TY - JOUR
T1 - Spectrum of diverse genomic alterations define non-clear cell renal carcinoma subtypes
AU - Durinck, Steffen
AU - Stawiski, Eric W.
AU - Pavía-Jiménez, Andrea
AU - Modrusan, Zora
AU - Kapur, Payal
AU - Jaiswal, Bijay S.
AU - Zhang, Na
AU - Toffessi-Tcheuyap, Vanina
AU - Nguyen, Thong T.
AU - Pahuja, Kanika Bajaj
AU - Chen, Ying Jiun
AU - Saleem, Sadia
AU - Chaudhuri, Subhra
AU - Heldens, Sherry
AU - Jackson, Marlena
AU - Peña-Llopis, Samuel
AU - Guillory, Joseph
AU - Toy, Karen
AU - Ha, Connie
AU - Harris, Corissa J.
AU - Holloman, Eboni
AU - Hill, Haley M.
AU - Stinson, Jeremy
AU - Rivers, Celina Sanchez
AU - Janakiraman, Vasantharajan
AU - Wang, Weiru
AU - Kinch, Lisa N.
AU - Grishin, Nick V
AU - Haverty, Peter M.
AU - Chow, Bernard
AU - Gehring, Julian S.
AU - Reeder, Jens
AU - Pau, Gregoire
AU - Wu, Thomas D.
AU - Margulis, Vitaly
AU - Lotan, Yair
AU - Sagalowsky, Arthur I
AU - Pedrosa, Ivan
AU - De Sauvage, Frederic J.
AU - Brugarolas, James B
AU - Seshagiri, Somasekar
N1 - Publisher Copyright:
© 2015 Nature America, Inc. All rights reserved.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
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U2 - 10.1038/ng.3146
DO - 10.1038/ng.3146
M3 - Article
C2 - 25401301
AN - SCOPUS:85028129789
SN - 1061-4036
VL - 47
SP - 13
EP - 21
JO - Nature genetics
JF - Nature genetics
IS - 1
ER -