Spectrum of diverse genomic alterations define non-clear cell renal carcinoma subtypes.
To further understand the molecular distinctions between kidney cancer subtypes, we analyzed exome, transcriptome and copy number alteration data from 167 primary human tumors that included renal oncocytomas and non-clear cell renal cell carcinomas (nccRCCs), consisting of papillary (pRCC), chromophobe (chRCC) and translocation (tRCC) subtypes. We identified ten significantly mutated genes in pRCC, including MET, NF2, SLC5A3, PNKD and CPQ. MET mutations occurred in 15% (10/65) of pRCC samples and included previously unreported recurrent activating mutations. In chRCC, we found TP53, PTEN, FAAH2, PDHB, PDXDC1 and ZNF765 to be significantly mutated. Gene expression analysis identified a five-gene set that enabled the molecular classification of chRCC, renal oncocytoma and pRCC. Using RNA sequencing, we identified previously unreported gene fusions, including ACTG1-MITF fusion. Ectopic expression of the ACTG1-MITF fusion led to cellular transformation and induced the expression of downstream target genes. Finally, we observed upregulation of the anti-apoptotic factor BIRC7 in MiTF-high RCC tumors, suggesting a potential therapeutic role for BIRC7 inhibitors.
Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.|Bioinformatics and Computational Biology Department, Genentech, Inc., South San Francisco, California, USA.
Steffen
S
Durinck
Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.|Bioinformatics and Computational Biology Department, Genentech, Inc., South San Francisco, California, USA.
Eric W
EW
Stawiski
Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Andrea
A
Pavía-Jiménez
Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
Zora
Z
Modrusan
Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Payal
P
Kapur
Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
Bijay S
BS
Jaiswal
Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
Na
N
Zhang
Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Vanina
V
Toffessi-Tcheuyap
Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
Thong T
TT
Nguyen
Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
Kanika Bajaj
KB
Pahuja
Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
Ying-Jiun
YJ
Chen
Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Sadia
S
Saleem
Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
Subhra
S
Chaudhuri
Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
Sherry
S
Heldens
Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
Marlena
M
Jackson
Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Samuel
S
Peña-Llopis
Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
Joseph
J
Guillory
Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
Karen
K
Toy
Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
Connie
C
Ha
Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
Corissa J
CJ
Harris
Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Eboni
E
Holloman
Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Haley M
HM
Hill
Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
Jeremy
J
Stinson
Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
Celina Sanchez
CS
Rivers
Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
Vasantharajan
V
Janakiraman
Structural Biology Department, Genentech, Inc., South San Francisco, California, USA.
Weiru
W
Wang
Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Hughes Medical Institute, Chevy Chase, Maryland, USA.
Lisa N
LN
Kinch
Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Hughes Medical Institute, Chevy Chase, Maryland, USA.
Nick V
NV
Grishin
Bioinformatics and Computational Biology Department, Genentech, Inc., South San Francisco, California, USA.
Peter M
PM
Haverty
Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
Bernard
B
Chow
Bioinformatics and Computational Biology Department, Genentech, Inc., South San Francisco, California, USA.
Julian S
JS
Gehring
Bioinformatics and Computational Biology Department, Genentech, Inc., South San Francisco, California, USA.
Jens
J
Reeder
Bioinformatics and Computational Biology Department, Genentech, Inc., South San Francisco, California, USA.
Gregoire
G
Pau
Bioinformatics and Computational Biology Department, Genentech, Inc., South San Francisco, California, USA.
Thomas D
TD
Wu
Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Vitaly
V
Margulis
Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Yair
Y
Lotan
Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Arthur
A
Sagalowsky
Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Ivan
I
Pedrosa
Molecular Oncology Department, Genentech, Inc., South San Francisco, California, USA.
Frederic J
FJ
de Sauvage
Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
James
J
Brugarolas
Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
Somasekar
S
Seshagiri
D018249:Adenoma, Oxyphilic / Q000145:classification / Q000235:genetics / Q000473:pathology; D000595:Amino Acid Sequence; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000145:classification* / Q000235:genetics / Q000473:pathology; D004273:DNA, Neoplasm; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006801:Humans; D007680:Kidney Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D019859:Proto-Oncogene Proteins c-met / Q000737:chemistry / Q000235:genetics; D014178:Translocation, Genetic
C000595921:ACTG1-MITF fusion protein, human; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met