Expression and Mutation Patterns of PBRM1, BAP1 and SETD2 Mirror Specific Evolutionary Subtypes in Clear Cell Renal Cell Carcinoma.
Biomarkers
Carcinoma, Renal Cell
/ diagnosis
Cell Line, Tumor
Computational Biology
/ methods
DNA-Binding Proteins
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
High-Throughput Nucleotide Sequencing
Histone-Lysine N-Methyltransferase
/ genetics
Humans
Immunohistochemistry
Kidney Neoplasms
/ diagnosis
Mutation
Nuclear Proteins
/ genetics
Transcription Factors
/ genetics
Tumor Suppressor Proteins
/ genetics
Ubiquitin Thiolesterase
/ genetics
Journal
Neoplasia (New York, N.Y.)
ISSN: 1476-5586
Titre abrégé: Neoplasia
Pays: United States
ID NLM: 100886622
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
31
10
2018
revised:
14
12
2018
accepted:
22
12
2018
pubmed:
20
1
2019
medline:
12
2
2019
entrez:
20
1
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30660076
pii: S1476-5586(18)30589-X
doi: 10.1016/j.neo.2018.12.006
pmc: PMC6355619
pii:
doi:
Substances chimiques
BAP1 protein, human
0
Biomarkers
0
DNA-Binding Proteins
0
Nuclear Proteins
0
PBRM1 protein, human
0
Transcription Factors
0
Tumor Suppressor Proteins
0
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
SETD2 protein, human
EC 2.1.1.43
Ubiquitin Thiolesterase
EC 3.4.19.12
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
247-256Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
Références
Oncogene. 2002 Oct 7;21(45):6915-35
pubmed: 12362274
J Pathol. 2008 Mar;214(4):464-71
pubmed: 18189328
Oncogene. 2009 Apr 9;28(14):1653-68
pubmed: 19234488
Nat Cell Biol. 2009 Aug;11(8):994-1001
pubmed: 19620968
Nature. 2010 Jan 21;463(7279):360-3
pubmed: 20054297
Cancer Res. 2010 Jun 1;70(11):4287-91
pubmed: 20501857
Nature. 2011 Jan 27;469(7331):539-42
pubmed: 21248752
Dev Dyn. 2011 Mar;240(3):627-39
pubmed: 21305651
Cancer Res. 2011 Aug 15;71(16):5500-11
pubmed: 21715564
Nature. 2011 Aug 10;476(7359):163-9
pubmed: 21833082
Nat Genet. 2012 Jun 10;44(7):751-9
pubmed: 22683710
Semin Cancer Biol. 2013 Feb;23(1):3-9
pubmed: 22722066
Int J Cancer. 2013 Jan 15;132(2):E11-7
pubmed: 22949125
Virchows Arch. 2012 Nov;461(5):571-80
pubmed: 23007645
Lancet Oncol. 2013 Feb;14(2):159-167
pubmed: 23333114
Epigenetics. 2013 May;8(5):486-93
pubmed: 23644518
Nature. 2013 Jul 4;499(7456):43-9
pubmed: 23792563
Nat Genet. 2013 Aug;45(8):860-7
pubmed: 23797736
BJU Int. 2014 May;113(5b):E157-63
pubmed: 24053427
J Urol. 2014 Mar;191(3):603-10
pubmed: 24076305
Nat Genet. 2014 Mar;46(3):225-233
pubmed: 24487277
Proc Natl Acad Sci U S A. 2014 Nov 18;111(46):16538-43
pubmed: 25359211
Annu Rev Pathol. 2015;10:263-89
pubmed: 25387056
Urol Oncol. 2015 Jan;33(1):23.e9-23.e14
pubmed: 25465300
Oncogene. 2015 Nov 12;34(46):5699-708
pubmed: 25728682
J Urol. 2015 Oct;194(4):1112-9
pubmed: 25997916
Urol Oncol. 2015 Aug;33(8):340.e9-16
pubmed: 26003625
J Pathol. 2015 Dec;237(4):460-71
pubmed: 26178300
J Urol. 2016 Jan;195(1):180-7
pubmed: 26300218
Cancer Lett. 2015 Dec 1;369(1):167-74
pubmed: 26300492
N Engl J Med. 2016 Jan 14;374(2):135-45
pubmed: 26536169
Medicine (Baltimore). 2015 Nov;94(45):e2004
pubmed: 26559293
Nat Commun. 2016 Jan 07;7:10292
pubmed: 26739236
Eur Urol. 2016 Jul;70(1):93-105
pubmed: 26935559
Urol Oncol. 2016 Aug;34(8):338.e11-8
pubmed: 27085487
J Urol. 2016 Nov;196(5):1363-1370
pubmed: 27288695
Neoplasia. 2016 Jun;18(6):339-46
pubmed: 27292023
BMC Cancer. 2016 Aug 17;16:638
pubmed: 27530247
Nat Rev Nephrol. 2016 Nov;12(11):655-666
pubmed: 27694978
PLoS One. 2016 Oct 20;11(10):e0164554
pubmed: 27764136
Mol Cancer. 2016 Dec 19;15(1):83
pubmed: 27993170
Proc Natl Acad Sci U S A. 2017 Jan 31;114(5):1027-1032
pubmed: 28082722
Oncogenesis. 2017 Jan 16;6(1):e287
pubmed: 28092369
Biosci Trends. 2017 May 23;11(2):214-220
pubmed: 28260718
BMC Urol. 2017 Mar 21;17(1):19
pubmed: 28327121
Cancer Discov. 2017 Aug;7(8):900-917
pubmed: 28473526
PLoS One. 2017 Jun 27;12(6):e0179610
pubmed: 28654655
Adv Med Biol. 2017 1st Quarter;118:83-122
pubmed: 28680740
Urol Oncol. 2018 Mar;36(3):94.e1-94.e14
pubmed: 29169846
Science. 2018 Feb 16;359(6377):770-775
pubmed: 29301958
Science. 2018 Feb 16;359(6377):801-806
pubmed: 29301960
Eur Urol. 2018 Apr;73(4):560-569
pubmed: 29325693
Cell. 2018 Apr 19;173(3):595-610.e11
pubmed: 29656894
Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9700-4
pubmed: 7937876
Nat Med. 1998 Jul;4(7):844-7
pubmed: 9662379