Driver somatic mutations identify distinct disease entities within myeloid neoplasms with myelodysplasia

Abstract

Our knowledge of the genetic basis of myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) has considerably improved. To define genotype/phenotype relationships of clinical relevance, we studied 308 patients with MDS, MDS/MPN, or acute myeloid leukemia evolving from MDS. Unsupervised statistical analysis, including the World Health Organization classification criteria and somatic mutations, showed that MDS associated with SF3B1-mutation (51 of 245 patients, 20.8%) is a distinct nosologic entity irrespective of current morphologic classification criteria. Conversely, MDS with ring sideroblasts with nonmutated SF3B1 segregated in different clusters with other MDS subtypes. Mutations of genes involved in DNA methylation, splicing factors other than SF3B1, and genes of the RAS pathway and cohesin complex were independently associated with multilineage dysplasia and identified a distinct subset (51 of 245 patients, 20.8%). No recurrent mutation pattern correlated with unilineage dysplasia without ring sideroblasts. Irrespective of driver somatic mutations, a threshold of 5% bone marrow blasts retained a significant discriminant value for identifying cases with clonal evolution. Comutation of TET2 and SRSF2 was highly predictive of a myeloid neoplasm characterized by myelodysplasia and monocytosis, including but not limited to, chronic myelomonocytic leukemia. These results serve as a proof of concept that a molecular classification of myeloid neoplasms is feasible.

Figure 1

Representation of unsupervised hierarchical clustering analyses including somatic mutations and current classification features according to WHO criteria within MDS without excess blasts. Diagnosis of each sample is shown by indicated colors. These analyses identified 3 main clusters: patients carrying the SF3B1 mutation, irrespective of current WHO classification criteria (MDS associated with SF3B1 mutation) (31 patients classified as RARS, 16 as RCMD-RS, 3 as RA, and 1 as RCMD according to WHO criteria) (left); patients with MD-associated mutations (mutations in genes involved in DNA methylation, splicing factors other than SF3B1, RAS pathway, and cohesin complex) classified as RCMD or SF3B1-negative RCMD-RS according to WHO criteria, as well as the 4 patients with unilineage dysplasia carrying mutation(s) in these genes (MDS with MD-associated mutations) (right); and all the patients with different mutation patterns (MDS NOS) irrespective of the presence of unilineage or MD (middle).

Figure 2

Survival and risk of leukemic evolution of patients with MDS classified according to the clusters resulting from the unsupervised analysis including WHO classification criteria and mutation patterns. (A) Overall survival and (B) risk of AML evolution of MDS patients clustered as follows: MDS associated with SF3B1 mutation; MDS with MD–associated mutations; MDS NOS; and MDS with excess blasts (RAEB).

Figure 3

Relationship between mutation pattern and disease phenotype in TET2, SRSF2, and ZRSR2-mutated myeloid neoplasms with myelodysplasia. The red rectangle identifies patients with monocytosis nonfulfilling criteria for classification of chronic myelomonocytic leukemia at the time of mutation analysis.

Figure 4

Mutation pattern in MDS and MDS/MPN with thrombocytosis. Diagnosis of each sample according to WHO criteria is shown by indicated colors.

Figure 5

Algorithm illustrating the classification process based on morphologic and genetic criteria identified by the unsupervised clustering analyses. According to these analyses, the threshold of 5% BM blasts retains a significant discriminant value, irrespective of the underlying driver mutation pattern. In MDS with no excess blasts, the presence of isolated del(5q), SF3B1 mutation or multilineage dysplasia-associated mutations recognize genetically-defined disease subtypes.