Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes.
Clear cell renal cell carcinoma (ccRCC) is the most common form of adult kidney cancer, characterized by the presence of inactivating mutations in the VHL gene in most cases, and by infrequent somatic mutations in known cancer genes. To determine further the genetics of ccRCC, we have sequenced 101 cases through 3,544 protein-coding genes. Here we report the identification of inactivating mutations in two genes encoding enzymes involved in histone modification-SETD2, a histone H3 lysine 36 methyltransferase, and JARID1C (also known as KDM5C), a histone H3 lysine 4 demethylase-as well as mutations in the histone H3 lysine 27 demethylase, UTX (KMD6A), that we recently reported. The results highlight the role of mutations in components of the chromatin modification machinery in human cancer. Furthermore, NF2 mutations were found in non-VHL mutated ccRCC, and several other probable cancer genes were identified. These results indicate that substantial genetic heterogeneity exists in a cancer type dominated by mutations in a single gene, and that systematic screens will be key to fully determining the somatic genetic architecture of cancer.
Dalgliesh
Gillian L
GL
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
Furge
Kyle
K
Greenman
Chris
C
Chen
Lina
L
Bignell
Graham
G
Butler
Adam
A
Davies
Helen
H
Edkins
Sarah
S
Hardy
Claire
C
Latimer
Calli
C
Teague
Jon
J
Andrews
Jenny
J
Barthorpe
Syd
S
Beare
Dave
D
Buck
Gemma
G
Campbell
Peter J
PJ
Forbes
Simon
S
Jia
Mingming
M
Jones
David
D
Knott
Henry
H
Kok
Chai Yin
CY
Lau
King Wai
KW
Leroy
Catherine
C
Lin
Meng-Lay
ML
McBride
David J
DJ
Maddison
Mark
M
Maguire
Simon
S
McLay
Kirsten
K
Menzies
Andrew
A
Mironenko
Tatiana
T
Mulderrig
Lee
L
Mudie
Laura
L
O'Meara
Sarah
S
Pleasance
Erin
E
Rajasingham
Arjunan
A
Shepherd
Rebecca
R
Smith
Raffaella
R
Stebbings
Lucy
L
Stephens
Philip
P
Tang
Gurpreet
G
Tarpey
Patrick S
PS
Turrell
Kelly
K
Dykema
Karl J
KJ
Khoo
Sok Kean
SK
Petillo
David
D
Wondergem
Bill
B
Anema
John
J
Kahnoski
Richard J
RJ
Teh
Bin Tean
BT
Stratton
Michael R
MR
Futreal
P Andrew
PA
D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D015687:Cell Hypoxia / Q000235:genetics; D002843:Chromatin / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D016515:Genes, Neurofibromatosis 2; D056466:Histone Demethylases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D017422:Sequence Analysis, DNA
D002843:Chromatin; D006657:Histones; D009687:Nuclear Proteins; D056466:Histone Demethylases; C086877:KDM5C protein, human; C523998:KDM6A protein, human; D010089:Oxidoreductases, N-Demethylating; D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human