARCB1) expression, caused by SMARCB1 ( INI1 , SNF5L4 , BAF47 ) inactivation, frequently occurs in epithelioid sarcoma (ES) and could aid in confirming the diagnosis. Except for INI1, the expression of switch in mating type/sucrose nonfermentation complex members in ES has never been examined. In this study, the expression of key subunits of this complex—INI1, BRG1 (SMARCA4), BRM (SNF2L2, SMARCA2), PBRM1 (hPB1, BAF180), and BAF155 (SMARCC1)—was analyzed in 23 ES cases: 15 conventional and 8 proximal type. All of the cases were reviewed and reclassified by hematoxylin-eosin staining and immunostaining for cytokeratin AE1/3, epithelial membrane antigen, CD34, vimentin, and INI1 expression. Of the 23 ES cases, 19 (82.6%) showed a loss of PBRM1, and 18 (78.3%), a loss of INI1. In most cases (17, 73.9%), loss of INI1 and PBRM1 expression was observed. The pattern of PBRM1 expression was similar to that of INI1, that is, not correlated with changes in cellular morphology. The concurrent loss of BRM, PBRM1, and INI1expression was detected in 2 cases with pure rhabdoid tumor features. The frequent observation of concurrent loss of INI1 and PBRM1 suggests that certain switch in mating type/sucrose nonfermentation complex components might act synergistically in the pathogenesis of ES by unknown mechanisms and that these components could provide new targets for therapy. The usefulness of PBRM1 as a biomarker of ES and its mechanism in ES require further investigation. Loss of BRM in ES with pure rhabdoid features suggests that BRM might be involved in the underlying mechanisms of this type of ES.

  • Concurrent loss of INI1, PBRM1, and BRM expression in epithelioid sarcoma: implications for the cocontributions of multiple SWI/SNF complex members to pathogenesis
    Human Pathology, 2014
    Co-Authors: Li Li, Bo Yu, Zhenfeng Lu, Xiaojun Zhou
    Abstract:

    Summary The loss of INI1 (SMARCB1) expression, caused by SMARCB1 ( INI1 , SNF5L4 , BAF47 ) inactivation, frequently occurs in epithelioid sarcoma (ES) and could aid in confirming the diagnosis. Except for INI1, the expression of switch in mating type/sucrose nonfermentation complex members in ES has never been examined. In this study, the expression of key subunits of this complex—INI1, BRG1 (SMARCA4), BRM (SNF2L2, SMARCA2), PBRM1 (hPB1, BAF180), and BAF155 (SMARCC1)—was analyzed in 23 ES cases: 15 conventional and 8 proximal type. All of the cases were reviewed and reclassified by hematoxylin-eosin staining and immunostaining for cytokeratin AE1/3, epithelial membrane antigen, CD34, vimentin, and INI1 expression. Of the 23 ES cases, 19 (82.6%) showed a loss of PBRM1, and 18 (78.3%), a loss of INI1. In most cases (17, 73.9%), loss of INI1 and PBRM1 expression was observed. The pattern of PBRM1 expression was similar to that of INI1, that is, not correlated with changes in cellular morphology. The concurrent loss of BRM, PBRM1, and INI1expression was detected in 2 cases with pure rhabdoid tumor features. The frequent observation of concurrent loss of INI1 and PBRM1 suggests that certain switch in mating type/sucrose nonfermentation complex components might act synergistically in the pathogenesis of ES by unknown mechanisms and that these components could provide new targets for therapy. The usefulness of PBRM1 as a biomarker of ES and its mechanism in ES require further investigation. Loss of BRM in ES with pure rhabdoid features suggests that BRM might be involved in the underlying mechanisms of this type of ES.

Li Li - One of the best experts on this subject based on the ideXlab platform.

