Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms

Abstract

In a previous study, we identified somatic mutations of SF3B1, a gene encoding a core component of RNA splicing machinery, in patients with myelodysplastic syndrome (MDS). Here, we define the clinical significance of these mutations in MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). The coding exons of SF3B1 were screened using massively parallel pyrosequencing in patients with MDS, MDS/MPN, or acute myeloid leukemia (AML) evolving from MDS. Somatic mutations of SF3B1 were found in 150 of 533 (28.1%) patients with MDS, 16 of 83 (19.3%) with MDS/MPN, and 2 of 38 (5.3%) with AML. There was a significant association of SF3B1 mutations with the presence of ring sideroblasts (P < .001) and of mutant allele burden with their proportion (P = .002). The mutant gene had a positive predictive value for ring sideroblasts of 97.7% (95% confidence interval, 93.5%-99.5%). In multivariate analysis including established risk factors, SF3B1 mutations were found to be independently associated with better overall survival (hazard ratio = 0.15, P = .025) and lower risk of evolution into AML (hazard ratio = 0.33, P = .049). The close association between SF3B1 mutations and disease phenotype with ring sideroblasts across MDS and MDS/MPN is consistent with a causal relationship. Furthermore, SF3B1 mutations are independent predictors of favorable clinical outcome, and their incorporation into stratification systems might improve risk assessment in MDS.

Figure 1

Histogram of SF3B1 mutant allele burden. The bimodal distribution has been highlighted by adding a Gaussian kernel density plot to the histogram. The first normal distribution (on the left) accounts for 22% of observations, with a mean value for SF3B1 mutant allele burden equal to 15%. The second normal distribution (on the right) accounts for 78% of observations, with a mean value equal to 41%.

Figure 2

Relationship between SF3B1 mutant allele burden and proportion of ring sideroblasts. Values for percentage of ring sideroblasts are grouped here in 3 arbitrary categories: < 15% (n = 183), 15% to 50% (n = 85), and > 50% (n = 57). Data are shown in a box plot depicting the smallest and largest observation (lowest and highest horizontal line, respectively), lower and upper quartile with median value (box), and outliers (dots).

Figure 3

Kaplan-Meier analysis of survival in MDS patients stratified according to SF3B1 mutation status. (A) OS. (B) LFS. (C) EFS. Vertical tick-marks indicate right-censored patients.

Figure 4

Kaplan-Meier analysis of survival in MDS patients with low or intermediate-1 IPSS risk stratified according to SF3B1 mutation status. (A) OS. (B) EFS. Vertical tick-marks indicate right-censored patients.