An 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 as CHEK2 and ATM. 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 are CHEK2 and ATM. We review the role that deleterious germline CHEK2 and ATM 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 FINDINGS: In recent large cohorts of patients diagnosed with myeloid or lymphoid
malignancies, deleterious germline loss of function variants in CHEK2 and ATM are among the most common identified. Germline CHEK2 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 germline ATM 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 associations between deleterious germline CHEK2 and ATM variants and development of clonal hematopoiesis. Identifying CHEK2 and ATM variants is crucial for the optimal management of patients and families affected by
hematopoietic malignancies. OPENING CLINICAL CASE: "A 45 year-old woman presents to your clinic with a history of
triple-negative breast cancer diagnosed five years ago, treated with surgery, radiation, and
chemotherapy. About six months ago, she developed cervical
lymphadenopathy, and a biopsy demonstrated small
lymphocytic leukemia. Peripheral blood shows a small population of lymphocytes with a
chronic lymphocytic leukemia immunophenotype, and FISH demonstrates a complex karyotype: gain of one to two copies of IGH and FGFR3; gain of two copies of CDKN2C at 1p32.3; gain of two copies of CKS1B at 1q21;
tetrasomy for chromosome 3;
trisomy and
tetrasomy for chromosome 7;
tetrasomy for chromosome 9;
tetrasomy for chromosome 12; gain of one to two copies of ATM at 11q22.3; deletion of chromosome 13 deletion positive; gain of one to two copies of TP53 at 17p13.1). Given her history of two
cancers, you arrange for germline genetic testing using
DNA from cultured skin fibroblasts, which demonstrates pathogenic variants in ATM [c.1898 + 2 T > G] and CHEK2 [p.T367Metfs]. Her family history is significant for multiple
cancers. (Fig. 1)." Fig. 1 Representative pedigree from a patient with germline pathogenic ATM and CHEK2 variants who was affected by early onset
breast cancer and
chronic lymphocytic leukemia. Arrow indicates proband. Colors indicate
cancer type/disease: purple,
breast cancer; blue,
lymphoma; brown,
melanoma; yellow,
colon cancer; and green,
autoimmune disease.