ORIGINAL RESEARCH REPORT
Could the mosaic pattern of chromosomal
abnormality predict overall survival of
patients with myelodysplastic syndrome?
Mehmet Sevki Uyanika,*
, Ahmet Muzaffer Demira
, Idris Kurtb
, Fulya Oz Puyanc
, Hakan Gurkand
, Elif Gulsum Umita
Gulsum Emel Pamuka
aDepartment of Hematology, Trakya University Medical Faculty, Edirne, Turkey b
Department of Internal Medicine, Trakya University Medical Faculty, Edirne, Turkey
cDepartment of Pathology, Trakya University Medical Faculty, Edirne, Turkey d
Department of Genetics, Trakya University Medical Faculty, Edirne, Turkey Received 7 July 2015; accepted 16 December 2015
Available online 16 January 2016
KEYWORDS Chromosomal abnormality; Mosaicism; Myelodysplastic syndrome; Prognosis Abstract
Objective/background: Myelodysplastic syndromes (MDSs) are a group of monoclonal hematopoietic diseases consisting of a number of various entities. The presence of differences in chromosomal content of cells within the same individual is known as chromosomal mosai-cism. The impact of mosaic pattern on the prognosis of MDS has been unclear. In this study, we aimed to determine the impact of mosaic pattern on the survival of patients with MDS. Methods: We retrospectively evaluated 119 patients diagnosed with MDS at the Trakya Univer-sity Faculty of Medicine, Department of Hematology. Giemsa–Trypsin–Giemsa banding was used to evaluate chromosomal abnormality.
The effect of chromosomal abnormality mosaicism on overall survival and transformation to acute leukemia was evaluated by Kaplan–Meier survival analysis.
Results: The mean age at diagnosis was 66.3 years, and the mean disease duration was 24.2 months. Chromosomal abnormality was observed in 32.5% of patients. Patients with chro-mosomal abnormalities comprising at least 50% metaphases had significantly lower overall sur-vival than patients with abnormality comprising up to 50% of all abnormal metaphases (p = .003). There were no differences in transformation to acute leukemia among patients with higher and lower chromosomal mosaicism (p = .056).
1658-3876/Ó 2016 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). * Corresponding author at: Sakarya University Faculty of Medicine, Korucuk Mah., Korucuk, Sakarya, Turkey.
E-mail address:email@example.com(M.S. Uyanik).
A v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m
Conclusion: The most important outcome of this study was to demonstrate worse overall sur-vival rates in MDS patients with higher abnormal chromosomal mosaicism than patients with lesser abnormal chromosomal mosaicism. Higher levels of abnormal chromosomal mosaicism did not predict transformation to acute leukemia. The cause of worse outcomes of patients with higher abnormal chromosomal mosaicism may be related to clonal mass.
Ó 2016 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).
Myelodysplastic syndromes (MDSs) are a group of mono-clonal hematopoietic diseases consisting of a number of var-ious entities . Certain artificial taxonomies and Prognostic Scoring Systems have emerged to overcome this heterogeneity and nonuniformity [2,3]. The World Health Organization’s (WHO) classification of myeloid neoplasms and acute leukemia  and the International Prognostic Scoring System (IPSS) have become standard tools for MDS classification and risk stratification. Bone marrow blast percentage, chromosomal abnormalities, and the number of cytopenias are used as markers to predict prognosis within the IPSS. The IPSS was not intended to be used after ini-tial diagnosis, and therefore, the WHO-based Prognostic Scoring System (WPSS) was developed for use as a dynamic scoring system [2,6]. Blast count, depth of peripheral cytopenias, chromosomal abnormalities, WHO subtype, and transfusion dependency are markers typically used in universal scoring systems[6–8]. Besides these well-known markers, additional markers such as serum lactate dehydro-genase, performance status, ferritin, albumin, b2-microglobulin, and bone marrow fibrosis are prognostic markers, which make independent contributions to the prognosis of MDS[3,5,6,9].
Chromosomal abnormalities are observed in approxi-mately 40% of patients with MDS[7,10]. Genome-wide asso-ciation studies typically show approximately 74% chromosomal abnormality in patients with MDS . MDS is a clonal process caused by the accumulation of cellular maturation defects and chromosomal abnormalities . Serial genetic abnormality inside the pluripotent stem cell gives rise to the abnormal proliferation of hematopoietic cells. Accumulation of immature cells in bone marrow disrupts normal hematopoiesis that demonstrates the importance of clonal mass in MDS. It is well-known that MDS patients with certain chromosomal abnormalities, such as chromosome 7 abnormalities and complex karyotypes, experience worse clinical outcomes than patients with nor-mal karyotypes. The impact of clonal mass on the prog-nosis of malignancy has been demonstrated in solid organ malignancies as well as in MDS. Different study groups have demonstrated the impact of the number of complex karyotypes on the prognosis of MDS, showing the effect of clonal mass on prognosis[7,14].
The presence of differences in chromosomal content of cells within the same individual is known as ‘‘chromosomal
mosaicism” . The association between chromosomal mosaicism and dermatological diseases , gynecological abnormalities [18,19], cognitive disorders [20,21], solid malignancies , and recently, hematological malignan-cies has already been demonstrated. By contrast, the impact of mosaic pattern on the prognosis of MDS remains unclear. It was recently demonstrated that MDS patients with a mosaic of normal and abnormal metaphases had better survival rates than patients with only abnormal meta-phases . These findings may be taken into account in terms of the impact of clonality on the prognosis of MDS. In this study, we aimed to determine the impact of the degree of mosaic pattern, one of the signs of clonal mass, on the survival of MDS.
Materials and methods
We evaluated 119 MDS patients at Trakya University Faculty of Medicine Department of Hematology between January 2010 and June 2014. Diagnosis of 88 patients were established at this time period. Cytopenia cutoff for absolute neutrophil counts was set at 1500/lL; 10 g/dL for hemoglobin; and 100,000/lL for platelets. Bone marrow aspiration and biopsies were performed for all patients. Bone marrow biopsies were evaluated by an experienced hematopathologist (F.O.P.). Dysplasia cutoff was defined as 10% for each serial. All karyotyping was performed from bone marrow samples. Patients diagnosed with chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, and atypical chronic myeloid leukemia were excluded from the study. The local ethical committee approved this study.
Giemsa–Trypsin–Giemsa/Giemsa–Trypsin–Leishman banding was used for karyotyping. As a rule, four bands from chromosomes 13–18 should be observed for a sample. Patients with a minimum of 400 bands were included in this study. The type of chromosomal abnormality (qualitative and/or quantitative) was recorded, and the metaphase count of the abnormality was also noted. The International System for Human Cytogenetic Nomenclature—1995 criteria were used to define abnormal clonality of chromosomes. Three groups of patients were observed: (a) patients with no chromosomal abnormality; (b) patients with a mosaic of normal and abnormal metaphases (abnormal chromoso-mal count < 50% of all abnorchromoso-mal metaphases); and (c) patients with a mosaic of normal and abnormal metaphases (abnormal chromosomal countP 50% of all abnormal meta-phases) or bearing only abnormal chromosomes.
SPSS software version 17.0 (SPSS Inc., Chicago, IL, USA) was used for data analysis. Differences between continuous vari-ables were evaluated using Student t test, and differences between categorical variables were evaluated using Chi-square test. Kaplan–Meier survival curves were used to define overall survival and progression to acute myeloid leukemia (AML). The effects of certain variables on overall survival were analyzed using Cox regression models with time-dependent covariates. Differences between patient groups were analyzed by log-rank test. Statistical signifi-cance was p < .05.
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimen-tation and with the Helsinki Declaration of 1975, as revised in 2008.
The mean age at diagnosis was 66.3 ± 12.3 years (27–91 years). The median age was 69 years. The mean
Table 1 Sociodemographic findings of myelodysplastic syndrome patients.
N % FAB RA 93 78.2 RARS 1 0.8 RAEB 18 15.1 RAEB-t 2 17 Total 114 95.8 WHO RAUC 21 17.4 RCMD 73 61.3 RARS 1 0.9 RAEB-I 8 6.7 RAEB-II 11 9.2 Total 114 95.8 WPSS Very low 17 14.3 Low 29 24.4 Intermediate 20 16.8 High 20 16.8 Very high 4 3.4 IPSS Low 27 22.7 Intermediate-1 43 36.1 Intermediate-2 17 14.3 High 4 3.4 Treatment No medication 40 33.2 Palliative therapy 39 32.7 ESAs 5 4.2 Thalidomide 1 0.8 HMAs 7 5.9 Eltrombopag 1 0.8 Chemotherapy 7 5.9 Transfusion dependency Transfusion dependent 23 19.3 Rarely transfused 16 13.4 Iron chelation 7 6
ESAs = erythroid stimulating agents; FAB = French–American–British; HMAs = hypo-methylating agents; IPSS = International Prognostic Scoring System; RA = refractory anemia; RAEB = refractory anemia with excessed blast; RARS = refractory anemia with ringed sideroblast; RAEB-t = refractory anemia with excessed blast-transformation; RAUC = refractory cytopenia with unilineage dysplasia; RCMD = refractory cytopenia with multilineage dysplasia; WHO = World Health Organization; WPSS = WHO Prognostic Scoring System.
disease duration was 24.2 ± 24.8 months (3–132 months). In this study, 50.4% of patients were women and 49.6% were men. Regarding therapy-related MDS, two patients had his-tory of malignancies. One patient had been treated with chemotherapy (0.8%) for Hodgkin’s lymphoma, and the other had been treated with radiotherapy (0.8%) for breast carcinoma. Distribution of the patients according to the Fr ench–American–British and WHO classifications, and distri-bution of patients according to the IPSS and WPSS risk scor-ing systems are presented inTable 1. According to the WHO classification, most of the patients (61.3%) were in the refractory cytopenia with multilineage dysplasia (RCMD) group. According to the IPSS risk scoring system, 60 patients (50.4%) were distributed in the Intermediate 1 and Interme-diate 2 groups.
Treatment and transfusion policy and dependency are also shown in Table 1. Transfusion dependency was observed in 23 (19.3%) patients. Transfusion was rarely used in palliative care for 16 (13.4%) patients. Iron chelation was used in seven (6%) patients and the mean chelation duration
was 17.6 ± 16.4 months. During the follow-up period, AML developed in 11 (9.3%) patients. A total of 16 (13.4%) patients died, and 14 (11.8%) patients were lost to follow up.
Patients’ overall survival and transformation to AML according to the WHO classification are demonstrated in Figure 1A and B. Overall survival of groups significantly dif-fered according to the WHO classification (p = .001). There was no overall survival difference between the refractory anemia with ringed sideroblasts and refractory cytopenia with unilineage dysplasia (RCUD) groups. Overall survival of RCUD was significantly longer than refractory anemia with excess blasts-I (RAEB-I; p = .008) and RAEB-II (p = .004). RCMD patients significantly lived longer than patients with RAEB-I (p = .01). There was no overall survival difference between RCMD and RAEB-II patients according to the WHO classification. Transformation to AML was signifi-cantly different between groups (p < .0001). AML transfor-mation was significantly lower in the RCUD group than in the RAEB-I (p = .008) and RAEB-II (p = .001) groups. Patients
Figure 1 (A) Overall survival according to the World Health Organization (WHO) classification. (B) Transformation to acute myeloid leukemia (AML) according to the WHO classification. (C) Overall survival according to the International Prognostic Scoring System (IPSS) classification. (D) Transformation to AML according to the IPSS classification.
with RCMD were significantly transformed to AML later than the RAEB-I (p = .001) and RAEB-II (p < .0001) groups. The IPSS was also used to demonstrate the differences in overall survival and transformation to AML between groups ( Fig-ure 1C and D). Overall survival and transformation to AML were significantly different according to the IPSS (p < .0001).
Chromosomal abnormality was observed in 32.5% of the patients. Chromosomal abnormality frequency and the mean values of abnormal metaphase counts are shown in Tables 2 and 3, respectively. We further divided chromoso-mal abnorchromoso-malities into two groups: (a) abnorchromoso-malities com-prising up to 50% of all abnormal metaphases, and (b) abnormalities comprising at least 50% of all metaphases. Patients in whom chromosomal abnormality comprised at least 50% metaphases significantly had lower overall survival than patients in whom abnormality comprised utmost 50% of all abnormal metaphases (p = .003;Figure 2). Eight of the 80 patients (9.1%) in whom abnormalities comprised up to 50% of all abnormal metaphases transformed to AML. Three of
nine patients (25%) with abnormalities comprising at least 50% of all metaphases transformed to AML. There was no difference in transformation to AML among patients with higher and lower chromosomal mosaicism (p = .056).
The following were chosen as covariates for multivariate analysis: presence of 50% or more abnormal metaphases of chromosomal mosaicism, age, transfusion dependency, dis-ease duration, and blast count demonstrated by flow cytom-etry. In multivariable analysis, chromosomal mosaicism (hazard ratio [HR] = 0.476, 95% confidence interval [CI], 0.264–0.859, p = .014), transfusion dependency (HR = 8.496, 95% CI, 1.3226–54.394, p = .024), disease dura-tion (HR = 0.872, 95% CI, 0.771–0.986, p = .029), and blast count (HR = 1.085, 95% CI, 1.025–1.150, p = .005) have been shown to affect overall survival.
The most important outcome of this study was demonstrat-ing shorter overall survival in MDS patients with larger clonal mass than patients with smaller clonal mass by implement-ing chromosomal mosaicism. Haase et al.  recently showed longer median survival for patients with mosaic pat-tern than patients harboring solely abnormal metaphases. However, researchers of that study did not determine any cutoff value for mosaic pattern. In this study, we evaluated
Table 2 Chromosomal abnormality distribution.
Quantitative abnormalities (%) Monosomy in 2 different chromosomes 4.8
Monosomy 20 3.6 Monosomy 19 2.4 Monosomy 22 2.4 Monosomy 17 1.2 Monosomy 18 1.2 Monosomy 21 1.2 Monosomy Y 1.2 Trisomy 8 1.2 Hypodiploidy 39 Hyperdiploidy 3 Hypo-tetra diploidy 4 Tetradiploidy 4 Qualitative abnormalities Complex karyotypea 8.4 Del 15q 8.4 inv (9)(11q13) 1.2 t(3;8) 1.2
aComplex karyotype was defined as the presence of three or
more unassociated structural abnormalities (International Prog-nostic Scoring System).
Table 3 Counts of abnormal metaphases.
Abnormality type Mean metaphase count (min–max) Abnormality type Mean metaphase count (min–max) Monosomy 2 0.80 ± 0.20 (0–20) Monosomy 20 0.21 ± 0.91 (0–4) Monosomy 7 0.04 ± 0.20 (0–1) Monosomy 21 0.25 ± 0.94 (0–4) Monosomy 11 0.04 ± 0.20 (0–1) Monosomy Y 0.28 ± 1.3 (0–9) Monosomy 14 0.16 ± 0.67 (0–3) Trisomy 8 0.16 ± 0.17 (0–1) Monosomy 15 0.14 ± 0.64 (0–3) Inv9 0.31 ± 2.0 (0–13) Monosomy 17 0.26 ± 0.91 (0–4) 11q23 0.21 ± 1.02 (0–5) Monosomy 18 0.40 ± 1.26 (0–4) Del15q 0.03 ± 0.24 (0–2) Monosomy 19 0.27 ± 0.92 (0–4)
Figure 2 Impact of abnormal clonal mosaicism on overall survival.
clonal mass based on the impact of chromosomal mosaic pattern and divided chromosomal abnormalities into two groups, namely, (a) abnormalities that comprised up to 50% of all abnormal metaphases and (b) abnormalities that comprised at least 50% of all metaphases.
Recently, it has been demonstrated that hematological cancers were 5.4 times higher in healthy individuals with chromosomal mosaicism than in controls with normal kary-otype. Furthermore, up to 35 times higher risk of acute leukemia progression was observed in healthy individuals with chromosomal mosaicism than their counterparts. In our study, there was no difference in transformation to AML between patients based on chromosomal mosaicism. In a study by Schick et al., MDS developed in only six of 229 individuals with chromosomal mosaicism. Research-ers emphasized that the strongest association was between abnormal chromosomal mosaicism and leukemia. In comparison to this, the association between chromosomal mosaicism and other hematological malignancies was weaker. These studies were performed on healthy indi-viduals with chromosomal mosaicism to predict hematolog-ical malignancies, whereas in our study, we used chromosomal mosaicism to predict AML transformation in MDS patients. Another reason for this inconsistency between our study and recently published data may be due to the methods used to demonstrate mosaicism.
