MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance

Abstract

Establishing a diagnosis in patients suspected of having a myelodysplastic syndrome (MDS) can be challenging and could be informed by the identification of somatic mutations. We performed a prospective study to examine the frequency and types of mutations encountered in 144 patients with unexplained cytopenias. Based on bone marrow findings, 17% were diagnosed with MDS, 15% with idiopathic cytopenias of undetermined significance (ICUS) and some evidence of dysplasia, and 69% with ICUS and no dysplasia. Bone marrow DNA was sequenced for mutations in 22 frequently mutated myeloid malignancy genes. Somatic mutations were identified in 71% of MDS patients, 62% of patients with ICUS and some dysplasia, and 20% of ICUS patients and no dysplasia. In total, 35% of ICUS patients carried a somatic mutation or chromosomal abnormality indicative of clonal hematopoiesis. We validated these results in a cohort of 91 lower-risk MDS and 249 ICUS cases identified over a 6-month interval. Mutations were found in 79% of those with MDS, in 45% of those with ICUS with dysplasia, and in 17% of those with ICUS without dysplasia. The spectrum of mutated genes was similar with the exception of SF3B1 which was rarely mutated in patients without dysplasia. Variant allele fractions were comparable between clonal ICUS (CCUS) and MDS as were mean age and blood counts. We demonstrate that CCUS is a more frequent diagnosis than MDS in cytopenic patients. Clinical and mutational features are similar in these groups and may have diagnostic utility once outcomes in CCUS patients are better understood.

Figure 1

Prospective trial schema and diagnostic groups. (A) Schema showing how patients were screened and selected for entry. Patients were placed into 1 of 3 groups based on their bone marrow findings. (B) Proportions of patients with and without mutations in each diagnostic group are shown after DNA sequencing 22 genes associated with myeloid neoplasms.

Figure 2

Mutations and VAFs in prospective study groups. (A) The frequency of mutations in each gene listed on the x-axis is shown for prospective cohort patients with MDS (red bars in lower half) and CCUS, separated by whether dysplasia was seen in the bone marrow or not (blue and purple bars, respectively, in upper half). (B) Variant allele fractions by diagnostic group. The VAF for each mutation identified in the prospective MDS and CCUS groups is shown. Colored dots represent the highest VAF found in a patient whereas black dots represent mutations with VAFs less than the maximum for a given patient. The colored dotted lines represent the mean of the highest VAFs (colored dots) whereas solid black lines represent the mean of all mutations (colored and black dots).

Figure 3

Mutations and VAFs in retrospective study groups. (A) The frequency of mutations in each gene listed on the x-axis is shown for retrospective cohort patients with MDS (red bars in lower half) and CCUS, separated by whether dysplasia was seen in the bone marrow or not (blue and purple bars, respectively, in upper half). (B) Variant allele fractions by diagnostic group. The VAF for each mutation identified in the retrospective MDS and CCUS groups is shown. Colored dots represent the highest VAF found in a patient whereas black dots represent mutations with VAFs less than the maximum for a given patient. The colored dotted lines represent the mean of the highest VAFs (colored dots) whereas solid black lines represent the mean of all mutations (colored and black dots).