Germline Events In GFI1 In Myelodysplastic Syndrome

Germ line mutations in growth factor independent-1 (GFI1) have been described in a small subset of patients (pts) with severe congenital neutropenia. Subsequently, the GFI1³⁶N polymorphism, present in 3-5% of controls, has been found overrepresented (11%) in pts with primary (p) acute myeloid leukemia (AML), conveying 1.6 fold risk of development of AML. Mutant GFI1³⁶S and N variants lack affinity to HOXA9 (overrepresented in corresponding AML cases), shows increased proliferative potential in vitro and accelerates RAS-driven myeloproliferative neoplasm (MPN) disease in mice.

Whole exome next generation (WE NGS) technology facilitates comprehensive screens for the presence of both somatic and germ line genetic alteration. In this study, we used NGS to search for germline variants of the GFI1 gene. We screened 140 pts (mean age 66.8 years, range 44-85) with MDS and related disorders (MDS/MPN and secondary (s) AML) for the presence of GFI1 variants. We found non-synonymous variants in 11 cases (8%), including the previously described pathogenic p.S36N (n=8), p.P107A (n=2), or p.L400F (n=1), while the corresponding frequencies for these alterations were .04 and .001, .002 in the general population. This frequency appears comparable or higher to those previously reported for pAML, but our screen of the TCGA AML cohort, perhaps due to very low coverage for this gene, did not reveal any GFI1 polymorphisms. We next focused on the clinical features of altered GFI1 carriers. A significant proportion of GFI1 cases were younger (age<60 years) 45% (5/11) compared to 19% (p=.05) for wild type (WT) and predominantly male (82% vs. 52%, p=.02). MDS and sAML and MDS/MPN were present in 4, 3 and 4 pts, respectively. Normal cytogenetics at presentation was present in 64% vs. 43% (p=0.22). The availability of the somatic mutational profile allowed us to investigate whether specific genes are more commonly mutated in GFI1 variant cases. Among the 100 most commonly mutated genes, somatic PTPN11 (18% vs. 2%, p=.09), ASXL1 (18% vs. 8% p=0.2), SF3B1 (18% vs. 9%, p=0.3) were the most frequently encountered. Response rate to therapy with hypomethylating agents amongst carriers of GFI1 variants was 50% compared to 35% among WT (p=.32). The mean overall survival of the GFI1mutants was also higher compared to WT (40 vs. 33.6m).

In sum, our results demonstrate that potentially pathogenic GFI1 mutations are present in increased frequency in younger pts with MDS and thus may constitute a new predisposing factor for MDS and related myeloid neoplasms.