ATM

Overview

ATM is a core DNA damage response kinase and one of the cardinal drivers of chronic lymphocytic leukemia.

Alterations observed in the corpus

  • Mutated in 11.2% of patients in the 1,148-patient CLL map, making it one of the top four cardinal CLL drivers alongside SF3B1, NOTCH1, and TP53 PMID:35927489.
  • Inactivating mutations (frameshift, nonsense, splice site) in 10% of sporadic ANGS vs only 2% of radiation-associated (RT) angiosarcoma (n=44 RT-AS, n=135 sporadic AS); ATM alterations were depleted in the RT-AS setting PMID:37350195.
  • ATM preferentially mutated in anaplastic thyroid carcinoma (ATC) and co-differentiated thyroid cancer (co-DTC) vs. paired PTC at both SNV and CNA levels in a multi-omic landscape study (n=87 specimens) PMID:38412093.
  • ATM, BRCA1, BRCA2, and CHEK2 — DDR pathway genes with driver genomic alterations predominantly in prostate adenocarcinoma PDXs vs. NEPC (44 PDXs from 38 patients) PMID:38488813.
  • ATM alterations were not independently associated with VTE risk in a 4,141-patient liquid biopsy VTE prediction study after multivariate adjustment PMID:39147831.
  • Germline ATM pathogenic alterations in 1.8% of all PDAC; enriched at 18% prevalence in MAPK-WT PDAC vs 1.4% in KRAS-mutant (P = 2 × 10⁻⁶); germline ATM and somatic TP53 alterations were mutually exclusive (P = 4 × 10⁻¹¹); GNAS co-occurrence elevated in gATM carriers in a 2,336-tumor PDAC genomic cohort PMID:39753968.
  • ATM alterations detected in 11 cases (5.5%) of a cfDNA study of metastatic urothelial carcinoma (mUC, n=200 patients, CALGB 90601); part of underpowered DDR pooled analysis PMID:40256659.
  • 14 mutations in 13 LUAD tumours (1 nonsense, 1 splice-site, 2 frameshift); first demonstration of significant ATM mutation frequency in LUAD; mutually exclusive with TP53 mutations (P=9.5e-5), suggesting either suffices for loss of cell-cycle checkpoint control. PMID:18948947
  • ATM screened as DDR candidate in FBXO7 synthetic lethality study; not prioritized as primary SL target PMID:36334560
  • ATM mutations associated with improved ICI survival in metastatic UC when combined with FANCC/RB1 alterations PMID:36333289
  • ATM oncogenic mutations in 5 GBC patients (OncoKB level 3B) PMID:36228155
  • Somatic mutations in 2 cases of TNBC; ranked 30th by driverNet network analysis in 65-tumor WGS breast cancer cohort PMID:22495314
  • Homozygous deletions identified as rare but potentially significant events in the METABRIC breast cancer cohort (2,000 tumors) PMID:22522925
  • Mutated in colorectal cancer WES study (Genentech, 74 tumors) as part of comprehensive genomic profiling PMID:22895193
  • Mutated in lung adenocarcinoma WES study (Broad, 183 tumors) PMID:22980975
  • Recurrently mutated in pancreatic cancer (ICGC WES, 142 tumors); ATM loss-of-function mutations identified among significantly mutated genes, implicating DNA-damage repair deficiency PMID:23103869
  • Recurrently mutated in CLL (Broad WES, 160 tumors); ATM mutations observed as part of the significantly mutated gene landscape in chronic lymphocytic leukemia PMID:23415222
  • Two missense mutations observed in ACC WES cohort (n=60); classified in the DNA-damage response pathway PMID:23685749
  • Missense p.R337C in the kinase domain in ACC (same residue recurrently mutated R337S/H/C in colorectal cancer and B-CLL, supporting oncogenicity) PMID:23778141
  • Inactivating mutation contributing to G2/M checkpoint pathway alteration in transitional cell carcinoma (TCC) of the bladder PMID:24121792
  • Truncating/functional-domain mutations in 12/29 (41%) WES mantle cell lymphoma (MCL) cases; 55% in SOX11-positive vs 0% SOX11-negative (P=0.023); often biallelic via 11q deletion; early/clonal event marking the SOX11-positive/IGHV-unmutated aggressive MCL subset PMID:24145436
  • Somatic mutation in 1/23 (4%) pancreatic acinar carcinomas; known familial pancreatic cancer susceptibility gene and candidate for PARP/DNA-PKcs inhibitor sensitivity PMID:24293293
  • Two expressed mutations (1 in PAX-fusion-positive, 1 in PAX-fusion-negative rhabdomyosarcoma) identified in a pediatric RMS genomic landscape study PMID:24436047
  • Significantly mutated in muscle-invasive bladder carcinoma (BLCA) identified by COSMIC restriction analysis; included in the 32 significantly mutated genes from TCGA bladder urothelial carcinoma cohort (n=131) PMID:24476821
