title: Recurrent Loss of NFE2L2 Exon 2 Is a Mechanism for Nrf2 Pathway Activation in Human Cancers.
abstract: The Nrf2 pathway is frequently activated in human cancers through mutations in Nrf2 or its negative regulator KEAP1. Using a cell-line-derived gene signature for Nrf2 pathway activation, we found that some tumors show high Nrf2 activity in the absence of known mutations in the pathway. An analysis of splice variants in oncogenes revealed that such tumors express abnormal transcript variants from the NFE2L2 gene (encoding Nrf2) that lack exon 2, or exons 2 and 3, and encode Nrf2 protein isoforms missing the KEAP1 interaction domain. The Nrf2 alterations result in the loss of interaction with KEAP1, Nrf2 stabilization, induction of a Nrf2 transcriptional response, and Nrf2 pathway dependence. In all analyzed cases, transcript variants were the result of heterozygous genomic microdeletions. Thus, we identify an alternative mechanism for Nrf2 pathway activation in human tumors and elucidate its functional consequences.
authors: Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080, USA; Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Leonard D
authors: LD
authors: Goldstein
authors: Department of Discovery Oncology, Genentech Inc., South San Francisco, CA 94080, USA.
authors: James
authors: J
authors: Lee
authors: Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Florian
authors: F
authors: Gnad
authors: Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Christiaan
authors: C
authors: Klijn
authors: Department of Discovery Oncology, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Annalisa
authors: A
authors: Schaub
authors: Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Jens
authors: J
authors: Reeder
authors: Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Anneleen
authors: A
authors: Daemen
authors: Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, CA 94080, USA; Department of Protein Chemistry, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Corey E
authors: CE
authors: Bakalarski
authors: Department of Oncology Biomarker Development, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Thomas
authors: T
authors: Holcomb
authors: Department of Oncology Biomarker Development, Genentech Inc., South San Francisco, CA 94080, USA.
authors: David S
authors: DS
authors: Shames
authors: Foundation Medicine Inc., Cambridge, MA 02141, USA.
authors: Ryan J
authors: RJ
authors: Hartmaier
authors: Foundation Medicine Inc., Cambridge, MA 02141, USA.
authors: Juliann
authors: J
authors: Chmielecki
authors: Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Somasekar
authors: S
authors: Seshagiri
authors: Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Robert
authors: R
authors: Gentleman
authors: Department of Discovery Oncology, Genentech Inc., South San Francisco, CA 94080, USA. Electronic address: stokoe.david@gene.com.
authors: David
authors: D
authors: Stokoe
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D005091:Exons / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D017384:Sequence Deletion / Q000235:genetics; D015398:Signal Transduction
chemical_list: C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger