Telomere Length and Somatic Mutation in Aplastic Anemia- Correlation with Response to Treatement

Background : Telomere length (TL) of cell reflects the cellular age and short TL suggest the potential susceptibility to DNA damage. We investigated whether 1) the treatment response is associated with TL of hematopoietic cells and 2) whether somatic mutations are associated with TL in patients with aplastic anemia (AA). Methods : We measured the mean TL and heterogeneity of bone marrow nucleated cells at the single cell level by quantitative fluorescence in situ hybridization. A total of 146 AA patients were enrolled; AA (n=146) and normal peripheral blood control (n=147). TL was expressed as telomere/centromere ratio. We analyzed the average and the distribution of TL belonging to the lowest 10 th percentile of cell population. Along with measurement of TL, target sequencing for 88 hematopoiesis-related genes was performed to detect somatic mutations. Results : We investigated the frequencies of cytogenetic aberrations and somatic mutations in 437 patients with aplastic anemia (AA) with prognostic relevance. Clonality was determined by G-banding/ fluorescent in situ hybridization (FISH) (n=280 patients), and targeted capture sequencing for 88 hematopoiesis-related genes (n=77). Of 437 patients, 20 (4.6%) showed disease progression and monosomy 7(50%) was the most predominant cytogenetic evolution at disease transformation. One third of patients (25/77, 32.4%) presented at least 1 mutation and the number of mutated genes was 18 and frequently mutated genes was NOTCH1 (3/25, 12%), NF1 (3/25, 12%), SCRIB (2/25, 8%), BCOR (2/25, 8%), DIS3 (2/25, 8%), DNMT3A (2/25, 8%), MED12 (2/25, 8%). In contrast to that 4.6% of AA patients showed disease progression, 4.0% of patients with SM showed disease progression. The telomere length of bone marrow nucleated cells was measured at single cell level by FISH (n=146) patients. Mean TL of AA (T/C ratio 6.99) was significantly shorter than normal control (T/C ratio 11.24). Patients with cytogenetic aberrations (CA) and/or somatic mutation (SM) showed significantly shorter TL compared to AA with normal karyotypes. However, the severity of AA did not correlate with TL. Patients with TL Conclusion : Patients with TL attrition showed poor response to IST. Short TL can be used not only as a biomarker for AA, but also as a predictive marker for treatment response to IST. In addition, CA and/or SM was strongly associated with adverse prognosis or treatment response, so we strongly suggest to adopt more sensitive test for the detection of minor clonal cell population in AA. Disclosures No relevant conflicts of interest to declare.