Recurrent Loss of NFE2L2 Exon 2 Is a Mechanism for Nrf2 Pathway Activation in Human Cancers

An, 2015, Truncated ERG oncoproteins from TMPRSS2-ERG fusions are resistant to SPOP-mediated proteasome degradation, Mol. Cell, 59, 904, 10.1016/j.molcel.2015.07.025 Anders, 2010, Differential expression analysis for sequence count data, Genome Biol., 11, R106, 10.1186/gb-2010-11-10-r106 Baba, 2013, Seven in absentia homolog 2 (Siah2) protein is a regulator of NF-E2-related factor 2 (Nrf2), J. Biol. Chem., 288, 18393, 10.1074/jbc.M112.438762 2012, Comprehensive genomic characterization of squamous cell lung cancers, Nature, 489, 519, 10.1038/nature11404 2014, Comprehensive molecular profiling of lung adenocarcinoma, Nature, 511, 543, 10.1038/nature13385 Cerami, 2012, The cBio Cancer Genomics Portal: an open platform for exploring multidimensional cancer genomics data, Cancer Discov., 2, 401, 10.1158/2159-8290.CD-12-0095 Cho, 2011, Glioblastoma-derived epidermal growth factor receptor carboxyl-terminal deletion mutants are transforming and are sensitive to EGFR-directed therapies, Cancer Res., 71, 7587, 10.1158/0008-5472.CAN-11-0821 Chorley, 2012, Identification of novel NRF2-regulated genes by ChIP-seq: influence on retinoid X receptor alpha, Nucleic Acids Res., 40, 7416, 10.1093/nar/gks409 Chowdhry, 2013, Nrf2 is controlled by two distinct β-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity, Oncogene, 32, 3765, 10.1038/onc.2012.388 DeNicola, 2015, NRF2 regulates serine biosynthesis in non-small cell lung cancer, Nat. Genet., 47, 1475, 10.1038/ng.3421 Frampton, 2013, Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing, Nat. Biotechnol., 31, 1023, 10.1038/nbt.2696 Fukutomi, 2014, Kinetic, thermodynamic, and structural characterizations of the association between Nrf2-DLGex degron and Keap1, Mol. Cell. Biol., 34, 832, 10.1128/MCB.01191-13 Gao, 2013, Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal, Sci. Signal., 6, pl1, 10.1126/scisignal.2004088 George, 2015, Comprehensive genomic profiles of small cell lung cancer, Nature, 524, 47, 10.1038/nature14664 Goldstein, 2016, Prediction and Quantification of Splice Events from RNA-Seq Data, PLoS ONE, 11, e0156132, 10.1371/journal.pone.0156132 2015, Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans, Science, 348, 648, 10.1126/science.1262110 Hart, 1999, The F-box protein beta-TrCP associates with phosphorylated beta-catenin and regulates its activity in the cell, Curr. Biol., 9, 207, 10.1016/S0960-9822(99)80091-8 Hirotsu, 2012, Nrf2-MafG heterodimers contribute globally to antioxidant and metabolic networks, Nucleic Acids Res., 40, 10228, 10.1093/nar/gks827 Imielinski, 2012, Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing, Cell, 150, 1107, 10.1016/j.cell.2012.08.029 Itoh, 1999, Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain, Genes Dev., 13, 76, 10.1101/gad.13.1.76 Iwao, 1998, Activation of the beta-catenin gene by interstitial deletions involving exon 3 in primary colorectal carcinomas without adenomatous polyposis coli mutations, Cancer Res., 58, 1021 Kataoka, 2015, Integrated molecular analysis of adult T cell leukemia/lymphoma, Nat. Genet., 47, 1304, 10.1038/ng.3415 Katoh, 2001, Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription, Genes Cells, 6, 857, 10.1046/j.1365-2443.2001.00469.x Klijn, 2015, A comprehensive transcriptional portrait of human cancer cell lines, Nat. Biotechnol., 33, 306, 10.1038/nbt.3080 Kong-Beltran, 2006, Somatic mutations lead to an oncogenic deletion of met in lung cancer, Cancer Res., 66, 283, 10.1158/0008-5472.CAN-05-2749 Law, 2014, voom: Precision weights unlock linear model analysis tools for RNA-seq read counts, Genome Biol., 15, R29, 10.1186/gb-2014-15-2-r29 Leinonen, 2014, Role of the Keap1-Nrf2 pathway in cancer, Adv. Cancer Res., 122, 281, 10.1016/B978-0-12-420117-0.00008-6 MacLeod, 2009, Characterization of the cancer chemopreventive NRF2-dependent gene battery in human keratinocytes: demonstration that the KEAP1-NRF2 pathway, and not the BACH1-NRF2 pathway, controls cytoprotection against electrophiles as well as redox-cycling compounds, Carcinogenesis, 30, 1571, 10.1093/carcin/bgp176 Malhotra, 2010, Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-seq profiling and network analysis, Nucleic Acids Res., 38, 5718, 10.1093/nar/gkq212 McMahon, 2006, Dimerization of substrate adaptors can facilitate cullin-mediated ubiquitylation of proteins by a “tethering” mechanism: a two-site interaction model for the Nrf2-Keap1 complex, J. Biol. Chem., 281, 24756, 10.1074/jbc.M601119200 Pruitt, 2005, NCBI Reference Sequence (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins, Nucleic Acids Res., 33, D501, 10.1093/nar/gki025 Riccardi, 2006, Analysis of apoptosis by propidium iodide staining and flow cytometry, Nat. Protoc., 1, 1458, 10.1038/nprot.2006.238 Rosenbloom, 2015, The UCSC Genome Browser database: 2015 update, Nucleic Acids Res., 43, D670, 10.1093/nar/gku1177 Sekine, 2015, The mediator subunit MED16 transduces NRF2-activating signals into antioxidant gene expression, Mol. Cell. Biol., 36, 407, 10.1128/MCB.00785-15 Shibata, 2008, Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy, Proc. Natl. Acad. Sci. USA, 105, 13568, 10.1073/pnas.0806268105 Tong, 2006, Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two-site molecular recognition model, Mol. Cell. Biol., 26, 2887, 10.1128/MCB.26.8.2887-2900.2006 Tong, 2006, Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism, Biol. Chem., 387, 1311, 10.1515/BC.2006.164 Vitari, 2011, COP1 is a tumour suppressor that causes degradation of ETS transcription factors, Nature, 474, 403, 10.1038/nature10005 Vogelstein, 2013, Cancer genome landscapes, Science, 339, 1546, 10.1126/science.1235122 Wu, 2010, Fast and SNP-tolerant detection of complex variants and splicing in short reads, Bioinformatics, 26, 873, 10.1093/bioinformatics/btq057 Zhang, 2006, BRG1 interacts with Nrf2 to selectively mediate HO-1 induction in response to oxidative stress, Mol. Cell. Biol., 26, 7942, 10.1128/MCB.00700-06