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

被引：156

作者：

Goldstein, Leonard D. ^{[1
,3
]}

Lee, James ^{[2
]}

Gnad, Florian ^{[3
]}

Klijn, Christiaan ^{[3
]}

Schaub, Annalisa ^{[2
,7
]}

Reeder, Jens ^{[3
]}

Daemen, Anneleen ^{[3
]}

Bakalarski, Corey E. ^{[3
,4
]}

Holcomb, Thomas ^{[5
]}

Shames, David S. ^{[5
]}

Hartmaier, Ryan J. ^{[6
]}

Chmielecki, Juliann ^{[6
]}

Seshagiri, Somasekar ^{[1
]}

Gentleman, Robert ^{[3
,8
]}

Stokoe, David ^{[2
]}

机构：

[1] Genentech Inc, Dept Mol Biol, San Francisco, CA 94080 USA

[2] Genentech Inc, Dept Discovery Oncol, San Francisco, CA 94080 USA

[3] Genentech Inc, Dept Bioinformat & Computat Biol, San Francisco, CA 94080 USA

[4] Genentech Inc, Dept Prot Chem, San Francisco, CA 94080 USA

[5] Genentech Inc, Dept Oncol Biomarker Dev, San Francisco, CA 94080 USA

[6] Fdn Med Inc, Cambridge, MA 02141 USA

[7] Helmholtz Ctr Munich, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany

[8] 23AndMe Inc, Mountain View, CA 94041 USA

来源：

CELL REPORTS | 2016年 / 16卷 / 10期

关键词：

KEAP1-NRF2; PATHWAY; BETA-CATENIN; RECOGNITION; BINDING; PROTEIN; MODEL; ANTIOXIDANT; MUTATIONS; PROFILES; GENOMICS;

D O I：

10.1016/j.celrep.2016.08.010

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：2605 / 2617

页数：13

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