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Rebecca Olin, MD, MS


Testing for Germline Mutations in Elderly Patients With AML

By: Lauren Harrison, MS
Posted: Friday, April 16, 2021

A group of researchers from France reported three cases of acute myeloid leukemia (AML) in patients older than age 60 for whom genetic testing was done, revealing various germline predispositions to developing the disease. Nicolas Duployez, PharmD, PhD, of the Université de Lille in France, and his colleagues published these findings in HemaSphere, a journal powered by the European Hematology Association.

“The cases reported here show that advanced age at AML diagnosis should not preclude a genetic predisposition,” concluded the authors.

Patients included in the study were referred to the university hospitals of Lille and Amiens-Picardie, France, and genetic analyses were performed on leukemic cells as part of the initial diagnostic screening. Genetic analyses were also performed on germline tissue from these patients and at least one of their relatives.

The first patient was a 74-year-old man whose leukemic cells had mutations in DNMT3A, IDH1, RUNX1, and SRSF2. Members of this patient’s family had previously been diagnosed with RUNX1-mutated familial platelet disorder with a propensity to AML. The RUNX1 gene plays a role in the expression of genes necessary for normal hematopoiesis. Those with a hereditary mutation classically have mild-to-moderate thrombocytopenia and a predisposition to developing hematologic malignancies. Of note, this patient’s leukemic progression did not involve a second hit to RUNX1 but rather a long period of DNMT3A-mutated clonal hematopoiesis.

The second patient was a 61-year-old man with mutations in BRAF, TET2, and ZRSR2. Family history was significant for polycythemia vera in one sister and chronic myeloid leukemia in another. All three of these siblings shared a germline mutation in the TET2 gene. This gene promotes DNA demethylation and is frequently mutated in myeloid and lymphoid malignancies.

The third patient was a 62-year-old man with notable mutations in ASXL1 and DDX41. The patient’s brother was also diagnosed with AML, and both brothers were found to have germline mutations in DDX41. DDX41 encodes an RNA helicase involved in RNA metabolism, and individuals with germline mutations tend to be at risk of developing myelodysplastic syndromes and AML.

Disclosure: The authors reported no conflicts of interest.

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