  • frequent co inactivation of the swi snf subunits smarcb1 smarca2 and PBRM1 in malignant rhabdoid tumours
    Histopathology, 2015
    Co-Authors: Zi-yu Wang, Li Li, Bo Yu, Zhenfeng Lu, Qin Shen, Xuan Wang, Yan-fen Wang, Yan He, Rusong Zhang, Xiaojun Zhou
    Abstract:

    Aims Malignant rhabdoid tumours (MRTs) are highly aggressive malignancies of early infancy characterized by inactivation of SMARCB1, a core member of the SWI/SNF chromatin-remodelling complex. The aim of this study was to explore the status of multiple key subunits of the SWI/SNF complex in MRTs. Methods and results We screened the key subunits of the SWI/SNF complex, including SMARCB1, SMARCA2, PBRM1, SMARCA4, and ARID1A, in four MRTs by immunohistochemistry, sequencing, and fluorescence in-situ hybridization (FISH). Complete loss of SMARCB1, SMARCA2 and PBRM1 expression and corresponding mutations in the same genes were observed in all cases. The mutations included seven missense, three same-sense, four frameshift and two truncating mutations. FISH revealed heterozygous deletion of SMARCB1 in one case, and monoploidy of chromosome 22, which harbours SMARCB1, in another case. Furthermore, trisomy of chromosome 9, which harbours SMARCA2, was observed in two cases. Abnormality of PBRM1 was not found in any case. Conclusions We report, for the first time, co-inactivation and frequent mutations of SMARCB1, SMARCA2 and PBRM1 in MRTs. Multiple subunit abnormalities of the SWI/SNF complex potentially act together to contribute to the tumorigenesis of MRTs, which provides unique insights into this disease.

  • Frequent co-inactivation of the SWI/SNF subunits SMARCB1, SMARCA2 and PBRM1 in malignant rhabdoid tumours
    Histopathology, 2015
    Co-Authors: Zi-yu Wang, Li Li, Qin Shen, Xuan Wang, Yan-fen Wang
    Abstract:

    Aims Malignant rhabdoid tumours (MRTs) are highly aggressive malignancies of early infancy characterized by inactivation of SMARCB1, a core member of the SWI/SNF chromatin-remodelling complex. The aim of this study was to explore the status of multiple key subunits of the SWI/SNF complex in MRTs. Methods and results We screened the key subunits of the SWI/SNF complex, including SMARCB1, SMARCA2, PBRM1, SMARCA4, and ARID1A, in four MRTs by immunohistochemistry, sequencing, and fluorescence in-situ hybridization (FISH). Complete loss of SMARCB1, SMARCA2 and PBRM1 expression and corresponding mutations in the same genes were observed in all cases. The mutations included seven missense, three same-sense, four frameshift and two truncating mutations. FISH revealed heterozygous deletion of SMARCB1 in one case, and monoploidy of chromosome 22, which harbours SMARCB1, in another case. Furthermore, trisomy of chromosome 9, which harbours SMARCA2, was observed in two cases. Abnormality of PBRM1 was not found in any case. Conclusions We report, for the first time, co-inactivation and frequent mutations of SMARCB1, SMARCA2 and PBRM1 in MRTs. Multiple subunit abnormalities of the SWI/SNF complex potentially act together to contribute to the tumorigenesis of MRTs, which provides unique insights into this disease.

  • concurrent loss of ini1 PBRM1 and brm expression in epithelioid sarcoma implications for the cocontributions of multiple swi snf complex members to pathogenesis
    Human Pathology, 2014
    Co-Authors: Li Li, Bo Yu, Zhenfeng Lu, Xiaojun Zhou
    Abstract:

    Summary The loss of INI1 (SMARCB1) expression, caused by SMARCB1 ( INI1 , SNF5L4 , BAF47 ) inactivation, frequently occurs in epithelioid sarcoma (ES) and could aid in confirming the diagnosis. Except for INI1, the expression of switch in mating type/sucrose nonfermentation complex members in ES has never been examined. In this study, the expression of key subunits of this complex—INI1, BRG1 (SMARCA4), BRM (SNF2L2, SMARCA2), PBRM1 (hPB1, BAF180), and BAF155 (SMARCC1)—was analyzed in 23 ES cases: 15 conventional and 8 proximal type. All of the cases were reviewed and reclassified by hematoxylin-eosin staining and immunostaining for cytokeratin AE1/3, epithelial membrane antigen, CD34, vimentin, and INI1 expression. Of the 23 ES cases, 19 (82.6%) showed a loss of PBRM1, and 18 (78.3%), a loss of INI1. In most cases (17, 73.9%), loss of INI1 and PBRM1 expression was observed. The pattern of PBRM1 expression was similar to that of INI1, that is, not correlated with changes in cellular morphology. The concurrent loss of BRM, PBRM1, and INI1expression was detected in 2 cases with pure rhabdoid tumor features. The frequent observation of concurrent loss of INI1 and PBRM1 suggests that certain switch in mating type/sucrose nonfermentation complex components might act synergistically in the pathogenesis of ES by unknown mechanisms and that these components could provide new targets for therapy. The usefulness of PBRM1 as a biomarker of ES and its mechanism in ES require further investigation. Loss of BRM in ES with pure rhabdoid features suggests that BRM might be involved in the underlying mechanisms of this type of ES.