  • Somatic mutation reported in the HCC molecular landscape (WES, n=1,289) as part of the non-actionable driver set PMID:24798001
  • Included in the standard multigene panel for hereditary gastric cancer risk (HBOC genes ATM, BRCA1, BRCA2, BRIP1, PALB2 must be ruled out before FNHGC labeling) PMID:24816255
  • Basally hyperphosphorylated in EWS::FLI1-expressing heMSCs but fails to further phosphorylate after etoposide; authors hypothesize EWS::FLI1-driven phosphatase activity (Ewing sarcoma cell-of-origin model) PMID:25186949
  • Candidate dark-matter driver in papillary thyroid carcinoma; among additional driver alterations helping reduce unexplained ‘dark matter’ cases to 3.5% in the TCGA PTC cohort of 402 tumors PMID:25417114
  • DNA double-strand-break and Fanconi-anaemia pathway lesion enriched in high-CNV PDA clusters; nominates olaparib (PARP inhibitor) and cross-linking agents (mitomycin-C) as therapeutic candidates PMID:25855536
  • Biallelic loss (somatic + germline) in mCRPC contributing to 19.3% DNA-repair pathway aggregate; patients with biallelic ATM showed clinical responses to PARP inhibition PMID:26000489
  • Referenced as the previously published SF3B1-Atm co-mutant CLL murine model; used as comparison context for the SF3B1/del(13q) double-mutant model demonstrating accelerated CLL development via mTOR pathway activation PMID:26200345
  • ATM shows high co-occurrence with del(11q) (OR 10.99) in 538 CLL WES cases; del(11q) typically precedes ATM sSNV/sINDEL second hits in biallelic inactivation; 9 instances of multiple distinct alleles per CLL indicate convergent evolution; ATM did not replicate as an independent PFS predictor in the CLL8 trial PMID:26466571
  • Nonsense mutation in 1 case and kinase-dead N2875 hotspot in 2 cases in primary prostate cancer; ATM loss-of-function contributes to the 19% DNA-repair-gene-defect prevalence that supports PARP-inhibitor candidacy PMID:26544944
  • ATM mutated in 7% PDTC and 9% ATC in a 341-gene targeted sequencing cohort (n=117 advanced thyroid tumors); ATM mutations associated with higher mutation burden in both PDTC (P = 0.04) and ATC (P = 7×10⁻³) PMID:26878173
  • Heterozygous inactivating ATM events (somatic or germline) included in the DNA-repair-defect classifier; men with mCRPC harboring such events had significantly longer time on carboplatin treatment (Kaplan-Meier log-rank P = 0.02, n=20 carboplatin-treated men) PMID:26928463
  • ATM: recurrent germline pathogenic/likely pathogenic variant in Indian familial NSCLC cohort enriched in young lung cancer PMID:27346245
  • ATM canonical driver mutations heterogeneously shared between primary and post-chemotherapy UC tumors; combined ATM/RB1/FANCC alteration signature present in 73.3% of pre-chemotherapy tumors vs 37.9% post-chemotherapy (p=0.05), suggesting selective elimination of these clones by cisplatin/gemcitabine PMID:27749842
  • ATM R189K + K2756* (missense + nonsense) germline variants in medulloblastoma (MBL) — returned as cancer-predisposition finding associated with increased risk for other cancers PMID:28007021
  • ATM kinase phosphorylates TRMT10A at Ser28 after ionizing radiation, enabling BRCA1 recruitment to DSBs; ATM knockdown reduces phospho-TRMT10A and HR but does not sensitize PCa lines to PARPi alone — consistent with clinical heterogeneity of ATM-loss PARPi response PMID:28068672
  • Less frequent DDR alteration in high-grade NMIBC, contributing to the 30% DDR-altered fraction; elevated mutational burden in DDR-altered tumors supports checkpoint immunotherapy trials PMID:28583311
  • ATM is a germline DDR gene contributing to the 27% combined HR-deficiency rate in prostate cancer; ATM also shows somatic enrichment specifically in mCRPC, identifying it as a clinically actionable target for PARP inhibitors PMID:28825054
  • Mutated in 14% (n=57) of MIBC tumors (TCGA, n=412); established as a recurrently mutated DNA-repair gene in muscle-invasive bladder cancer PMID:28988769
  • Four monoallelic pLoF ATM LP/PVs were identified in a pediatric cancer predisposition cohort (n=372); burden OR=3.2, p=0.040 in single-cohort analysis but not significant in joint analysis; carriers developed BCP-ALL, medulloblastoma, or hepatoblastoma without ataxia-telangiectasia features. PMID:29489754
  • ATM is an SMG uniquely called by MutSig2CV (not MuSiC2) in KIRC using the TCGA MC3 open-access MAF. PMID:29596782

