CHEK2

Overview

CHEK2 encodes checkpoint kinase 2 (CHK2), a serine/threonine kinase activated by ATM in response to DNA double-strand breaks. CHEK2 phosphorylates multiple substrates including BRCA1, BRCA2, and CDC25C to enforce cell cycle arrest and promote DNA repair or apoptosis. Germline CHEK2 variants are moderate-penetrance cancer predisposition alleles associated with elevated risk of breast, prostate, and other cancers. In the context of the DNA damage response (DDR) pathway in prostate cancer, CHEK2 is one of several genes whose alteration characterizes adenocarcinoma models.

Alterations observed in the corpus

  • DDR pathway genes including CHEK2 harbored driver genomic alterations predominantly in prostate adenocarcinoma (PRAD) patient-derived xenograft (PDX) models, while neuroendocrine prostate cancer (NEPC) showed DDR upregulation at the transcriptomic level without driver genomic alterations PMID:38488813.
  • In MSK-CHORD (24,950 patients), CHEK2 and PPM1D clonal-haematopoiesis variants were enriched in patients who had received prior systemic therapy, as annotated by NLP of clinical records; CHEK2 was identified as a post-treatment alteration across cancer types PMID:39506116.
  • In 2,336 PDAC patients (pdac_msk_2024), CHEK2 germline pathogenic variants were reported at higher prevalence in patients with Ashkenazi Jewish ancestry PMID:39753968.
  • CHEK2 identified as a secondary synthetic lethal candidate in DDR screen in FBXO7-deficient CRC cells (checkpoint signaling pathway) PMID:36334560
  • Identified as pharmacogenomically relevant in NCI-60 cell line panel; CHEK2 alteration status correlates with drug sensitivity profiles in CellMiner analysis PMID:22802077
  • Mutated in neuroblastoma (Broad WES/WGS, 240 tumors); CHEK2 mutations identified among recurrently mutated DNA-damage checkpoint genes, implicating checkpoint deficiency in neuroblastoma pathogenesis PMID:23334666
  • Co-deleted with TP53 in one prostate carcinoma chromoplexy chain; disrupted by structural rearrangement PMID:23622249
  • Missense somatic mutations in 1 patient each with PV, ET, and MF (q=0.008 by MutSigCV); not previously reported in MPN at time of publication PMID:24325359
  • Genomic-stability mutation detected in prostate cancer cell lines derived from CRPC PMID:25201530
  • Significantly mutated gene (SMG) in papillary thyroid carcinoma (q<0.1); DNA-repair-related SMG co-occurring with MAPK pathway drivers; CHEK2 mutations associated with 22q loss (p=0.0035) in the SCNA-22q-del subtype PMID:25417114
  • Harbors at least one identical previously COSMIC-reported mutation in HNSCC (279-tumor TCGA cohort) PMID:25631445
  • DNA double-strand-break and Fanconi-anaemia pathway lesion enriched in high-CNV PDAC clusters; nominates PARP inhibitor and cross-linking agent therapy PMID:25855536
  • CHEK2 identified as a DNA damage pathway driver in CLL in a 538-sample WES study, alongside BRCC3, ELF4, and DYRK1A PMID:26466571
  • CHEK2 pathogenic germline mutations found in 2.22% of the METABRIC 2,433-tumor breast cancer cohort; confirmed as a DNA damage & apoptosis Mut-driver TSG in ER+ breast cancer via homozygous deletion + inactivating mutation evidence PMID:27161491.
  • CHEK2: recurrent germline pathogenic/likely pathogenic variant in Indian familial NSCLC cohort enriched in young lung cancer PMID:27346245
  • Recurrently mutated in 3% of unclassified renal cell carcinoma (uRCC) cases in a 62-case MSKCC MSK-IMPACT cohort; listed among additional recurrent mutations beyond the dominant NF2/SETD2/FH/mTORC1 subsets PMID:27713405
  • Less-frequent DNA damage repair (DDR) gene alteration contributing to the 30% DDR-altered fraction in high-grade BLCA NMIBC tumors (n=82); DDR alterations associated with significantly higher mutational burden vs DDR-intact (median 26 vs 8 mut/Mb, p < 0.001) PMID:28583311
  • Germline pathogenic/predicted-pathogenic mutation (PPGM) enriched in the MET500 metastatic pan-cancer cohort relative to ExAC controls; identified as a DNA-repair PPGM gene alongside BRCA1, BRCA2, and MLH1 PMID:28783718.
  • Germline DDR alteration contributing to the 27% combined HR-deficiency rate in prostate cancer across disease states (locoregional to mCRPC); identified alongside BRCA1 and ATM as drivers of PARP-inhibitor therapeutic rationale PMID:28825054.
  • CHEK2 germline LP/PVs identified in 5 of 28 LP/PV carriers (17.9%) in a pediatric cancer predisposition cohort; burden OR=9.6, p=2.42×10⁻⁴; 4 carriers had BCP-ALL and 1 had Langerhans-cell histiocytosis (with co-occurring NF1 LP/PV); 3 of 5 were pLoF; CHEK2 is among the candidate HBOC genes assessed by WES PMID:29489754.

Cancer types (linked)

  • PRAD/PRNE: CHEK2 driver alterations in the DDR pathway are enriched in adenocarcinoma PDX models; NEPC shows DDR transcriptomic upregulation instead of genomic alterations, suggesting distinct DDR biology between these prostate cancer subtypes PMID:38488813.
  • Pan-cancer (MSK-CHORD): CHEK2 clonal-haematopoiesis variants enriched after prior systemic therapy; represents a therapy-driven rather than tumor-intrinsic alteration context PMID:39506116.
  • PAAD: CHEK2 germline pathogenic variants enriched in patients with Ashkenazi Jewish ancestry in the 2,336-patient PDAC MSK-IMPACT cohort PMID:39753968.

Co-occurrence and mutual exclusivity

  • CHEK2 alterations co-occur in the DDR pathway with ATM, BRCA1, BRCA2, and CDK12 alterations in prostate adenocarcinoma PDXs; this cluster of DDR gene alterations is largely absent in NEPC models PMID:38488813.

Therapeutic relevance

  • DDR gene alterations including CHEK2 in prostate adenocarcinoma provide a rationale for PARP inhibitor therapy (e.g., olaparib, rucaparib, niraparib), consistent with FDA-approved indications for BRCA1/2-mutant and HRD-positive CRPC PMID:38488813.

Open questions

  • The specific frequency of CHEK2 alterations among DDR genes in the MDA PCa PDX series was not individually quantified; the aggregate DDR rate was stated as enriched in adenocarcinoma PDXs.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:26466571

This page was processed by crosslinker on 2026-05-14. - PMID:27161491

This page was processed by wiki-cli on 2026-05-14. - PMID:27346245

This page was processed by wiki-cli on 2026-05-14. - PMID:27713405

This page was processed by entity-page-writer on 2026-05-15. - PMID:28583311

This page was processed by entity-page-writer on 2026-05-15. - PMID:28783718

This page was processed by wiki-cli on 2026-05-15. - PMID:28825054

This page was processed by wiki-cli on 2026-05-15. - PMID:29489754

This page was processed by wiki-cli on 2026-05-15.