  • Concurrent loss of INI1, PBRM1, and BRM expression in epithelioid sarcoma: implications for the cocontributions of multiple SWI/SNF complex members to pathogenesis
    Human Pathology, 2014
    Co-Authors: Li Li, Bo Yu, Zhenfeng Lu, Xiaojun Zhou
    Abstract:

    Summary The loss of INI1 (SMARCB1) expression, caused by SMARCB1 ( INI1 , SNF5L4 , BAF47 ) inactivation, frequently occurs in epithelioid sarcoma (ES) and could aid in confirming the diagnosis. Except for INI1, the expression of switch in mating type/sucrose nonfermentation complex members in ES has never been examined. In this study, the expression of key subunits of this complex—INI1, BRG1 (SMARCA4), BRM (SNF2L2, SMARCA2), PBRM1 (hPB1, BAF180), and BAF155 (SMARCC1)—was analyzed in 23 ES cases: 15 conventional and 8 proximal type. All of the cases were reviewed and reclassified by hematoxylin-eosin staining and immunostaining for cytokeratin AE1/3, epithelial membrane antigen, CD34, vimentin, and INI1 expression. Of the 23 ES cases, 19 (82.6%) showed a loss of PBRM1, and 18 (78.3%), a loss of INI1. In most cases (17, 73.9%), loss of INI1 and PBRM1 expression was observed. The pattern of PBRM1 expression was similar to that of INI1, that is, not correlated with changes in cellular morphology. The concurrent loss of BRM, PBRM1, and INI1expression was detected in 2 cases with pure rhabdoid tumor features. The frequent observation of concurrent loss of INI1 and PBRM1 suggests that certain switch in mating type/sucrose nonfermentation complex components might act synergistically in the pathogenesis of ES by unknown mechanisms and that these components could provide new targets for therapy. The usefulness of PBRM1 as a biomarker of ES and its mechanism in ES require further investigation. Loss of BRM in ES with pure rhabdoid features suggests that BRM might be involved in the underlying mechanisms of this type of ES.

James Brugarolas - One of the best experts on this subject based on the ideXlab platform.

  • 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, 2016
    Co-Authors: Guillermo Velasco, James Brugarolas, Thai H Ho, Payal Kapur, Kathryn P Gray, Jiaxi Song, Laurence Albiges, David F Mcdermott, Daniel Yick Chin Heng, Toni K Choueiri
    Abstract:

    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 PB...

  • clear cell renal cell carcinoma subtypes identified by bap1 and PBRM1 expression
    The Journal of Urology, 2016
    Co-Authors: Richard W. Joseph, Daniel J Serie, Alexander S Parker, Eugene P Frenkel, Mansi Parasramka, Thai H Ho, John C. Cheville, Payal Kapur, James Brugarolas
    Abstract:

    Purpose: In clear cell renal cell carcinoma BAP1 and PBRM1 are 2 of the most commonly mutated genes (10% to 15% and 40% to 50%, respectively). We sought to determine the prognostic significance of PBRM1 and BAP1 expression in clear cell renal cell carcinoma.Materials and Methods: We used immunohistochemistry to assess PBRM1 protein expression in 1,479 primary clear cell renal cell carcinoma tumors that were previously stained for BAP1. A centralized pathologist reviewed all cases and categorized tumors as positive or deficient for PBRM1 and BAP1. Kaplan-Meier and Cox regression models were used to evaluate association of PBRM1 and BAP1 expression with the risk of death from renal cell carcinoma and the risk of metastasis after adjustment for age and the Mayo Clinic SSIGN (stage, size, grade and necrosis) score.Results: PBRM1 and BAP1 expression was PBRM1+ BAP1+ in 40.1% of tumors, PBRM1– BAP1+ in 48.6%, PBRM1+ BAP1– in 8.7% and PBRM1– BAP1– in 1.8%. The incidence of PBRM1 and BAP1 loss in the same tumor w...

