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CHEK2 – CHEK2 and Acute Myeloid Leukemia

Inherited germline CHEK2 variants have been identified in adult acute myeloid leukemia (AML) cohorts but without clear enrichment or familial segregation. In a whole-exome study of 391 AML patients, pathogenic/likely pathogenic CHEK2 variants were found in 8 patients (PMID:34482403). A separate analysis of 47 unselected AML cases also reported 6 carriers of CHEK2 P/LP variants in the absence of clinical suspicion for hereditary syndromes (PMID:37450374). Conversely, constitutional CHEK2 mutations (including c.470T>C (p.Ile157Thr)) showed no significant association with de novo AML in 117 patients (p = 0.798) (PMID:29902706). No affected relatives with segregating CHEK2 variants have been reported in AML pedigrees.

Mechanistic data derive from non‐myeloid contexts and do not demonstrate AML‐specific functional impact. CHEK2’s role in DNA‐damage response is well established, but AML‐lineage models and rescue experiments are lacking. Taken together, the evidence for CHEK2 as an AML predisposition gene is conflicting and limited by small patient numbers, absence of segregation, and lack of AML‐focused functional validation. CHEK2 testing is not currently supported for routine AML risk assessment.

References

  • Blood • 2021 • Inherited predisposition to myeloid malignancies is more common than previously appreciated. PMID:34482403
  • Leukemia research • 2018 • Constitutional mutations of the CHEK2 gene are a risk factor for MDS, but not for de novo AML. PMID:29902706
  • Blood advances • 2023 • Germ line variants in patients with acute myeloid leukemia without a suspicion of hereditary hematologic malignancy syndrome. PMID:37450374

Evidence Based Scoring (AI generated)

Gene–Disease Association

Disputed

8 CHEK2 P/LP variants in 391 AML cases ([PMID:34482403]) and 6 in 47 unselected cases ([PMID:37450374]) versus no enrichment in 117 de novo AML patients (p = 0.798) ([PMID:29902706]); lack of familial segregation and AML‐specific functional data.

Genetic Evidence

Limited

Small numbers of germline CHEK2 P/LP variants in unselected AML cohorts without segregation or replication in larger familial studies.

Functional Evidence

Limited

Mechanistic roles of CHEK2 in DNA damage response are characterized, but no AML‐specific functional assays or model rescue experiments have been reported.