Cancer types (linked)

  • CLL — ATM is a cardinal known driver recovered as significantly mutated across the integrated CLL cohort PMID:35927489.
  • ANGS — inactivating ATM mutations depleted in RT-AS (2%) relative to sporadic AS (10%) in the MSK RT-sarcoma comparative genomic study PMID:37350195.
  • THPA (anaplastic thyroid carcinoma) — ATM preferentially mutated in ATC and co-DTC at both SNV and CNA levels; recurrent DDR alteration rationalizing PARP inhibitor trials PMID:38412093.
  • PRAD — ATM driver alterations predominantly in prostate adenocarcinoma PDXs; NEPC shows transcriptomic DDR upregulation without equivalent genomic alterations PMID:38488813.
  • PAAD — Germline ATM enriched in MAPK-WT PDAC (18% vs 1.4% KRAS-mutant); mutually exclusive with somatic TP53; GNAS co-occurs in gATM carriers PMID:39753968.
  • BLCA — ATM alterations in 5.5% of mUC cfDNA; part of underpowered DDR analysis in platinum-based chemotherapy cohort PMID:40256659.

Co-occurrence and mutual exclusivity

  • Not specifically reported in the corpus for ATM partners PMID:35927489.

Therapeutic relevance

  • No ATM-directed therapy is reported in the corpus for CLL PMID:35927489.

Open questions

  • The CLL map does not resolve whether ATM mutation prognostic impact is preserved in the ibrutinib/venetoclax era PMID:35927489.

Sources

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This page was processed by crosslinker on 2026-05-14. - PMID:22895193

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This page was processed by crosslinker on 2026-05-14. - PMID:25417114

This page was processed by crosslinker on 2026-05-14. - PMID:25855536

This page was processed by crosslinker on 2026-05-14. - PMID:26000489

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This page was processed by entity-page-writer on 2026-05-15. - PMID:26466571

This page was processed by entity-page-writer on 2026-05-15. - PMID:26544944

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:26928463

This page was processed by entity-page-writer on 2026-05-15. - PMID:27346245

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This page was processed by entity-page-writer on 2026-05-15. - PMID:28068672

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This page was processed by entity-page-writer on 2026-05-15. - PMID:28825054

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