  • abstract 10 concordance of bap1 PBRM1 ki 67 and topoiia protein expression in primary clear cell renal cell carcinoma tumors and patient matched metastatic tumors
    Clinical Cancer Research, 2016
    Co-Authors: Jeanette E Eckelpassow, Daniel J Serie, Thai H Ho, John C. Cheville, Payal Kapur, Amanda Shreders, Sue M Harrington, Tracy W Hilton, Christine M Lohse, James Brugarolas
    Abstract:

    Introduction: Efforts to improve clear cell renal cell carcinoma (ccRCC) mortality have focused primarily on evaluating prognostic biomarkers in primary tumors in order to identify indicators of response to treatment and targets for novel therapies. To date little attention has been paid to the status of these biomarkers in the more therapeutically-relevant metastatic tumor. Thus, we evaluated concordance of expression of four key prognostic ccRCC biomarkers (BAP1, PBRM1, Ki-67 and TOPOIIa) in a large cohort of patient-matched primary ccRCC and metastatic tumors. Methods: We identified 114 patients treated surgically for ccRCC between 1990 and 2005 who had synchronous (M1) or metachronous (M0) metastases, underwent metastasectomy for at least one metastatic lesion and had archived tissue available from the primary and at least one metastatic tumor. We performed IHC on all primary and metastatic tumors for BAP1, PBRM1, Ki-67, and TOPOIIa using previously-published protocols. BAP1 and PBRM1 expression was categorized as positive or negative and Ki-67 and TOPOIIa was quantified as the number of positive cells per mm2. For BAP1 and PBRM1, we calculated the concordance between patient-matched primary and metastatic tumors as the percentage of pairs where the primary and metastatic tumor had the same designation (i.e., positive or negative). For TOPOIIa and Ki-67, we assessed concordance using Spearman correlation coefficient. Analysis of variance was used to evaluate if concordance between primary-metastatic tumor pairs for TOPOIIa and Ki-67 was associated with metastatic site, metastatic timing (M0/M1), metastatic tumor grade, metastatic tumor necrosis, and metastatic tumor sarcomatoid differentiation. Results: There were a total of 161 patient-matched metastatic tumors available for the 114 patients: 78 patients had only a single metastasis while 36 patients had two or more metastases. While sites of metastases varied, pulmonary metastases were the most common (44% of all metastases). Loss of BAP1 expression was observed in19% of the primary ccRCC and 98.6% of the tumor pairs had concordant BAP1 status between the paired primary and metastatic tumors. Loss of PBRM1 was observed in 56% of the primary ccRCC tumors and 89.3% of tumor pairs showed concordant PBRM1 status. By comparison, median expression of Ki-67 was 65.0mm2 in the primary ccRCC tumors and the Pearson correlation with the patient-matched metastatic tumors was 0.43. The difference in Ki-67 expression between primary-metastatic tumor pairs was associated with necrosis in the metastatic tumor (p=0.014). Median expression of TOPOIIa was 2.6mm2 in the primary ccRCC tumors and the Pearson correlation with the patient-matched metastatic tumors was 0.25. The difference in TOPOIIa expression between primary-metastatic tumor pairs was associated with metastatic site (p=0.0006) and metastases to the heart were significantly different than pulmonary metastases (p Conclusion: We observed high concordance for loss of BAP1 and PBRM1 expression between primary ccRCC and metastatic tumors in the same patient. Conversely, we noted high discordance in protein expression of Ki-67 and TOPOIIa between patient-matched primary-metastatic tumor pairs. Moreover, this discordance varied by key pathological features. Our results suggest that using the status of a biomarker in primary ccRCC as a guide for the status in metastatic tumors is not always appropriate and needs to be evaluated on a marker-by-marker basis. Citation Format: Jeanette E. Eckel-Passow, Daniel J. Serie, John C. Cheville, Thai H. Ho, Sue M. Harrington, Tracy Hilton, Christine Lohse, Amanda Shreders, Payal Kapur, James Brugarolas, R Houston Thompson, Bradley C. Leibovich, Eugene D. Kwon, Richard W. Joseph, Alexander S. Parker. Concordance of BAP1, PBRM1, Ki-67, and TOPOIIa protein expression in primary clear cell renal cell carcinoma tumors and patient-matched metastatic tumors. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 10.

