CUL3 and NRF2 mutations confer an NRF2 activation phenotype in a sporadic form of papillary renal cell carcinoma

Aikseng Ooi; Karl Dykema; Asif Ansari; David Petillo; John Snider; Richard Kahnoski; John Anema; David Craig; John Carpten; Bin-Tean Teh; Kyle A Furge

doi:10.1158/0008-5472.CAN-12-3227

CUL3 and NRF2 mutations confer an NRF2 activation phenotype in a sporadic form of papillary renal cell carcinoma

Cancer Res. 2013 Apr 1;73(7):2044-51. doi: 10.1158/0008-5472.CAN-12-3227. Epub 2013 Jan 30.

Authors

Aikseng Ooi¹, Karl Dykema, Asif Ansari, David Petillo, John Snider, Richard Kahnoski, John Anema, David Craig, John Carpten, Bin-Tean Teh, Kyle A Furge

Affiliation

¹ Interdisciplinary Renal Oncology Laboratory, Van Andel Research Institute, Grand Rapids, MI 49503, USA. aikseng.ooi@vai.org

PMID: 23365135
DOI: 10.1158/0008-5472.CAN-12-3227

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism
Blotting, Western
Carcinoma, Renal Cell / genetics*
Carcinoma, Renal Cell / metabolism
Carcinoma, Renal Cell / pathology
Cells, Cultured
Cullin Proteins / genetics*
Cullin Proteins / metabolism
Gene Expression Profiling
High-Throughput Nucleotide Sequencing
Humans
Immunoenzyme Techniques
Intracellular Signaling Peptides and Proteins / metabolism
Kelch-Like ECH-Associated Protein 1
Kidney Neoplasms / genetics*
Kidney Neoplasms / metabolism
Kidney Neoplasms / pathology
Kidney Tubules, Proximal / cytology
Kidney Tubules, Proximal / metabolism
Molecular Sequence Data
Mutation / genetics*
NF-E2-Related Factor 2 / genetics*
NF-E2-Related Factor 2 / metabolism*
Oligonucleotide Array Sequence Analysis
Phenotype
Sequence Homology, Amino Acid
Sirtuin 1 / metabolism

Substances

Biomarkers, Tumor
CUL3 protein, human
Cullin Proteins
Intracellular Signaling Peptides and Proteins
KEAP1 protein, human
Kelch-Like ECH-Associated Protein 1
NF-E2-Related Factor 2
NFE2L2 protein, human
SIRT1 protein, human
Sirtuin 1