|Year : 2017 | Volume
| Issue : 3 | Page : 572-575
Prevalence of cytogenetic abnormalities in chronic lymphocytic leukemia in the southern part of Turkey
Emine Kilic Bagir1, Arbil Acikalin1, Perihan Alsancak1, Semra Paydas2, Emel Gurkan3, Melek Ergin1
1 Department of Pathology, Faculty of Medicine, Çukurova University, Adana, Turkey
2 Department of Medical Oncology, Faculty of Medicine, Çukurova University, Adana, Turkey
3 Department of Hematology, Faculty of Medicine, Çukurova University, Adana, Turkey
|Date of Web Publication||24-May-2018|
Dr. Emine Kilic Bagir
Department of Pathology, Faculty of Medicine, Çukurova University, Adana
Source of Support: None, Conflict of Interest: None
BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most common type of leukemia among adults in Western populations. CLL has a wide range of clinical presentations and varied outcomes. For CLL, cytogenetic assessment is essential for estimating prognoses and determining the treatment of choice. The fluorescence in situ hybridization (FISH) technique is widely used for genetic assessment due to its high sensitivity. AIM: This study aimed to evaluate the frequencies of deletions of 13q14.3, 17p13.1, 11q22.3, and 13q34 and of trisomy 12 and to observe their effects on survival in 226 Turkish CLL patients using FISH analysis. RESULT AND CONCLUSION: The frequencies of abnormalities were 65.4% for del 13q14.3, 39.8% for del 17p13.1, 19% for del 11q22.3 (del ATM), and 15.9% for trisomy 12. No patients had a 13q34.3 aberration. Our results are partially consistent with literature findings. However, certain conflicts with prior results were observed, particularly with respect to the high prevalence of 17p13.1 deletions and the enhanced survival of patients with such deletions. These inconsistencies may represent population-based differences in the genetic epidemiology of CLL.
Keywords: B-cell, chronic lymphocytic, cytogenetic, fluorescence in situ hybridization, leukemia
|How to cite this article:|
Bagir EK, Acikalin A, Alsancak P, Paydas S, Gurkan E, Ergin M. Prevalence of cytogenetic abnormalities in chronic lymphocytic leukemia in the southern part of Turkey. Indian J Cancer 2017;54:572-5
|How to cite this URL:|
Bagir EK, Acikalin A, Alsancak P, Paydas S, Gurkan E, Ergin M. Prevalence of cytogenetic abnormalities in chronic lymphocytic leukemia in the southern part of Turkey. Indian J Cancer [serial online] 2017 [cited 2020 Sep 27];54:572-5. Available from: http://www.indianjcancer.com/text.asp?2017/54/3/572/233141
| » Introduction|| |
In Western populations, the most common type of leukemia among adults is chronic lymphocytic leukemia (CLL). Current data suggest that the incidence rate of CLL is 3–5/100,000;, in European and North American countries, CLL accounts for approximately one of every three leukemia cases. The median age at first diagnosis is between 67 and 72 years, and males are more affected than females., Disease presentation encompasses a broad spectrum ranging from indolent to aggressive disease. The clinical presentation of CLL is particularly important for determining the most appropriate treatment and predicting survival. In addition to clinical presentations, prognoses for CLL are also distributed across a wide range; thus, the determination of prognostic markers is essential for providing appropriate counseling and for treatment design.
The characteristic feature of CLL is CD5+ B-cell accumulation in the circulatory system, lymph nodes, spleen, and bone marrow. There exist several well-identified genetic aberrations in CLL that initiate leukemogenic transformation; these aberrations include single chromosomal deletions on 6q, 11q, 13q, and 17p, trisomy 12, and certain specific deletions of microRNA genes that result in apoptosis inhibition., Next-generation sequencing techniques have provided evidence regarding other factors with potential importance in the clinical heterogeneity of CLL, including mutations in NOTCH1 and SF3B1 and BIRC3 disruptions.
The most frequently used laboratory techniques for evaluating genetic abnormalities in CLL during the preceding four decades include Sanger sequencing, conventional G-banding cytogenetic techniques, microsatellite analysis to detect loss of heterozygosity, and fluorescence in situ hybridization (FISH). Among these approaches, Sanger sequencing is regarded as the first-generation technique, whereas the remaining approaches are regarded as second- and third-generation sequencing techniques. At present, cytogenetic analyses using FISH provide the most widely used and validated prognostic markers worldwide. The success rate of the FISH technique for determining genetic abnormalities in CLL is approximately 80%., This study aimed to evaluate the frequency and clinical significance of recurrent genetic abnormalities in CLL patients.
| » Subjects and Methods|| |
Patients and design
This study included 226 patients with CLL who were first diagnosed in the Department of Pathology, Faculty of Medicine, Çukurova University, Turkey, between 2010 and 2015. Diagnoses of CLL were based on the guidelines from the International Workshop on CLL. Patients without regular follow-up and who were previously diagnosed and treated were excluded from the study.
