Germline CHEK2 and ATM Variants in Myeloid and Other Hematopoietic Malignancies

AbstractPurpose of ReviewAn intact DNA damage response is crucial to preventing cancer development, including in myeloid and lymphoid malignancies. Deficiencies in the homologous recombination (HR) pathway can lead to defective DNA damage responses, and this can occur through inherited germline mutations in HR pathway genes, such asCHEK2 andATM. We now understand that germline mutations can be identified frequently (~  5–10%) in patients with myeloid and lymphoid malignancies, and among the most common of these areCHEK2 andATM. We review the role that deleterious germlineCHEK2 andATM variants play in the development of hematopoietic malignancies, and how this influences clinical practice, including cancer screening, hematopoietic stem cell transplantation, and therapy choice.Recent FindingsIn recent large cohorts of patients diagnosed with myeloid or lymphoid malignancies, deleterious germline loss of function variants inCHEK2 andATM are among the most common identified. GermlineCHEK2 variants predispose to a range of myeloid malignancies, most prominently myeloproliferative neoplasms and myelodysplastic syndromes (odds ratio range: 2.1 –12.3), and chronic lymphocytic leukemia (odds ratio 14.83). Deleterious germlineATM variants have been shown to predispose to chronic lymphocytic leukemia (odds ratio range: 1.7 –10.1), although additional studies are needed to demonstrate the risk they confer for myeloid malignancies. Early studies suggest there may also be associati...
Source: Current Hematologic Malignancy Reports - Category: Hematology Source Type: research