Germ line mutations associated with leukemias

Abstract

Several genetic syndromes have long been associated with a predisposition to the development of leukemia, including bone marrow failure syndromes, Down syndrome, and Li Fraumeni syndrome. Recent work has better defined the leukemia risk and outcomes in these syndromes. Also, in the last several years, a number of other germ line mutations have been discovered to define new leukemia predisposition syndromes, including ANKRD26, GATA2, PAX5, ETV6, and DDX41 In addition, data suggest that a substantial proportion of patients with therapy related leukemias harbor germ line mutations in DNA damage response genes such as BRCA1/2 and TP53 Recognition of clinical associations, acquisition of a thorough family history, and high index-of-suspicion are critical in the diagnosis of these leukemia predisposition syndromes. Accurate identification of patients with germ line mutations associated with leukemia can have important clinical implications as it relates to management of the leukemia, as well as genetic counseling of family members.

Figure 1.

Clinical features of GATA2 deficiency. Common manifestations are shown by organ system, with primary features in bold. Reprinted from Spinner et al. C difficile, Clostridium difficile; HSV, herpes simplex virus; NTM, nontuberculous mycobacteria.

Figure 2.

Distribution and frequency of reported germ line mutations in ETV6. The ETV6 protein is diagrammed with its pointed (SAM_PNT) and canonical ETS family DNA binding (Ets) domains. Germ line mutations associated with leukemia are clustered in the Ets domain, but spread throughout the protein.

Figure 3.

Distribution and frequency of germ line and acquired mutations in CEBPA. Reprinted from Tawana et al.