Background: DNMT3A and SF3B1 are two of the most commonly mutated genes in myeloid neoplasms. DNMT3A mutations have been found to be associated poor prognosis in acute myeloid leukemia (AML), while SF3B1 mutations have been reported to be associated with favorable prognosis in myelodysplastic syndrome (MDS). Studies exploring the clinical significance of DNMT3A and SF3B1 co-mutation are limited and conflicting. Furthermore, the previous studies did not control for the presence of other co-mutated genes, which could be confounding factors.

Materials and Methods: 4390 in-house patients with confirmed or suspected myeloid neoplasms were tested by Next Generation Sequencing (NGS) (up to 54 gene panel). From these, we identified 68 patients with only DNMT3A mutation, 61 patients with only SF3B1 mutation, and 23 patients with only SF3B1/DNMT3A co-mutation, for a total of 152 patients. Patient demographics, diagnosis, cytogenetic abnormalities, and overall survival time were collated and analyzed.

Results: Patients with SF3B1 mutation alone or SF3B1/DNMT3A double mutations were found to be significantly older (median age of 76 and 75, respectively) than patients with isolated DNMT3A mutation (median age of 66, p values = 0.00016 and 0.00174 respectively). Patients with SF3B1/DNMT3A double mutations or isolated SF3B1 mutations occurred more commonly in MDS. They occurred less frequently in acute myeloid leukemia (AML) (1.63% and 21.74% respectively) than isolated DNMT3A mutation (41.76%, p values < 0.00001 and p = 0.00529 respectively). Patients with double mutations demonstrated increased ring sideroblasts (100%) at a rate similar to patients with isolated SF3B1 mutation (92.16%), which are unsurprisingly higher than patents with DNMT3A mutation alone (8%, p value < 0.000001). The patients with SF3B1 mutation alone or SF3B1/DNMT3A co-mutation were less likely to have poor cytogenetics and more likely to have intermediate cytogenetics than patients with DNMT3A mutation alone. Finally, patients with sole SF3B1 mutation or SF3B1/DNMT3A co-mutation showed significantly longer median survival time (26.60 months and 19.93 months respectively) and better overall survival curve (Figure 1) than patients with DNMT3A mutation alone (8.32 months, p value = 0.001 and 0.01078 respectively), for all the patients in this study as well as for patients with only myelodysplastic syndrome.

Conclusion: Patients with SF3B1/DNMT3A double mutations showed a prognosis similar to patients with isolated SF3B1 mutation and better clinical outcomes than patients with isolated DNMT3A mutation. This suggests that the favorable prognosis of SF3B1 mutation in MDS or AML patients is not abrogated by the concurrent presence of a DNMT3A mutation.

Figure 1
Figure 1
View largeDownload slide
Disclosures

No relevant conflicts of interest to declare.

Topics:
chromosome abnormality, dnmt3a gene, leukemia, myelocytic, acute, massively-parallel genome sequencing, mutation, myelodysplastic syndrome, neoplasms, sf3b1 gene, median survival time, survival curve

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2019 by The American Society of Hematology
2019
Sign in via your Institution