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Erschienen in: Virchows Archiv 1/2017

09.05.2017 | Original Article

Prognostic role of BAP1 in pT1 clear cell carcinoma in partial nephrectomy specimens

verfasst von: Daniele Minardi, Guendalina Lucarini, Giulio Milanese, Rodolfo Montironi, Roberto Di Primio

Erschienen in: Virchows Archiv | Ausgabe 1/2017

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Abstract

BAP1 is a gene situated on chromosome 3p in a region that can be modified in renal cell carcinomas (RCCs). Mutations that cause loss of expression of BAP1 frequently occur in primary clear cell renal carcinoma (ccRCC). In a previous work, we observed that loss of nuclear BAP1 expression was crucial in ccRCC progression; in the current study, we investigated BAP1 expression in a large series of small conventional ccRCCs treated with partial nephrectomy, to assess a possible role as biomarker and the prognostic value in terms of patients’ survival at long-term follow-up. One hundred sixty-two patients with single pT1 ccRCC were selected from those who underwent surgery at our Institute of Urology between 1987 and 2000. The features considered in this study were gender, age, tumor size, grade, incidence of metastasis, and patient-specific survival; they were correlated with immunohistochemical BAP1 nuclear expression in tumoral tissue. Median follow-up was 197.24 months (range 19 to 274); median survival was 125.34 months (range 5 to 274 months). None of our pT1 ccRCCs showed total loss of nuclear BAP1 staining; we found a significant negative correlation between nuclear BAP1 expression and tumor size and between nuclear BAP1 expression and grade. In small ccRCCs, nuclear BAP1 staining was not correlated with disease-specific 5-year survival.
Our data confirm the established role of BAP1 as a tumor suppressor protein. This is the first report where BAP1 has been studied in pT1 ccRCC tumors, but nuclear BAP1 expression cannot help identify patients having high-risk disease in these patients.
Literatur
1.
Zurück zum Zitat Joseph RW, Kapur P, Serie DJ, Eckel-Passow JE, Parasramka M, Ho T, Cheville JC, Frenkel E, Rakheja D, Brugarolas J, Parker A (2014) Loss of BAP1 protein expression is an independent marker of poor prognosis in patients with low-risk clear cell renal cell carcinoma. Cancer 120:1059–1067CrossRefPubMed Joseph RW, Kapur P, Serie DJ, Eckel-Passow JE, Parasramka M, Ho T, Cheville JC, Frenkel E, Rakheja D, Brugarolas J, Parker A (2014) Loss of BAP1 protein expression is an independent marker of poor prognosis in patients with low-risk clear cell renal cell carcinoma. Cancer 120:1059–1067CrossRefPubMed
2.
4.
Zurück zum Zitat Hakimi AA, Ostrovnaya I, Reva B, Schultz N, Chen YB, Gonen M, Liu H, Takeda S, Voss MH, Tickoo SK, Reuter VE, Russo P, Cheng EH, Sander C, Motzer RJ, Hsieh JJ, ccRCC Cancer Genome Atlas (KIRC TCGA) Research Network investigators (2013) Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: a report by MSKCC and the KIRC TCGA research network. Clin Cancer Res 19:3259–3267CrossRefPubMedPubMedCentral Hakimi AA, Ostrovnaya I, Reva B, Schultz N, Chen YB, Gonen M, Liu H, Takeda S, Voss MH, Tickoo SK, Reuter VE, Russo P, Cheng EH, Sander C, Motzer RJ, Hsieh JJ, ccRCC Cancer Genome Atlas (KIRC TCGA) Research Network investigators (2013) Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: a report by MSKCC and the KIRC TCGA research network. Clin Cancer Res 19:3259–3267CrossRefPubMedPubMedCentral
5.
Zurück zum Zitat Kapur P, Peña-Llopis S, Christie A, Zhrebker L, Pavía-Jiménez A, Rathmell WK, Xie XJ, Brugarolas J (2013) Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation. Lancet Oncol 14:159–167CrossRefPubMedPubMedCentral Kapur P, Peña-Llopis S, Christie A, Zhrebker L, Pavía-Jiménez A, Rathmell WK, Xie XJ, Brugarolas J (2013) Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation. Lancet Oncol 14:159–167CrossRefPubMedPubMedCentral
6.