Genetic aberrations were evaluated using the FISH technique at the Department of Pathology, Faculty of Medicine, Çukurova University. The study was approved by the Ethics Committee of Çukurova University.
Fluorescence in situ hybridization
Samples for FISH analysis were obtained from patients' peripheral blood or bone marrow. Chromosomal abnormalities were evaluated using CLL locus-specific identifier probes; the examined aberrations included del ATM (del 11q22.3), del 13q14.3, del p53 (del 17p13.1), trisomy 12, and del 13q34. The cutoff value for p53 positivity was 15%; this value was 10% for ATM, 13q14 deletions, and trisomy 12. Images generated by FISH analysis for p53, ATM, and 13q14 deletions and trisomy 12 are presented in [Figure 1].
|Figure 1: Determination of genetic aberrations using the fluorescence in situ hybridization technique|
Click here to view
For descriptive data, the format mean (range) was used for numerical data, whereas frequencies and percentages were provided for categorical data. Age, gender, and survival time were compared for patients with and without each genetic abnormality using the Mann–Whitney U-test, Chi-square tests, and log-rank tests, as appropriate. A type I error level of 5% was regarded as the upper limit of statistical significance. Predictive Analytics Software (SPSS, Inc., Chicago, IL, USA), version 18.0 for Windows, was used for statistical analyses in this study.
| » Results|| |
A total of 226 patients with a mean age of 61.8 years (range, 26–88 years) were included in this study. The male-to-female ratio was 3.2:1 (170 males, 75.2%; 56 females, 24.8%). FISH analysis revealed that 148 of 226 patients (65.4%) had at least one chromosomal abnormality. The rates of the examined abnormalities were 65.4% for del 13q14.3, 39.8% for del 17p13.1, 19% for del 11q22.3 (del ATM), and 15.9% for trisomy 12. No patients had a 13q34.3 aberration. Certain patients had multiple chromosomal abnormalities; in particular, 167, 22, and 3 patients had 2, 3, and 4 genetic aberrations, respectively. The most frequently paired chromosomal abnormalities were del 17p13.1 and del 13q14.3.
Age, gender, and survival time were compared for patients with and without each genetic abnormality. The only significant difference was between the ages of patients with and without trisomy 12 (P = 0.003). The remaining comparisons for other abnormalities revealed no significant differences in age, gender, or survival time. Patients' demographic and clinical data are presented in [Table 1], and survival statuses according to the frequency of each abnormality are indicated in [Figure 2].
|Figure 2: Survival statuses according to the presence of genetic aberrations|
Click here to view
| » Discussion|| |
Cytogenetic assessments are crucial for the proper management of patients with CLL. The FISH technique is widely used to determine genetic aberrations because of its high sensitivity and resolution power. We used this technique to identify chromosomal abnormalities in a group of patients with CLL. Our results revealed that 65.4% of the assessed patients had at least one chromosomal abnormality. The most frequently observed abnormality was 13q14.3 deletion. Current literature suggests that chromosomal abnormalities are observed in 65–82% of CLL patients, and our results are consistent with this range. Previous studies that evaluated the frequencies of genetic aberrations in CLL have reported that the most frequent abnormality is 13q14.3 deletion, which is detected in 18–66% of patients with CLL., This aberration was also the most frequent abnormality in our study group; within this group, the prevalence of 13q14.3 deletion was relatively high (65.4%). The next most frequent aberrations detected by FISH analysis in our study were 17p13.1 deletion (39.8%), 11q22.3 deletion (19.0%), and trisomy 12 (15.9%). These frequencies were all consistent with those calculated in prior studies that reported genetic abnormalities in CLL patients. Specifically, reported frequencies for 17p13.1 deletion, ATM deletion, and trisomy 12 are 3.4–16%, 20%, and 15–23%, respectively. Our results were similar to those of previous investigations on this topic, although our calculated frequencies of 17p13.1 deletion were higher than reported frequencies. This discrepancy may be related to the etiology of this aberration, which is generally acquired after chemotherapy., Thus, it is important to obtain specimens for genetic sequencing at the time of diagnosis or as close as possible to the initiation of treatment before genetic alterations are triggered.