  • high concordance of bap1 and PBRM1 expression in patient matched primary and metastatic ccrcc tumors
    Journal of Clinical Oncology, 2015
    Co-Authors: Amanda Shreders, Daniel J Serie, Richard W. Joseph, James Brugarolas, Thai H Ho, Payal Kapur, Jeanette E Eckelpassow, Alexander S Parker
    Abstract:

    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 largel...

  • loss of bap1 and PBRM1 expression in non clear cell renal cell carcinomas compared to clear cell renal cell carcinomas
    Journal of Clinical Oncology, 2014
    Co-Authors: Thai H Ho, Daniel J Serie, Richard W. Joseph, Mansi Parasramka, James Brugarolas, John C. Cheville, Payal Kapur, Jeanette E Eckelpassow, Alexander S Parker
    Abstract:

    4529 Background: Loss of function mutations in PBRM1 (41-50%) and BAP1(5-15%) are associated with poor outcomes for patients with clear cell renal cell carcinoma (ccRCC) tumors. However, there are ...

James J Hsieh - One of the best experts on this subject based on the ideXlab platform.

  • swi snf tumor suppressor gene PBRM1 baf180 in human clear cell kidney cancer
    Molecular and Cellular Oncology, 2017
    Co-Authors: Amrita M Nargund, Hatice U Osmanbeyoglu, Emily H Cheng, James J Hsieh
    Abstract:

    ABSTRACTMutations within chromatin modulating protein complexes have dominated the novel cancer gene landscape. However, little is known about how individual aberrations contribute to cancer formation. A novel PBRM1 kidney cancer mouse model examining the role of PBRM1 provides much needed clue concerning how SWI/SNF complexes might function as tumor suppressors.

  • SWI/SNF tumor suppressor gene PBRM1/BAF180 in human clear cell kidney cancer.
    Molecular and Cellular Oncology, 2017
    Co-Authors: Amrita M Nargund, Hatice U Osmanbeyoglu, Emily H Cheng, James J Hsieh
    Abstract:

    ABSTRACTMutations within chromatin modulating protein complexes have dominated the novel cancer gene landscape. However, little is known about how individual aberrations contribute to cancer formation. A novel PBRM1 kidney cancer mouse model examining the role of PBRM1 provides much needed clue concerning how SWI/SNF complexes might function as tumor suppressors.

  • 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 t
    Journal of Clinical Oncology, 2017
    Co-Authors: Martin H Voss, Toni K Choueiri, Timothy A Chan, James J Hsieh, Mahtab Marker, Parul Patel, David Chen, Almedina Redzematovic, Nadeem Riaz, Robert J Motzer
    Abstract:

    4523Background: 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% o...

  • 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, 2016
    Co-Authors: James J Hsieh, Patricia Wang, David J Chen, Yingbei Chen, Mahtab Marker, Parul Patel, Michael Chevinsky, Umesh Bhanot, Patrizia Pinciroli, Michael F Berger
    Abstract:

    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-naive 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 W...

  • 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, 2016
    Co-Authors: James J Hsieh, Patricia Wang, David J Chen, Yingbei Chen, Mahtab Marker, Parul Patel, Michael Chevinsky, Umesh Bhanot, Patrizia Pinciroli, Michael F Berger
    Abstract:

    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-naive 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 W...

Payal Kapur - One of the best experts on this subject based on the ideXlab platform.

  • 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, 2016
    Co-Authors: Guillermo Velasco, James Brugarolas, Thai H Ho, Payal Kapur, Kathryn P Gray, Jiaxi Song, Laurence Albiges, David F Mcdermott, Daniel Yick Chin Heng, Toni K Choueiri
    Abstract:

    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 PB...