Zurück zum Zitat The Cancer Genome Atlas Research Network (2013) Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499:43–49CrossRefPubMedCentral The Cancer Genome Atlas Research Network (2013) Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499:43–49CrossRefPubMedCentral
7.
Zurück zum Zitat Minardi D, Lucarini G, Milanese G, Di Primio R, Montironi R, Muzzonigro G (2016) Loss of nuclear BAP1 protein expression is a marker of poor prognosis in patients with clear cell renal cell carcinoma. Urol Oncol 34(338e):11–18 Minardi D, Lucarini G, Milanese G, Di Primio R, Montironi R, Muzzonigro G (2016) Loss of nuclear BAP1 protein expression is a marker of poor prognosis in patients with clear cell renal cell carcinoma. Urol Oncol 34(338e):11–18
8.
Zurück zum Zitat Fuhrman SA, Lasky LC, Limas C (1982) Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 6:655–666CrossRefPubMed Fuhrman SA, Lasky LC, Limas C (1982) Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 6:655–666CrossRefPubMed
9.
Zurück zum Zitat Sobin LH, Witteking CH (2002) TNM classification of malignant tumours, 6th edn. Wiley-Liss, New York Sobin LH, Witteking CH (2002) TNM classification of malignant tumours, 6th edn. Wiley-Liss, New York
10.
Zurück zum Zitat Varela I, Tarpey P, Raine K, Huang D, Ong CK, Stephens P, Davies H, Jones D, Lin ML, Teague J, Bignell G, Butler A, Cho J, Dalgliesh GL, Galappaththige D, Greenman C, Hardy C, Jia M, Latimer C, Lau KW, Marshall J, McLaren S, Menzies A, Mudie L, Stebbings L, Largaespada DA, Wessels LF, Richard S, Kahnoski RJ, Anema J, Tuveson DA, Perez-Mancera PA, Mustonen V, Fischer A, Adams DJ, Rust A, Chan-on W, Subimerb C, Dykema K, Furge K, Campbell PJ, Teh BT, Stratton MR, Futreal PA (2011) Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469:539–542CrossRefPubMedPubMedCentral Varela I, Tarpey P, Raine K, Huang D, Ong CK, Stephens P, Davies H, Jones D, Lin ML, Teague J, Bignell G, Butler A, Cho J, Dalgliesh GL, Galappaththige D, Greenman C, Hardy C, Jia M, Latimer C, Lau KW, Marshall J, McLaren S, Menzies A, Mudie L, Stebbings L, Largaespada DA, Wessels LF, Richard S, Kahnoski RJ, Anema J, Tuveson DA, Perez-Mancera PA, Mustonen V, Fischer A, Adams DJ, Rust A, Chan-on W, Subimerb C, Dykema K, Furge K, Campbell PJ, Teh BT, Stratton MR, Futreal PA (2011) Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469:539–542CrossRefPubMedPubMedCentral
11.
Zurück zum Zitat Dalgliesh GL, Furge K, Greenman C, Chen L, Bignell G, Butler A, Davies H, Edkins S, Hardy C, Latimer C, Teague J, Andrews J, Barthorpe S, Beare D, Buck G, Campbell PJ, Forbes S, Jia M, Jones D, Knott H, Kok CY, Lau KW, Leroy C, Lin ML, McBride DJ, Maddison M, Maguire S, McLay K, Menzies A, Mironenko T, Mulderrig L, Mudie L, O’Meara S, Pleasance E, Rajasingham A, Shepherd R, Smith R, Stebbings L, Stephens P, Tang G, Tarpey PS, Turrell K, Dykema KJ, Khoo SK, Petillo D, Wondergem B, Anema J, Kahnoski RJ, Teh BT, Stratton MR, Futreal PA (2010) Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463:360–363CrossRefPubMedPubMedCentral Dalgliesh GL, Furge K, Greenman C, Chen L, Bignell G, Butler A, Davies H, Edkins S, Hardy C, Latimer C, Teague J, Andrews J, Barthorpe S, Beare D, Buck G, Campbell PJ, Forbes S, Jia M, Jones D, Knott H, Kok CY, Lau KW, Leroy C, Lin ML, McBride DJ, Maddison M, Maguire S, McLay K, Menzies A, Mironenko T, Mulderrig L, Mudie L, O’Meara S, Pleasance E, Rajasingham A, Shepherd R, Smith R, Stebbings L, Stephens P, Tang G, Tarpey PS, Turrell K, Dykema KJ, Khoo SK, Petillo D, Wondergem B, Anema J, Kahnoski RJ, Teh BT, Stratton MR, Futreal PA (2010) Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463:360–363CrossRefPubMedPubMedCentral
12.
