Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma.
The genetics of renal cancer is dominated by inactivation of the VHL tumour suppressor gene in clear cell carcinoma (ccRCC), the commonest histological subtype. A recent large-scale screen of ∼3,500 genes by PCR-based exon re-sequencing identified several new cancer genes in ccRCC including UTX (also known as KDM6A), JARID1C (also known as KDM5C) and SETD2 (ref. 2). These genes encode enzymes that demethylate (UTX, JARID1C) or methylate (SETD2) key lysine residues of histone H3. Modification of the methylation state of these lysine residues of histone H3 regulates chromatin structure and is implicated in transcriptional control. However, together these mutations are present in fewer than 15% of ccRCC, suggesting the existence of additional, currently unidentified cancer genes. Here, we have sequenced the protein coding exome in a series of primary ccRCC and report the identification of the SWI/SNF chromatin remodelling complex gene PBRM1 (ref. 4) as a second major ccRCC cancer gene, with truncating mutations in 41% (92/227) of cases. These data further elucidate the somatic genetic architecture of ccRCC and emphasize the marked contribution of aberrant chromatin biology.
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
Ignacio
I
Varela
Patrick
P
Tarpey
Keiran
K
Raine
Dachuan
D
Huang
Choon Kiat
CK
Ong
Philip
P
Stephens
Helen
H
Davies
David
D
Jones
Meng-Lay
ML
Lin
Jon
J
Teague
Graham
G
Bignell
Adam
A
Butler
Juok
J
Cho
Gillian L
GL
Dalgliesh
Danushka
D
Galappaththige
Chris
C
Greenman
Claire
C
Hardy
Mingming
M
Jia
Calli
C
Latimer
King Wai
KW
Lau
John
J
Marshall
Stuart
S
McLaren
Andrew
A
Menzies
Laura
L
Mudie
Lucy
L
Stebbings
David A
DA
Largaespada
L F A
LF
Wessels
Stephane
S
Richard
Richard J
RJ
Kahnoski
John
J
Anema
David A
DA
Tuveson
Pedro A
PA
Perez-Mancera
Ville
V
Mustonen
Andrej
A
Fischer
David J
DJ
Adams
Alistair
A
Rust
Waraporn
W
Chan-on
Chutima
C
Subimerb
Karl
K
Dykema
Kyle
K
Furge
Peter J
PJ
Campbell
Bin Tean
BT
Teh
Michael R
MR
Stratton
P Andrew
PA
Futreal
D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C102195:PBRM1 protein, human; D014157:Transcription Factors
Cell. 2007 Feb 23;128(4):693-705
17320507
N Engl J Med. 2010 Oct 14;363(16):1532-43
20942669
Oncogene. 2005 Apr 14;24(16):2735-8
15735765
Cancer Cell. 2002 Jun;1(5):459-68
12124175
Cancer Res. 2008 Mar 15;68(6):1667-74
18339845
Cancer Res. 2000 Nov 1;60(21):6171-7
11085541
Nat Genet. 2009 May;41(5):521-3
19330029
Int J Cancer. 2004 Nov 20;112(4):636
15382044
Nat Genet. 2009 Sep;41(9):1006-10
19684604
Nat Cell Biol. 2008 Mar;10(3):361-9
18297059
Proc Natl Acad Sci U S A. 2000 Nov 21;97(24):13015-20
11078522
Nature. 2010 Jan 21;463(7279):360-3
20054297
Nat Biotechnol. 2009 Mar;27(3):264-74
19234449
Genes Dev. 2005 Mar 15;19(6):665-70
15769941
Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14280-5
20660729
Biochimie. 2009 Mar;91(3):309-19
19084573
Genes Chromosomes Cancer. 1998 Jul;22(3):200-9
9624531
Oncogene. 2009 Apr 9;28(14):1653-68
19234488
Nature. 1998 Jul 9;394(6689):203-6
9671307
Nat Biotechnol. 2009 Feb;27(2):182-9
19182786
Nature. 2005 Jul 14;436(7048):272-6
16015333
Cell. 2008 May 16;133(4):727-41
18485879
Science. 2010 Oct 8;330(6001):228-31
20826764
Am J Hum Genet. 2010 Feb 12;86(2):279-84
20137775
Bioinformatics. 2009 Nov 1;25(21):2865-71
19561018
Cancer Cell. 2003 Dec;4(6):437-50
14706336
Science. 2008 Sep 26;321(5897):1801-6
18772397
J Biol Chem. 2009 Feb 13;284(7):4123-31
19097995
Science. 2009 Mar 27;323(5922):1747-50
19251594
Biochem Biophys Res Commun. 2007 Apr 13;355(3):661-6
17320048