Germ line variants in patients with acute myeloid leukemia without a suspicion of hereditary hematologic malignancy syndrome.

Germline predisposition in acute myeloid leukemia (AML) has gained importance in recent years due to a non-negligible frequency and impact on management of patients and their relatives. Risk alleles for AML development may be present in patients without a clinical suspicion of hereditary hematologic malignancy syndrome. In this study we investigated the presence of germline variants (GV) in 288 genes related to cancer predisposition in 47 patients with available paired tumor-normal material, namely bone marrow stroma cells (BMSC, n=29), post-remission bone marrow (PRBM, n=17) and saliva (n=1). These patients correspond to two broad AML categories with heterogeneous genetic background (AML myelodysplasia-related and AML defined by differentiation) and none of them had phenotypic abnormalities, previous history of cytopenia nor strong cancer aggregation. We found 11 pathogenic or likely pathogenic variants, six affecting genes related to autosomal dominant cancer predisposition syndromes (ATM, DDX41 and CHEK2) and 5 related to autosomal recessive bone marrow failure syndromes (FANCA, FANCM, SBDS, DNAJC21 and CSF3R). We did not find differences in clinical characteristics nor outcome between GV carriers vs non-carriers. Further studies in unselected AML cohorts are needed to determine GV incidence and penetrance and, in particular, to clarify the role of ATM nonsense mutations in AML predisposition.