Zurück zum Zitat Ventii KH, Devi NS, Friedrich KL, Chernova TA, Tighiouart M, Van Meir EG, Wilkinson KD (2008) BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization. Cancer Res 68:6953–6962CrossRefPubMedPubMedCentral Ventii KH, Devi NS, Friedrich KL, Chernova TA, Tighiouart M, Van Meir EG, Wilkinson KD (2008) BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization. Cancer Res 68:6953–6962CrossRefPubMedPubMedCentral
13.
Zurück zum Zitat Kapur P, Christie A, Raman JD, Then MT, Nuhn P, Buchner A, Bastian P, Seitz C, Shariat SF, Bensalah K, Rioux-Leclercq N, Xie XJ, Lotan Y, Margulis V, Brugarolas J (2014) BAP1 immunohistochemistry predicts outcomes in a multi-institutional cohort with clear cell renal cell carcinoma. J Urol 191:603–610CrossRefPubMed Kapur P, Christie A, Raman JD, Then MT, Nuhn P, Buchner A, Bastian P, Seitz C, Shariat SF, Bensalah K, Rioux-Leclercq N, Xie XJ, Lotan Y, Margulis V, Brugarolas J (2014) BAP1 immunohistochemistry predicts outcomes in a multi-institutional cohort with clear cell renal cell carcinoma. J Urol 191:603–610CrossRefPubMed
14.
Zurück zum Zitat Popova T, Hebert L, Jacquemin V, Gad S, Caux-Moncoutier V, Dubois-d'Enghien C, Richaudeau B, Renaudin X, Sellers J, Nicolas A, Sastre-Garau X, Desjardins L, Gyapay G, Raynal V, Sinilnikova OM, Andrieu N, Manié E, de Pauw A, Gesta P, Bonadona V, Maugard CM, Penet C, Avril MF, Barillot E, Cabaret O, Delattre O, Richard S, Caron O, Benfodda M, Hu HH, Soufir N, Bressac-de Paillerets B, Stoppa-Lyonnet D, Stern MH (2013) Germline BAP1 mutations predispose to renal cell carcinomas. Am J Hum Genet 92:974–978CrossRefPubMedPubMedCentral Popova T, Hebert L, Jacquemin V, Gad S, Caux-Moncoutier V, Dubois-d'Enghien C, Richaudeau B, Renaudin X, Sellers J, Nicolas A, Sastre-Garau X, Desjardins L, Gyapay G, Raynal V, Sinilnikova OM, Andrieu N, Manié E, de Pauw A, Gesta P, Bonadona V, Maugard CM, Penet C, Avril MF, Barillot E, Cabaret O, Delattre O, Richard S, Caron O, Benfodda M, Hu HH, Soufir N, Bressac-de Paillerets B, Stoppa-Lyonnet D, Stern MH (2013) Germline BAP1 mutations predispose to renal cell carcinomas. Am J Hum Genet 92:974–978CrossRefPubMedPubMedCentral
15.
