SETDB1

Overview

SETDB1 encodes a histone H3K9 methyltransferase involved in transcriptional repression. In the corpus, somatic loss-of-function mutations in SETDB1 are the defining molecular feature of genomic near-haploidization (GNH) in diffuse pleural mesothelioma (DPM), a newly recognized aggressive subset.

Alterations observed in the corpus

  • Somatic loss-of-function mutations in SETDB1 were identified in 8 of 10 GNH DPM cases; absent in non-GNH DPMs. SETDB1 inactivation in the context of genome-wide loss of heterozygosity may rescue expression of monoallelically expressed genes PMID:38630790.
  • SETDB1 mutations are highly specific for the GNH DPM subset and may serve as a molecular marker when detected on panels covering this gene (e.g., IMPACT505) PMID:38630790.
  • Chromatin-modifier mutation identified in MSK prostate cancer cell lines, consistent with Grasso 2012 CRPC findings of frequent epigenetic gene alterations in castration-resistant prostate cancer PMID:25201530
  • 1q21.1 SETDB1/MLLT11 co-amplification (P=0.0002) defines CN Cluster B in urothelial carcinoma, enriched for TP53 mutations (P=0.0001), in a cohort of 72 tumours from 32 patients undergoing WES pre/post platinum-based chemotherapy. PMID:27749842

Cancer types (linked)

  • PLMESO — loss-of-function mutations define the GNH subset (n=10); associated with poor OS (10.9 months) and possible ICB sensitivity PMID:38630790.

Co-occurrence and mutual exclusivity

  • SETDB1 mutations co-occur with early clonal TP53 mutations in GNH DPMs; NF2 alterations are frequent but confounded by biphasic histology enrichment in this subset PMID:38630790.

Therapeutic relevance

  • Among 3 GNH patients treated with ipilimumab/nivolumab or pembrolizumab, 2 achieved partial response (67%), vs. only 1/44 (2%) in non-GNH patients, suggesting SETDB1-mutant/GNH DPM may be ICB-sensitive PMID:38630790.

Open questions

  • Sample size of GNH cases is small (n=10 primary, n=4 validation); larger prospective cohorts are required to confirm ICB response rates and validate SETDB1 as a diagnostic biomarker PMID:38630790.

Sources

This page was processed by entity-page-writer on 2026-05-15. - PMID:25201530

This page was processed by entity-page-writer on 2026-05-15. - PMID:27749842

This page was processed by entity-page-writer on 2026-05-15.