Inherited germline predisposition in hematological malignancy

Increased use of next-generation sequencing (NGS) in the evaluation of hematological malignancies has improved our understanding of disease ontogeny and uncovered potential novel mechanisms. This technique has allowed the identification of recurrently mutated genetic events with high variant allele frequencies, suggestive of germline involvement in putatively acquired disorders like acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Most dramatically, the identification of germline DDX41 mutations as a predisposition event in up to 6% of patients with MDS and select patients with AML presenting at standard age for these disorders has changed the paradigm for whom to consider for evaluation of inherited predisposition syndromes. Recognition of these states in individual patients with hematological malignancy and their families is critically important since related donors are often prioritized for curative strategies such as allogeneic bone marrow transplantation. Moreover, recognition of an inherited predisposition state in a family kindred has potential implications for cancer screening across their lifespans. A growing number of germline events are now recognized as inherited predispositions for hematological malignancy, many discovered over the past decade. This chapter focuses on inherited forms of myeloid malignancies, including MDS, AML, and the myeloproliferative neoplasms (MPN), with a specific focus on relevant germline mutations, including ANKRD26, CEBPA, DDX41, ETV6, GATA2, RUNX1, and SAMD9/9L. Also described are inherited bone marrow failure syndromes, Li-Fraumeni syndrome, Lynch syndrome, hereditary breast and ovarian cancer syndrome, other rare DNA damage and DNA repair deficiency syndromes, Down syndrome, and the Rasopathies, with guidelines for evaluation and testing.