The effect of normal residual metaphases was evaluated in patients with AML in a couple of studies[14,24,25]. In a study by Xie et al., the influence of residual normal meta-phases in AML patients with monosomal karyotype was stud-ied, and a higher percentage of normal metaphases was found to be associated with longer survival in the univariate/ multivariate model. These results indicate that even in well-defined cytogenetic groups, such as monosomal kary-otype, chromosomal mosaicism could cause heterogeneity. The study population of Estey et al.was composed of AML/high-risk MDS patients with chromosome 5 and/or 7 abnormalities, treated with conventional chemotherapy. One of the characteristics that Estey et al.demonstrated to find out the relatively longer surviving patients was the presence or absence of more than one normal karyotype. They found that patients with normal karyotype with chromo-some 5 and/or 7 abnormalities had a better survival rate than patients with no accompanying normal karyotype . Beyond this finding, 10% of the patients bearing chromosome 5 and/or 7 abnormalities with normal karyotype had essen-tially identical outcomes to patients with a normal karyotype treated in the same facility at the same period.
The reason for the adverse effect of higher abnormal chromosome mosaicism in MDS is unclear. In a study by Medeiros et al.  higher normal karyotype mosaicism was associated with worse outcomes among core-binding factor-AML patients. The hypothesis used by the authors to explain the worse outcome was proposed as ‘‘blasts with normal karyotype were more resistant to conventional chemotherapy than blasts with core-binding factor kary-otype.” Similarly, patients with chromosome 5 and/or 7 abnormalities and normal karyotype mosaicism were associ-ated with better outcome . Although we are able to demonstrate worse outcomes in patients with higher abnor-mal chromosoabnor-mal mosaicism, the effect of chromosoabnor-mal mosaicism should differ in patients having very good
karyotypes such as monosomy Y and del (11q) or poor or very poor karyotypes according to the information presented in these two studies. Our hypothesis is that the reason for worse outcome of patients with higher abnormal chromosomal mosaicism may be the association between higher clonal mass and higher abnormal chromosome count. Further studies on the effect of chromosomal mosaicism on disease prognosis within different risk groups would be help-ful to elucidate the effect of mosaicism in MDS.
The limitations of our study were (a) its cross-sectional nature, (b) small sample size, (c) not using fluorescence in situ hybridization (FISH) next to Giemsa–Trypsin–Giemsa banding, (d) relatively small follow-up time, and (e) only one hematopathologist evaluated the tissue samples. Typi-cally, G-banded chromosomal analysis and FISH are the two most useful techniques to identify chromosomal mosai-cism. We used G-banded chromosomal analysis, a relatively low-resolution technique, to evaluate chromosomal abnormality. It is known that aberrations can be detected by G-banded karyotyping at a resolution 5–10 megabases. FISH enables visualization of targeted chromosomal regions at a resolution greater than 150 kilobases within a specific genetic locus. Karyotyping and FISH have been commonly used in tandem to overcome the limitation of FISH to detect only specific regions in clinical practice. One of the major weaknesses of our study was that only one hematopatholo-gist evaluated the bone marrow samples. It would be ideal to report concordance rates among the hematopathologists, to increase the value of the study. Further studies with two or more techniques to evaluate the mosaic patterns of chro-mosomal abnormality would be appropriate to demonstrate the impact of mosaic pattern on survival for MDS patients.
In conclusion, higher abnormal chromosomal mosaicism is associated with worse overall survival in MDS patients with chromosomal abnormality. Chromosomal mosaicism was not shown to have an impact on transformation to AML in MDS patients. The reason for the worse outcomes observed for abnormal chromosomal mosaicism may be related to higher clonal mass.
Conflicts of interest
The authors declare no competing financial interests.
M.S.U., A.M.D., and G.E.P. designed the study; M.S.U., M. M., I.K., and E.G.U. provided the patients’ samples; M.S. U. performed statistical analysis; M.S.U. and A.M.D. designed the tables; M.S.U. and M.M. performed the exper-iments and analyzed the data; G.E.P. and A.M.D. reviewed the manuscript. All authors contributed to the writing of the manuscript.
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