To our knowledge, this investigation is the second study evaluating chromosome alterations in CLL patients by utilizing the FISH technique to assess a Turkish population. The first such study was conducted by Durak et al., who reported frequencies of 32.9, 15.2, 7.6, and 5.1% for 13q14.3 deletion, trisomy 12, 17p13.1 deletion, and 11q22.3 deletion among Turkish CLL patients, respectively. Our results are similar to those of Durak et al. with respect to trisomy 12; however, the frequencies of the remaining examined genetic abnormalities were significantly higher in our patient group than among those assessed by Durak et al. These disparities may relate to the differences in patient characteristics and biological specimens involved in these studies. Durak et al. used only bone marrow samples for FISH analysis, whereas we used both peripheral blood samples and bone marrow samples from our patients. This methodological distinction may partially explain the different frequency rates detected in these studies. Another possible explanation may be population-based characteristics such as ethnic factors. This difference may be due to the fact that our region experiences intensive migration. Because neither study reported data regarding patients' ethnic backgrounds, no definitive conclusion could be reached regarding this possibility.
The clinical importance and outcomes of genetic aberrations in CLL are generally mentioned in terms of prognosis and survival. Prior reports by Reddy  and Ripollés et al. have indicated that a single genetic aberration in 13q14.3 was associated with the longest survival times and most favorable outcomes. In our patient group, the 13q14.3 deletion was the most frequent abnormality, and patients with this deletion experienced the longest survival. Literature data indicating that 13q14.3 aberrations are linked to more favorable outcomes and survival are compatible with our results. Xu et al. and Zenz et al. reported that trisomy 12 was correlated with intermediate clinical outcomes and survival. These authors' studies also revealed that 11q22.3 deletion and 17p13.1 deletion were related to poor clinical outcomes and relatively short survival times. However, in our study population, we found that patients with trisomy 12 and patients with 11q22.3 deletion had similar survival times, which were shorter than the survival times for patients with 17p13.1 deletion. These findings are somewhat inconsistent with data reported in recent literature. The absence of genetic alterations in posttreatment follow-up constitutes a limitation of our study. However, earlier studies of trisomy 12 reported that this abnormality might be related to a more aggressive clinical course of CLL., There are debates regarding the clinical outcomes of trisomy 12, although this aberration is known to be associated with a heterogeneous clinical spectrum. Moreover, there exist recent data on the clinical outcomes of 17p deletions. Notably, Tam et al. reported that patients who acquired 17p deletions at an early stage (de novo) had longer survival than patients who acquired these deletions during clonal evolution. Therefore, this observation may provide a possible explanation for the longer survival of our patients with 17p13.1 deletion.
| » Conclusions|| |
In this study, we have determined the prevalence of the most prominent genetic aberrations associated with CLL in a population of Turkish CLL patients. Our results are consistent with those of a previous Turkish study on the frequencies of genetic abnormalities in CLL. In addition, our results confirmed data in recent literature, but were inconsistent with these data in certain respects. The role of population-based characteristics should be considered when interpreting study results. Ethnic factors and diagnosis- and treatment-related differences might lead to conflicting results. Our findings will be useful for further studies that control for these potential confounders.
We believe that data from larger studies and the evaluation of the observed differences will help clarify appropriate follow-up and treatment of patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Nabhan C, Aschebrook-Kilfoy B, Chiu BC, Smith SM, Shanafelt TD, Evens AM, et al.
The impact of race, ethnicity, age and sex on clinical outcome in chronic lymphocytic leukemia: A comprehensive Surveillance, Epidemiology, and End Results analysis in the modern era. Leuk Lymphoma 2014;55:2778-84.
Talab F, Allen JC, Thompson V, Lin K, Slupsky JR. LCK is an important mediator of B-cell receptor signaling in chronic lymphocytic leukemia cells. Mol Cancer Res 2013;11:541-54.
Dighiero G, Hamblin TJ. Chronic lymphocytic leukaemia. Lancet 2008;371:1017-29.
Molica S. Sex differences in incidence and outcome of chronic lymphocytic leukemia patients. Leuk Lymphoma 2006;47:1477-80.
Watson L, Wyld P, Catovsky D. Disease burden of chronic lymphocytic leukaemia within the European Union. Eur J Haematol 2008;81:253-8.