  • clear cell renal cell carcinoma subtypes identified by bap1 and PBRM1 expression
    The Journal of Urology, 2016
    Co-Authors: Richard W. Joseph, Daniel J Serie, Alexander S Parker, Eugene P Frenkel, Mansi Parasramka, Thai H Ho, John C. Cheville, Payal Kapur, James Brugarolas
    Abstract:

    Purpose: In clear cell renal cell carcinoma BAP1 and PBRM1 are 2 of the most commonly mutated genes (10% to 15% and 40% to 50%, respectively). We sought to determine the prognostic significance of PBRM1 and BAP1 expression in clear cell renal cell carcinoma.Materials and Methods: We used immunohistochemistry to assess PBRM1 protein expression in 1,479 primary clear cell renal cell carcinoma tumors that were previously stained for BAP1. A centralized pathologist reviewed all cases and categorized tumors as positive or deficient for PBRM1 and BAP1. Kaplan-Meier and Cox regression models were used to evaluate association of PBRM1 and BAP1 expression with the risk of death from renal cell carcinoma and the risk of metastasis after adjustment for age and the Mayo Clinic SSIGN (stage, size, grade and necrosis) score.Results: PBRM1 and BAP1 expression was PBRM1+ BAP1+ in 40.1% of tumors, PBRM1– BAP1+ in 48.6%, PBRM1+ BAP1– in 8.7% and PBRM1– BAP1– in 1.8%. The incidence of PBRM1 and BAP1 loss in the same tumor w...

  • abstract 10 concordance of bap1 PBRM1 ki 67 and topoiia protein expression in primary clear cell renal cell carcinoma tumors and patient matched metastatic tumors
    Clinical Cancer Research, 2016
    Co-Authors: Jeanette E Eckelpassow, Daniel J Serie, Thai H Ho, John C. Cheville, Payal Kapur, Amanda Shreders, Sue M Harrington, Tracy W Hilton, Christine M Lohse, James Brugarolas
    Abstract:

    Introduction: Efforts to improve clear cell renal cell carcinoma (ccRCC) mortality have focused primarily on evaluating prognostic biomarkers in primary tumors in order to identify indicators of response to treatment and targets for novel therapies. To date little attention has been paid to the status of these biomarkers in the more therapeutically-relevant metastatic tumor. Thus, we evaluated concordance of expression of four key prognostic ccRCC biomarkers (BAP1, PBRM1, Ki-67 and TOPOIIa) in a large cohort of patient-matched primary ccRCC and metastatic tumors. Methods: We identified 114 patients treated surgically for ccRCC between 1990 and 2005 who had synchronous (M1) or metachronous (M0) metastases, underwent metastasectomy for at least one metastatic lesion and had archived tissue available from the primary and at least one metastatic tumor. We performed IHC on all primary and metastatic tumors for BAP1, PBRM1, Ki-67, and TOPOIIa using previously-published protocols. BAP1 and PBRM1 expression was categorized as positive or negative and Ki-67 and TOPOIIa was quantified as the number of positive cells per mm2. For BAP1 and PBRM1, we calculated the concordance between patient-matched primary and metastatic tumors as the percentage of pairs where the primary and metastatic tumor had the same designation (i.e., positive or negative). For TOPOIIa and Ki-67, we assessed concordance using Spearman correlation coefficient. Analysis of variance was used to evaluate if concordance between primary-metastatic tumor pairs for TOPOIIa and Ki-67 was associated with metastatic site, metastatic timing (M0/M1), metastatic tumor grade, metastatic tumor necrosis, and metastatic tumor sarcomatoid differentiation. Results: There were a total of 161 patient-matched metastatic tumors available for the 114 patients: 78 patients had only a single metastasis while 36 patients had two or more metastases. While sites of metastases varied, pulmonary metastases were the most common (44% of all metastases). Loss of BAP1 expression was observed in19% of the primary ccRCC and 98.6% of the tumor pairs had concordant BAP1 status between the paired primary and metastatic tumors. Loss of PBRM1 was observed in 56% of the primary ccRCC tumors and 89.3% of tumor pairs showed concordant PBRM1 status. By comparison, median expression of Ki-67 was 65.0mm2 in the primary ccRCC tumors and the Pearson correlation with the patient-matched metastatic tumors was 0.43. The difference in Ki-67 expression between primary-metastatic tumor pairs was associated with necrosis in the metastatic tumor (p=0.014). Median expression of TOPOIIa was 2.6mm2 in the primary ccRCC tumors and the Pearson correlation with the patient-matched metastatic tumors was 0.25. The difference in TOPOIIa expression between primary-metastatic tumor pairs was associated with metastatic site (p=0.0006) and metastases to the heart were significantly different than pulmonary metastases (p Conclusion: We observed high concordance for loss of BAP1 and PBRM1 expression between primary ccRCC and metastatic tumors in the same patient. Conversely, we noted high discordance in protein expression of Ki-67 and TOPOIIa between patient-matched primary-metastatic tumor pairs. Moreover, this discordance varied by key pathological features. Our results suggest that using the status of a biomarker in primary ccRCC as a guide for the status in metastatic tumors is not always appropriate and needs to be evaluated on a marker-by-marker basis. Citation Format: Jeanette E. Eckel-Passow, Daniel J. Serie, John C. Cheville, Thai H. Ho, Sue M. Harrington, Tracy Hilton, Christine Lohse, Amanda Shreders, Payal Kapur, James Brugarolas, R Houston Thompson, Bradley C. Leibovich, Eugene D. Kwon, Richard W. Joseph, Alexander S. Parker. Concordance of BAP1, PBRM1, Ki-67, and TOPOIIa protein expression in primary clear cell renal cell carcinoma tumors and patient-matched metastatic tumors. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 10.

