TY - JOUR
T1 - CUL3 and NRF2 mutations confer an NRF2 activation phenotype in a sporadic form of papillary renal cell carcinoma
AU - Ooi, Aikseng
AU - Dykema, Karl
AU - Ansari, Asif
AU - Petillo, David
AU - Snider, John
AU - Kahnoski, Richard
AU - Anema, John
AU - Craig, David
AU - Carpten, John
AU - Teh, Bin Tean
AU - Furge, Kyle A.
N1 - Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.
PY - 2013/4/1
Y1 - 2013/4/1
N2 - Sustained activation of the stress-regulated transcription factor NRF2 (NFE2L2) is a prominent feature of many types of cancer, implying that mutations driving NRF2 may be important to tumor progression. In hereditary type 2 papillary renal cell carcinoma (PRCC2, also known as hereditary leiomyomatosis and renal cell cancer), NRF2 activation is a direct consequence of the accumulation of intracellular fumarate, a result of fumarate hydratase (FH) inactivation, but it is not clear how NRF2 may be activated in sporadic forms of PRCC2. Here we show that somatic mutations in NRF2, CUL3, and SIRT1 are responsible for driving the NRF2 activation phenotype in sporadic PRCC2. Transcriptome sequencing revealed the expression pattern of mutant alleles of NRF2, CUL3, and SIRT1 and also confirmed NRF2 activation in clinical specimens. Our results show a convergence in somatic mutations in sporadic PRCC2 with FH mutation in hereditary PRCC2.
AB - Sustained activation of the stress-regulated transcription factor NRF2 (NFE2L2) is a prominent feature of many types of cancer, implying that mutations driving NRF2 may be important to tumor progression. In hereditary type 2 papillary renal cell carcinoma (PRCC2, also known as hereditary leiomyomatosis and renal cell cancer), NRF2 activation is a direct consequence of the accumulation of intracellular fumarate, a result of fumarate hydratase (FH) inactivation, but it is not clear how NRF2 may be activated in sporadic forms of PRCC2. Here we show that somatic mutations in NRF2, CUL3, and SIRT1 are responsible for driving the NRF2 activation phenotype in sporadic PRCC2. Transcriptome sequencing revealed the expression pattern of mutant alleles of NRF2, CUL3, and SIRT1 and also confirmed NRF2 activation in clinical specimens. Our results show a convergence in somatic mutations in sporadic PRCC2 with FH mutation in hereditary PRCC2.
UR - http://www.scopus.com/inward/record.url?scp=84876005313&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84876005313&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-12-3227
DO - 10.1158/0008-5472.CAN-12-3227
M3 - Article
C2 - 23365135
AN - SCOPUS:84876005313
VL - 73
SP - 2044
EP - 2051
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 7
ER -