DUX4

Overview

DUX4 (Double Homeobox 4) encodes a transcription factor expressed during early embryogenesis; its aberrant reactivation is the molecular basis of facioscapulohumeral muscular dystrophy (FSHD). DUX4 resides in a tandem-repeat region at 10q26.3 alongside DUX4L paralogs, which complicates somatic copy-number calling. In the context of adenoid cystic carcinoma (ACC), a deletion spanning the DUX4/DUX4L locus at 10q26.3 was identified in 3/25 tumors, though the authors noted this finding requires orthogonal validation given the tandem-repeat genomic context.

Alterations observed in the corpus

  • Homozygous deletion at chromosomal region 10q26.3 spanning DUX4/DUX4L homeobox genes detected in 3/25 (12%) salivary-gland adenoid cystic carcinomas by whole-genome sequencing; deletion calls flagged as potentially artifactual due to the tandem-repeat genomic context and require orthogonal validation. PMID:26862087
  • IGH-DUX4 rearrangement is universal (100%) in the DUX4/ERG B-ALL subtype; C-terminal truncation alleles (e.g. E415, Q334) insert adjacent to the IGH enhancer; DUX4 directly binds the ERG exon 6 alt promoter region (two binding motifs in a 372 nt region) PMID:27776115

Cancer types (linked)

  • ACYC (adenoid cystic carcinoma): Homozygous 10q26.3 deletion spanning DUX4/DUX4L in 3/25 tumors (12%) in a whole-genome sequencing cohort of 25 fresh-frozen ACCs (acyc_jhu_2016). Authors note that DUX4/DUX4L tandem-repeat context requires caution in interpreting these calls. PMID:26862087

Co-occurrence and mutual exclusivity

  • The DUX4 deletion was observed alongside other copy-number variations; it was not correlated with specific fusion subtypes (MYB-NFIB status) or Notch pathway mutations in this small cohort. PMID:26862087

Therapeutic relevance

  • No therapeutic implication established. DUX4 deletion is a low-frequency event of uncertain biological significance in ACC. PMID:26862087

Open questions

  • Whether DUX4 deletion is a true somatic driver or a sequencing artifact in the tandem-repeat region (10q26.3) is unresolved; orthogonal validation (e.g., FISH or alternative sequencing strategies) is required. The functional role of DUX4 loss in ACC — if the deletion is validated — is entirely unexplored. PMID:26862087

Sources

  • PMID:26862087 — Rettig et al. (2016), whole-genome sequencing of 25 ACC tumors with matched normals (acyc_jhu_2016), somatic copy-number landscape of salivary-gland ACC.

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