Zurück zum Zitat Farley MN, Schmidt LS, Mester JL, Peña-Llopis S, Pavia-Jimenez A, Christie A, Vocke CD, Ricketts CJ, Peterson J, Middelton L, Kinch L, Grishin N, Merino MJ, Metwalli AR, Xing C, Xie XJ, Dahia PL, Eng C, Linehan WM, Brugarolas J (2013) A novel germline BAP1 mutation predisposes to familial clear cell renal cell carcinoma. Mol Cancer Res 11:1061–1071CrossRefPubMedPubMedCentral Farley MN, Schmidt LS, Mester JL, Peña-Llopis S, Pavia-Jimenez A, Christie A, Vocke CD, Ricketts CJ, Peterson J, Middelton L, Kinch L, Grishin N, Merino MJ, Metwalli AR, Xing C, Xie XJ, Dahia PL, Eng C, Linehan WM, Brugarolas J (2013) A novel germline BAP1 mutation predisposes to familial clear cell renal cell carcinoma. Mol Cancer Res 11:1061–1071CrossRefPubMedPubMedCentral
16.
Zurück zum Zitat Peña-Llopis S, Vega-Rubín-de-Celis S, Liao A, Leng N, Pavía-Jiménez A, Wang S, Yamasaki T, Zhrebker L, Sivanand S, Spence P, Kinch L, Hambuch T, Jain S, Lotan Y, Margulis V, Sagalowsky AI, Summerour PB, Kabbani W, Wong SW, Grishin N, Laurent M, Xie XJ, Haudenschild CD, Ross MT, Bentley DR, Kapur P, Brugarolas (2012) BAP1 loss defines a new class of renal cell carcinoma. Nat Genet 44:751–759CrossRefPubMedPubMedCentral Peña-Llopis S, Vega-Rubín-de-Celis S, Liao A, Leng N, Pavía-Jiménez A, Wang S, Yamasaki T, Zhrebker L, Sivanand S, Spence P, Kinch L, Hambuch T, Jain S, Lotan Y, Margulis V, Sagalowsky AI, Summerour PB, Kabbani W, Wong SW, Grishin N, Laurent M, Xie XJ, Haudenschild CD, Ross MT, Bentley DR, Kapur P, Brugarolas (2012) BAP1 loss defines a new class of renal cell carcinoma. Nat Genet 44:751–759CrossRefPubMedPubMedCentral
17.
Zurück zum Zitat Guo G, Gui Y, Gao S, Tang A, Hu X, Huang Y, Jia W, Li Z, He M, Sun L, Song P, Sun X, Zhao X, Yang S, Liang C, Wan S, Zhou F, Chen C, Zhu J, Li X, Jian M, Zhou L, Ye R, Huang P, Chen J, Jiang T, Liu X, Wang Y, Zou J, Jiang Z, Wu R, Wu S, Fan F, Zhang Z, Liu L, Yang R, Liu X, Wu H, Yin W, Zhao X, Liu Y, Peng H, Jiang B, Feng Q, Li C, Xie J, Lu J, Kristiansen K, Li Y, Zhang X, Li S, Wang J, Yang H, Cai Z, Wang J (2011) Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma. Nat Genet 44:17–19CrossRefPubMed Guo G, Gui Y, Gao S, Tang A, Hu X, Huang Y, Jia W, Li Z, He M, Sun L, Song P, Sun X, Zhao X, Yang S, Liang C, Wan S, Zhou F, Chen C, Zhu J, Li X, Jian M, Zhou L, Ye R, Huang P, Chen J, Jiang T, Liu X, Wang Y, Zou J, Jiang Z, Wu R, Wu S, Fan F, Zhang Z, Liu L, Yang R, Liu X, Wu H, Yin W, Zhao X, Liu Y, Peng H, Jiang B, Feng Q, Li C, Xie J, Lu J, Kristiansen K, Li Y, Zhang X, Li S, Wang J, Yang H, Cai Z, Wang J (2011) Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma. Nat Genet 44:17–19CrossRefPubMed
18.
Zurück zum Zitat Pawlowski R, Muhl SM, Sulser T, Krek W, Moch H, Schraml P (2013) Loss of PBRM1 expression is associated with renal cell carcinoma progression. Int J Cancer 132:E11–E17CrossRefPubMed Pawlowski R, Muhl SM, Sulser T, Krek W, Moch H, Schraml P (2013) Loss of PBRM1 expression is associated with renal cell carcinoma progression. Int J Cancer 132:E11–E17CrossRefPubMed
19.
