ATRX

Overview

ATRX is a SWI/SNF-family chromatin remodeler whose loss enables the alternative lengthening of telomeres (ALT) phenotype and is a defining alteration of IDH-mutant astrocytomas.

Alterations observed in the corpus

  • ATRX mutations observed in 77% of 1p19q intact IDH-mutant astrocytomas in the MSK-IMPACT subcohort (n=73) of a low-grade glioma active-surveillance study PMID:37910594.
  • Inactivating mutations (frameshift, nonsense, splice site) in 7% of sporadic ANGS vs only 2% of radiation-associated (RT) angiosarcoma (n=44 RT-AS, n=135 sporadic AS); ATRX alterations were depleted in RT-AS PMID:37350195.
  • ATRX mutations in 10% of soft-tissue LMS (STLMS) and 32% of uterine LMS (ULMS); prognostically significant in both risk models; co-occurrence with RB1 mutations (STLMS) or TP53 mutations (ULMS) defines high-risk classification (multi-institutional study, n=~450 LMS) PMID:38488807.
  • ATRX/DAXX mutations unique to treatment-refractory corticotroph pituitary neuroendocrine tumors (PitNETs), implicated in alternative lengthening of telomeres (ALT); found in aggressive/treatment-refractory cases not in benign PitNETs (n=23 refractory, n=69 benign) PMID:38758238.
  • Found recurrently mutated by exome sequencing of pancreatic neuroendocrine tumors (PanNET), with mutations in 17.6% of tumors PMID:21252315
  • Recurrently mutated in neuroblastoma (Broad WES/WGS, 240 tumors); ATRX mutations enriched in older patients and associated with alternative lengthening of telomeres (ALT) phenotype PMID:23334666
  • Single somatic mutation observed in ACC WES cohort (n=60); chromatin remodeler PMID:23685749
  • Mutations in 6% of GBM (TCGA); enriched in G-CIMP+ and TERT-promoter-wild-type tumors; consistent with ALT (alternative lengthening of telomeres) pathway; part of the near-obligate TERT/ATRX binary telomere-maintenance axis in primary GBM PMID:24120142
  • Recurrent loss-of-function in pancreatic neuroendocrine neoplasms (PanNENs); all DAXX/ATRX-mutant cases fell into transcriptome Cluster A in WGTA-guided therapy study PMID:24326773
  • Shared early-driver mutation in low-grade glioma showing convergent-evolution pattern similar to TP53; same ATRX mutation acquired independently in initial and recurrent tumors of patient 17, demonstrating branched clonal evolution under temozolomide treatment PMID:24336570
  • Genomic-stability mutation detected in prostate cancer cell lines derived from CRPC PMID:25201530
  • ATRX inactivating mutations identified in 7/56 WGS neuroblastoma cases, exclusively in tumors lacking MYCN amplification and TERT rearrangement; ATRX-mutant tumors show alternative lengthening of telomeres (ALT) as the third axis of telomere maintenance in high-risk neuroblastoma PMID:26466568
  • Mutated in n=220 diffuse gliomas (1,122-tumour TCGA pan-glioma cohort); mutations nearly mutually exclusive with TERT promoter mutations and associated with significantly longer telomeres (ALT phenotype); ALT-positive ATRX-mutant gliomas nominated as candidates for ATR-inhibitor sensitivity PMID:26824661
  • ATRX, as part of the SWI/SNF complex, mutated in 36% ATC vs 6% PDTC (P = 1×10⁻⁴) in a 341-gene targeted sequencing cohort (n=117 advanced thyroid tumors); first report of SWI/SNF disruption in advanced thyroid cancer PMID:26878173
  • ATRX mutated in 7% of unclassified renal cell carcinoma (uRCC) cases in a 62-patient MSK-IMPACT cohort PMID:27713405
  • ATRX T1747fs frameshift in neuroblastoma (NBL) — poor-prognosis marker identified in a pediatric pan-cancer sequencing cohort PMID:28007021
  • ATRX somatic mutations co-occurring with SDHB germline mutations in pheochromocytoma/paraganglioma (PCC/PGL); marker of aggressive disease, metastasis, and poor aggressive-disease-free survival (ADFS) PMID:28162975
  • C1531 mutation detected in 1/19 sequenced 1p/19q-codeleted anaplastic oligodendrogliomas; notable as ATRX loss is typically associated with 1p/19q-intact astrocytoma/GBM rather than oligodendroglioma PMID:28472509
  • Pan-sarcoma SMG; deletions/mutations in ~30% of DDLPS; loss associated with telomere lengthening in UPS/MFS (p=0.013); proposed as a correlative biomarker for CDK4 inhibitor trials in DDLPS PMID:29100075

Cancer types (linked)

  • ASTR / DIFG — canonical co-alteration in IDH-mutant 1p19q intact astrocytoma PMID:37910594.
  • ANGS — inactivating ATRX mutations depleted in RT-AS (2%) relative to sporadic AS (7%) in the MSK RT-sarcoma comparative genomic study PMID:37350195.
  • LMS — ATRX mutations present in 10% of STLMS and 32% of ULMS; high-risk co-occurrence with RB1 or TP53 mutations defines genomic risk stratification models PMID:38488807.
  • Pituitary neuroendocrine tumor (corticotroph subtype) — ATRX/DAXX mutations exclusively in treatment-refractory corticotroph PitNETs; linked to ALT mechanism PMID:38758238.

Co-occurrence and mutual exclusivity

Therapeutic relevance

  • Not directly therapeutically targeted in the corpus.

Open questions

  • None flagged in the corpus.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:21252315

This page was processed by crosslinker on 2026-05-14. - PMID:23334666

This page was processed by crosslinker on 2026-05-14. - PMID:23685749

This page was processed by crosslinker on 2026-05-14. - PMID:24120142

This page was processed by crosslinker on 2026-05-14. - PMID:24326773

This page was processed by crosslinker on 2026-05-14. - PMID:24336570

This page was processed by crosslinker on 2026-05-14. - PMID:25201530

This page was processed by crosslinker on 2026-05-14. - PMID:26466568

This page was processed by crosslinker on 2026-05-14. - PMID:26824661

This page was processed by entity-page-writer on 2026-05-15. - PMID:26878173

This page was processed by entity-page-writer on 2026-05-15. - PMID:28007021

This page was processed by entity-page-writer on 2026-05-15. - PMID:28162975

This page was processed by entity-page-writer on 2026-05-15. - PMID:28472509

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