ETS2
Overview
ETS2 is a member of the ETS family of transcription factors, characterized by a conserved ETS DNA-binding domain. Unlike its oncogenic ETS family relatives (ERG, ETV1, ETV5), ETS2 functions as a tumor suppressor in prostate cancer. It is frequently deleted through the genomic rearrangements that create TMPRSS2:ERG fusions, and point mutations in its ETS domain impair its suppressive activity. ETS2 loss may be a critical co-event enabling ETS fusion-driven prostate cancer progression.
Alterations observed in the corpus
- ETS2 identified as a potential tumor suppressor in prostate cancer WES cohort (Michigan, 112 tumors); deleted in approximately 1/3 of castration-resistant prostate cancers (CRPCs) through TMPRSS2:ERG fusion-associated genomic rearrangements; R437C point mutation in the ETS domain promotes cancer cell migration and invasion PMID:22722839
Cancer types (linked)
- PRAD: ETS2 deletion occurs in ~1/3 of CRPCs, co-incident with TMPRSS2:ERG fusions. The R437C ETS-domain mutation has functional consequence (promotes migration/invasion). Loss of ETS2 tumor suppressor activity may cooperate with oncogenic ETS fusions in driving castration-resistant disease PMID:22722839
Co-occurrence and mutual exclusivity
- ETS2 deletion co-occurs with TMPRSS2:ERG fusions in prostate cancer; the genomic rearrangement creating the fusion simultaneously deletes ETS2, suggesting a dual oncogenic hit PMID:22722839
Therapeutic relevance
- ETS2 tumor suppressor loss in CRPC may define a subset of patients with convergent ETS pathway dysregulation (oncogenic ERG gain + ETS2 loss); therapeutic strategies targeting ETS transcriptional output may be relevant PMID:22722839
Open questions
- Functional validation of ETS2 as tumor suppressor was performed for R437C mutation and deletion; other ETS2 alterations await characterization PMID:22722839
- Frequency of ETS2 deletion in localized (non-CRPC) prostate cancer is not well-established from this cohort
Sources
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