Zurück zum Zitat Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366:883–892CrossRefPubMedPubMedCentral Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366:883–892CrossRefPubMedPubMedCentral
20.
Zurück zum Zitat Angeloni D (2007) Molecular analysis of deletions in human chromosome 3p21 and the role of resident cancer genes in disease. Brief Funct Genomic Proteomic 6:19–39CrossRefPubMed Angeloni D (2007) Molecular analysis of deletions in human chromosome 3p21 and the role of resident cancer genes in disease. Brief Funct Genomic Proteomic 6:19–39CrossRefPubMed
21.
Zurück zum Zitat Ladanyi M, Zauderer MG, Krug LM, Ito T, McMillan R, Bott M, Giancotti F (2012) New strategies in pleural mesothelioma: BAP1 and NF2 as novel targets for therapeutic development and risk assessment. Clin Cancer Res 18:4485–4490CrossRefPubMedPubMedCentral Ladanyi M, Zauderer MG, Krug LM, Ito T, McMillan R, Bott M, Giancotti F (2012) New strategies in pleural mesothelioma: BAP1 and NF2 as novel targets for therapeutic development and risk assessment. Clin Cancer Res 18:4485–4490CrossRefPubMedPubMedCentral
22.
Zurück zum Zitat Wiesner T, Murali R, Fried I, Cerroni L, Busam K, Kutzner H, Bastian BC (2012) A distinct subset of atypical Spitz tumors is characterized by BRAF mutation and loss of BAP1 expression. Am J Surg Pathol 36:818–830CrossRefPubMedPubMedCentral Wiesner T, Murali R, Fried I, Cerroni L, Busam K, Kutzner H, Bastian BC (2012) A distinct subset of atypical Spitz tumors is characterized by BRAF mutation and loss of BAP1 expression. Am J Surg Pathol 36:818–830CrossRefPubMedPubMedCentral
23.
Zurück zum Zitat Duns G, Hofstra RM, Sietzema JG, Hollema H, van Duivenbode I, Kuik A, Giezen C, Jan O, Bergsma JJ, Bijnen H, van der Vlies P, van den Berg E, Kok K (2012) Targeted exome sequencing in clear cell renal cell carcinoma tumors suggests aberrant chromatin regulation as a crucial step in ccRCC development. Hum Mutat :1059–1062 Duns G, Hofstra RM, Sietzema JG, Hollema H, van Duivenbode I, Kuik A, Giezen C, Jan O, Bergsma JJ, Bijnen H, van der Vlies P, van den Berg E, Kok K (2012) Targeted exome sequencing in clear cell renal cell carcinoma tumors suggests aberrant chromatin regulation as a crucial step in ccRCC development. Hum Mutat :1059–1062
24.
Zurück zum Zitat Piva F, Santoni M, Matrana MR, Satti S, Giulietti M, Occhipinti G, Massari F, Cheng L, Lopez-Beltran A, Scarpelli M, Principato G, Cascinu S, Montironi R (2015) BAP1, PBRM1 and SETD2 in clear-cell renal cell carcinoma: molecular diagnostics and possible targets for personalized therapies. Expert Rev Mol Diagn 15:1201–1210CrossRefPubMed Piva F, Santoni M, Matrana MR, Satti S, Giulietti M, Occhipinti G, Massari F, Cheng L, Lopez-Beltran A, Scarpelli M, Principato G, Cascinu S, Montironi R (2015) BAP1, PBRM1 and SETD2 in clear-cell renal cell carcinoma: molecular diagnostics and possible targets for personalized therapies. Expert Rev Mol Diagn 15:1201–1210CrossRefPubMed
Metadaten
Titel
Prognostic role of BAP1 in pT1 clear cell carcinoma in partial nephrectomy specimens
verfasst von
Daniele Minardi
Guendalina Lucarini
Giulio Milanese
Rodolfo Montironi
Roberto Di Primio
Publikationsdatum
09.05.2017
Verlag
Springer Berlin Heidelberg
Erschienen in
Virchows Archiv / Ausgabe 1/2017
Print ISSN: 0945-6317
Elektronische ISSN: 1432-2307
DOI
https://doi.org/10.1007/s00428-017-2143-x

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