ZFHX3

Overview

ZFHX3 (Zinc Finger Homeobox 3, also known as ATBF1) is a large transcription factor containing multiple AT-motif binding domains and zinc finger motifs. ZFHX3 has been implicated as a tumor suppressor in prostate cancer, where recurrent mutations suggest loss-of-function contributes to CRPC progression. It is one of nine significantly mutated genes identified in lethal prostate cancer exome sequencing, indicating a driver role in advanced disease.

Alterations observed in the corpus

  • ZFHX3 identified as one of nine significantly mutated genes (FDR ≤ 0.10) in prostate cancer WES of 112 tumors (Michigan cohort, including 50 lethal CRPCs); mutations present in castration-resistant disease PMID:22722839
  • ZFHX3 mutated in 7/402 (1.7%, q=0.79) PTCs; near-significant putative tumor suppressor in PTC; does not meet the q<0.1 threshold for SMG designation but represents a candidate dark-matter driver. PMID:25417114

Cancer types (linked)

  • Prostate adenocarcinoma (PRAD): Significantly mutated in castration-resistant prostate cancer (CRPC); ranked among the top recurrently altered genes alongside TP53, AR, RB1, PTEN, APC, KMT2D, and CDK12 PMID:22722839

Co-occurrence and mutual exclusivity

  • Co-occurs with other significantly mutated genes in CRPC including TP53 and AR mutations; no specific exclusivity patterns reported in the corpus.

Therapeutic relevance

  • No direct targeted therapies identified for ZFHX3-mutant prostate cancer in the corpus. Given its role alongside chromatin modifiers in CRPC, pathway context may offer indirect therapeutic opportunities.

Open questions

  • The precise tumor suppressor mechanism of ZFHX3 in prostate cancer (transcriptional targets, interaction with AR signaling) is not characterized in the corpus.
  • Whether ZFHX3 mutations are more prevalent in CRPC vs. localized prostate cancer requires direct comparison in larger cohorts.

Sources

  • PMID:22722839 — Prostate cancer WES, 112 tumors, Michigan cohort

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