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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• The Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is crucial for cellular defense against oxidative stress.
• Aberrant activation of the Nrf2 pathway is a common event in human cancers, often driven by mutations in Nrf2 or its inhibitor KEAP1.

Purpose of the Study:

• To investigate alternative mechanisms of Nrf2 pathway activation in human tumors beyond canonical mutations.
• To identify and characterize novel Nrf2 alterations contributing to oncogenesis.

Main Methods:

• Utilized a gene expression signature to identify tumors with high Nrf2 pathway activity.
• Analyzed oncogene splice variants, focusing on the NFE2L2 gene (encoding Nrf2).
• Investigated the functional consequences of identified Nrf2 alterations, including protein interactions and pathway dependence.

Main Results:

• Identified tumors with high Nrf2 activity lacking known pathway mutations.
• Discovered abnormal NFE2L2 splice variants lacking critical exons (exon 2, or exons 2 and 3).
• These variants encode Nrf2 isoforms unable to interact with KEAP1, leading to Nrf2 stabilization and pathway activation, driven by heterozygous genomic microdeletions.

Conclusions:

• Established a novel mechanism for Nrf2 pathway activation in cancer via specific NFE2L2 splice variants.
• Demonstrated that these alterations result in functional Nrf2 pathway dependence in tumors.
• Highlighted the role of genomic microdeletions in generating these oncogenic splice variants.