Short telomere length and its correlation with gene mutations in myelodysplastic syndrome

Abstract

BackgroundTelomere erosion can lead to genomic instability and cancer progression. It has been suggested that the shortest telomere, not the average telomere length (TL), is critical for cell viability. Some studies have shown shorter TL in myelodysplastic syndrome (MDS) patients but the critically short telomeres, the variability of TL within individual patient has not been evaluated. Thus, we aimed to investigate the TL of MDS patients and assessed the association of TL with recurrent genetic mutations in MDS.MethodsWe measured the TL of bone marrow nucleated cells for diagnostic samples at a single-cell level by quantitative fluorescence in situ hybridization (Q-FISH) for 58 MDS patients and analyzed the minimum, median, average, standard deviation, average of the 0th to 10th percentile TL within a patient, and the proportion of cells with TL that is shorter than the lowest 10th percentile of the normal control (NC). The correlations of TL to clinical parameters, cytogenetic results, and genetic mutations were assessed.ResultsMDS patients showed eroded telomeres and narrow distribution compared to the NC (P < 0.001, P = 0.018, respectively). Patients with mutation showed significantly lesser cells with short TL, below the lowest 10th percentile of the NC (P = 0.017), but no differences in TL were found according to mutations/cytogenetic abnormalities except for CSF3R mutation. However, those patients with a high percentage (≥80 %) of cells with short TL showed poorer overall survival (P = 0.021), and this was an independent prognostic factor, along with TP53, U2AF1 mutation, and high BM blast count (P = 0.044, 0.001, 0.004, 0.012, respectively).ConclusionsThe shortest TL, which determines the fate of the cell, was significantly shorter, and higher burden of cells with short TL were found in MDS, which correlated with poor survival, suggesting the need to measure TL in single cells by Q-FISH.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0287-9) contains supplementary material, which is available to authorized users.

Prognostic significance of U2AF1 mutations in myelodysplastic syndromes: a meta-analysis

“…HRs and 95% CIs for OS and LFS were also extracted from the included studies together with the number of patients which survived every year after diagnosis. If the article provided 19 Wu, 2016 20 Jung, 2016 17 Hwang, 2016 16 Kang, 2015 18 Hong, 2015 15 Kim, 2017 13 Tefferi, 2018 21 Hamilton, 2019 22 Xu, 2017 26 Tefferi, 2017 24 Heuser, 2017 23 Wu, 2013 25 Journal Genes Chromosomes…”

“…Abnormal karyotypes were encountered significantly more often in patients with than without U2AF1 mutations (49.6% vs. 37.8%, P < 0.05); similarly, patients with abnormal karyotypes were significantly more likely to have U2AF1 mutations (19.3% vs 12.1%, P < 0.05) ( Figure 2). As shown in Figure 3a-d, we analyzed the ORs of OS in MDS patients with U2AF1 mutations in eight studies; 13,[15][16][17][18][19][20][21] summary ORs for OS of 1, 2, 3, and 5 years were 0.76 (95% CI: 0.54-1.09), 0.47 (95% CI: 0.35-0.62, P < 0.001), 0.43 (95% CI: 0.24-0.78, P ¼ 0.006), and 0.37 (95% CI: 0.26-0.51, P < 0.001), respectively. In the case of 3-year OS, high heterogeneity was observed with an I 2 of 64% (P ¼ 0.006).…”

Molecular evidence supporting the precursor nature of atypical adenomatous hyperplasia of the prostate

“…In this study, we found that a subset of AAH showed significant telomere shortening and expression of AMACR, suggesting a precursor role for AAH lesions in adenocarcinoma evolution. Telomere shortening induces chromosomal instability that can result in tumorigenesis . Because telomere shortening is a progressive process related to cell replication, the discrepancies of relative telomere length among AAH lesions may represent different stages in their development toward malignancy.…”

Monosomy 7/del (7q) in inherited bone marrow failure syndromes: A systematic review

“…It has been shown that telomere attrition along with somatic mutation precede monosomy 7 and the accumulation of short telomeres gives rise to aneuploidy, which may lead to the progression of MDS/AML in patients with severe aplastic anemia . On the other hand, it has also been argued that the regulation of telomere length occurs because of oncogenic mutations already existing in MDS patients …”

“…21 On the other hand, it has also been argued that the regulation of telomere length occurs because of oncogenic mutations already existing in MDS patients. 22 Our third aim was to evaluate the survival outcomes of patients who developed MDS/AML. Patients with Fanconi anemia had the worst survival outcome.…”