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

Abstract

Key Points• Acquired mutations of myeloid-related genes are present in a proportion of AA patients.• Somatic mutations in AA predict higher risk of transformation to MDS.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 5 12), DNMT3A (n 5 8) and BCOR (n 5 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. (Blood. 2014;124(17):2698-2704

Clonal hematopoiesis in acquired aplastic anemia

“…8 More recently, the issue has been newly addressed by using revolutionized sequencing technologies, unmasking a unique picture of CH in AA frequently accompanied by somatic mutations commonly seen in myeloid malignancies. [13][14][15][16][17][18] Combined with seminal findings on CH in aged normal individuals, [19][20][21] as well as on preleukemic clones 22 in patients with hematologic malignancies, [23][24][25] the finding on somatic mutations in AA provides new insight into the origin and the mechanism of frequent CH in AA and its impact on the late development of MDS and AML. 13,15,18 This review summarizes recent progress in the current understanding of CH in AA in relation to the pathogenesis of late clonal diseases.…”

“…15 Excluding PIGA mutations, somatic mutations were detected in 29 of 150 (19.3%) patients. In accordance with Yoshizato et al's report, mutations were more frequently observed in older patients and in those having longer (.6 months) disease durations.…”

“…DNMT3A and ASXL1 mutations tend to increase their clone size over years, whereas BCOR/BCORL1 and PIGA mutations are likely to show a decreasing or stable clone size. Generally, frequency and the mean number of mutations increase with age, which is not 13 Kulasekararaj et al 15 Heuser et al 14 Babushok et al 16 Yoshizato the case for the latter set of mutations. As a whole, mutations do not significantly affect response to IST, progression to MDS/AML, or overall survival.…”

“…The revolutionized technologies of next-generation DNA sequencing (NGS), together with the accumulated knowledge about the major driver mutations in MDS/AML, 42,64 have prompted investigations on somatic mutations in AA in relation to clonal evolution to MDS/AML. Thus, since the first report by Lane et al, 13 there have been several NGS-based mutation studies on AA during the past 2 years reporting varying mutation frequencies ranging from 5.3% to 72% [13][14][15][16][17][18] (Table 1). Among these studies, mutations were most comprehensively studied by Yoshizato et al, who surveyed mutations in 106 genes commonly mutated in myeloid cancers in 439 patients using targeted-capture deep sequencing.…”

“…Kulasekararaj et al also reported a significant association of mutations with faster progression to MDS (38% for mutated vs 6% for unmutated cases, P , .01), particularly for patients with longer disease durations and larger clone size, although the small cohort size seemed to prevent the analysis of the differential effect of mutations. 15 …”