Somatic mutations identify a subgroup of aplastic anemia patients who progress to myelodysplastic syndrome

Abstract

The distinction between acquired aplastic anemia (AA) and hypocellular myelodysplastic syndrome (hMDS) is often difficult, especially nonsevere AA. We postulated that somatic mutations are present in a subset of AA, and predict malignant transformation. From our database, we identified 150 AA patients with no morphological evidence of MDS, who had stored bone marrow (BM) and constitutional DNA. We excluded Fanconi anemia, mutations of telomere maintenance, and a family history of BM failure (BMF) or cancer. The initial cohort of 57 patients was screened for 835 known genes associated with BMF and myeloid cancer; a second cohort of 93 patients was screened for mutations in ASXL1, DNMT3A, BCOR, TET2, and MPL. Somatic mutations were detected in 19% of AA, and included ASXL1 (n = 12), DNMT3A (n = 8) and BCOR (n = 6). Patients with somatic mutations had a longer disease duration (37 vs 8 months, P < .04), and shorter telomere lengths (median length, 0.9 vs 1.1, P < .001), compared with patients without mutations. Somatic mutations in AA patients with a disease duration of >6 months were associated with a 40% risk of transformation to MDS (P < .0002). Nearly one-fifth of AA patients harbor mutations in genes typically seen in myeloid malignancies that predicted for later transformation to MDS.

Figure 1

Telomere lengths of patients in the study cohort segregated into different subgroups as compared with healthy age-matched controls. The groups are AA patients with no acquired mutations (green triangles) and AA patients with somatic mutations (red circles). The trend line for normal controls (black rhomboid) is also shown. The relative telomere lengths of normal controls and AA patients with or without somatic mutations is shown in the figure inset.

Figure 2

Schematic representation of patients in the study cohort based on severity of AA, presence of PNH clone, and presence of somatic mutations with or without transformation to MDS. The detailed data on PIGA mutations are provided in the supplemental Data. Only patients in the first cohort (n = 57) were screened for PIGA mutations, and 23 of 57 patients had a PNH clone detected by flow cytometry.