  • high concordance of bap1 and PBRM1 expression in patient matched primary and metastatic ccrcc tumors
    Journal of Clinical Oncology, 2015
    Co-Authors: Amanda Shreders, Daniel J Serie, Richard W. Joseph, James Brugarolas, Thai H Ho, Payal Kapur, Jeanette E Eckelpassow, Alexander S Parker
    Abstract:

    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 largel...

  • loss of PBRM1 and bap1 expression is less common in non clear cell renal cell carcinoma than in clear cell renal cell carcinoma
    Urologic Oncology-seminars and Original Investigations, 2015
    Co-Authors: Thai H Ho, Daniel J Serie, Eugene P Frenkel, Richard W. Joseph, Mansi Parasramka, John C. Cheville, Payal Kapur, Jeanette E Eckelpassow, Kevin J Wu, Dinesh Rakheja
    Abstract:

    Abstract Background Recurrent mutations in polybromo-1 ( PBRM1 , ~40%) and BRCA1-associated protein-1 ( BAP1 , ~10%) occur in clear cell renal cell carcinoma (ccRCC), but their prevalence in non-ccRCC or renal oncocytoma (RO) is unknown. We evaluated loss of PBRM1 and BAP1 staining in ccRCC, papillary RCC (pRCC), chromophobe RCC (chRCC), and RO tumors using an immunohistochemistry assay in which negative staining was associated with loss-of-function mutations. Methods We identified 458 patients treated surgically for ccRCC, pRCC, chRCC, and RO between 2004 and 2012. We performed immunohistochemistry assays to evaluate PBRM1 and BAP1 protein expression to classify tumors as PBRM1 or BAP1 negative. We compared loss of staining of these 2 proteins in ccRCC and non-ccRCC using the Fisher exact test. Results For the total cohort of 458 patients, we successfully stained both PBRM1 and BAP1 in 408 tumor samples. Consistent with the mutation rate, loss of PBRM1 and BAP1 staining occurred in 43% (80/187) and 10% (18/187) of ccRCC cases, respectively. However, loss of PBRM1 staining occurred in only 3% (2/59), 6% (1/17), and 0% (0/34) of pRCC, chRCC, and RO tumors, respectively ( P n = 61), chRCC ( n = 17), or RO ( n = 34) tumors, ( P = 0.00021). Conclusion Our data suggest that biallelic inactivation of PBRM1 or BAP1 is less common in non-ccRCC when compared with ccRCC tumors. These findings suggest that loss of PBRM1 or BAP1 are key events in ccRCC, whereas other pathways may support tumorigenesis in non-ccRCC subtypes.