Somatic Genetic and Epigenetic Architecture of Myelodysplastic Syndromes Arising from GATA2 Deficiency

The emergence of GATA2 deficiency as a germline predisposition to myeloid malignancies raises questions about the nature of acquired secondary genetic and epigenetic events facilitating leukemogenesis. Previously, mutations in ASXL1 were implicated as a possible somatic driver in single cases of GATA2-related MDS. However the landscape of secondary changes had not yet been systematically examined in larger MDS cohorts, and accounting for confounding factors. In this study, we used next-generation genomic platforms to investigate targeted mutational landscape and global epigenetic profiles in patients with GATA2 deficiency. In a large cohort of consecutively diagnosed children with MDS we had initially established that GATA2 deficiency accounts for 7% of primary MDS cases. Exploring the known association between GATA2 mutated (GATA2mut) cases and monosomy 7 (-7), the prevalence of GATA2 deficiency was very high in patients with -7 (37%), reaching its peak in adolescence (>70%). We next tested 60 GATA2-deficient patients with MDS for the presence of secondary mutations using targeted NGS for genes involved in myeloid malignancies. Somatic status was confirmed by matched analysis of fibroblasts, hair follicles or T-cells. Single hematopoietic CFU colonies were sequenced to identify subclonal patterns. For comparison, a GATA2 wildtype (GATA2-WT) cohort of 422 children and adolescents with MDS enrolled in the studies of the European Working Group of Childhood MDS were analyzed by targeted NGS. Somatic mutations were detected in 45% (27/60) of GATA2mut as compared to 19% (82/422) GATA2-WT MDS cases (p In summary, somatic SETBP1 and STAG2 mutations are associated with MDS arising from GATA2 deficiency. The remaining targeted clonal landscape is essentially determined by the presence of monosomy 7. Similarly, the global epigenetic changes correlate with morphological and cytogenetic subgroups, rather than with germline GATA2 status. The prospect of potential drug targetability of mutations frequently found in children, particularly in the SETBP1 oncogene, and in histone modifiers ASXL1 and EZH2, warrants further biological studies. Disclosures No relevant conflicts of interest to declare.