Puiggros A, Blanco G, Espinet B. Genetic abnormalities in chronic lymphocytic leukemia: Where we are and where we go. Biomed Res Int 2014;2014:435983.
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al.
Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: A report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008;111:5446-56.
Davids MS, Vartanov A, Werner L, Neuberg D, Dal Cin P, Brown JR. Controversial fluorescence in situ
hybridization cytogenetic abnormalities in chronic lymphocytic leukaemia: New insights from a large cohort. Br J Haematol 2015;170:694-703.
Rozman C, Montserrat E. Chronic lymphocytic leukemia. N
Engl J Med 1995;333:1052-7.
Baliakas P, Iskas M, Gardiner A, Davis Z, Plevova K, Nguyen-Khac F, et al.
Chromosomal translocations and karyotype complexity in chronic lymphocytic leukemia: A systematic reappraisal of classic cytogenetic data. Am J Hematol 2014;89:249-55.
Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al.
Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 2002;99:15524-9.
Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N
Engl J Med 2005;352:804-15.
Morozova O, Marra MA. Applications of next-generation sequencing technologies in functional genomics. Genomics 2008;92:255-64.
Carney DA, Wierda WG. Genetics and molecular biology of chronic lymphocytic leukemia. Curr Treat Options Oncol 2005;6:215-25.
Haferlach C, Dicker F, Schnittger S, Kern W, Haferlach T. Comprehensive genetic characterization of CLL: A study on 506 cases analysed with chromosome banding analysis, interphase FISH, IgV(H) status and immunophenotyping. Leukemia 2007;21:2442-51.
Reddy KS. Chronic lymphocytic leukaemia profiled for prognosis using a fluorescence in situ
hybridisation panel. Br J Haematol 2006;132:705-22.
Ripollés L, Ortega M, Ortuño F, González A, Losada J, Ojanguren J, et al.
Genetic abnormalities and clinical outcome in chronic lymphocytic leukemia. Cancer Genet Cytogenet 2006;171:57-64.
Gozzetti A, Crupi R, Tozzuoli D, Raspadori D, Forconi F, Lauria F. Molecular cytogenetic analysis of B-CLL patients with aggressive disease. Hematology 2004;9:383-5.
Durak B, Akay OM, Aslan V, Ozdemir M, Sahin F, Artan S, et al.
Prognostic impact of chromosome alterations detected by FISH in Turkish patients with B-cell chronic lymphocytic leukemia. Cancer Genet Cytogenet 2009;188:65-9.
Xu W, Li JY, Pan JL, Qiu HR, Shen YF, Li L, et al.
Interphase fluorescence in situ
hybridization detection of cytogenetic abnormalities in B-cell chronic lymphocytic leukemia. t J Hematol 2007;85:430-6.
Wawrzyniak E, Kotkowska A, Blonski JZ, Siemieniuk-Rys M, Ziolkowska E, Giannopoulos K, et al.
Clonal evolution in CLL patients as detected by FISH versus chromosome banding analysis, and its clinical significance. Eur J Haematol 2014;92:91-101.
Stilgenbauer S, Zenz T, Winkler D, Bühler A, Schlenk RF, Groner S, et al.
Subcutaneous alemtuzumab in fludarabine-refractory chronic lymphocytic leukemia: Clinical results and prognostic marker analyses from the CLL2H study of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 2009;27:3994-4001.
Zenz T, Döhner H, Stilgenbauer S. Genetics and risk-stratified approach to therapy in chronic lymphocytic leukemia. Best Pract Res Clin Haematol 2007;20:439-53.
Oscier DG, Stevens J, Hamblin TJ, Pickering RM, Lambert R, Fitchett M. Correlation of chromosome abnormalities with laboratory features and clinical course in B-cell chronic lymphocytic leukaemia. Br J Haematol 1990;76:352-8.
Matutes E, Oscier D, Garcia-Marco J, Ellis J, Copplestone A, Gillingham R, et al.
Trisomy 12 defines a group of CLL with atypical morphology: Correlation between cytogenetic, clinical and laboratory features in 544 patients. Br J Haematol 1996;92:382-8.
Tam CS, Shanafelt TD, Wierda WG, Abruzzo LV, Van Dyke DL, O'Brien S, et al. De novo
deletion 17p13.1 chronic lymphocytic leukemia shows significant clinical heterogeneity: The M. D. Anderson and Mayo Clinic experience. Blood 2009;114:957-64.
[Figure 1], [Figure 2]