|Year : 2012 | Volume
| Issue : 4 | Page : 257-261
The percentage of deletion of the B-cell neoplasia-associated gene with multiple splicing ( an indicator for the prognosis of CLL)
Nahela A. Shalaby1, Dina A. Fouad1, Doaa G. Eissa1, Rasha I. Ibrahim2
1 Department of Clinical Pathology, Ain Shams University, Cairo, Egypt
2 Department of Internal Medicine, Ain Shams University, Cairo, Egypt
|Date of Submission||28-Jun-2012|
|Date of Acceptance||14-Jul-2012|
|Date of Web Publication||21-Jun-2014|
Rasha I. Ibrahim
Department of Internal Medicine, Faculty of Medicine, Ain Shams University, 11535 Cairo
Source of Support: None, Conflict of Interest: None
Deletion of the B-cell neoplasia-associated gene with multiple splicing (BCMS) maps to 13q14 is the most common genetic abnormality in B-chronic lymphocytic leukaemia (B-CLL) patients. Previously, CLL patients with del 13q14.1 were known to have a favourable outcome. However, recent research has shown that increased percentage of cells with del 13q may lead to a poor prognosis or may exert an adverse effect on the biological characteristics of this disease.
To assess the influence of the number of malignant cells carrying del 13q14 (BCMS) on the clinical characteristics and prognosis of CLL patients.
Patients and methods
Fluorescence in-situ hybridization technique using a locus-specific identifier 13q14 probe was applied on 76 peripheral blood samples of B-CLL patients, in addition to the routine panel of probes (locus-specific identifier 17p13,11q23 and centromeric 12) together with immunophenotyping using the routine panel for lymphoproliferative disorder.
Deletion of 13q14 was detected in 40/76 (52.6%) patients. Those patients with greater than 84% positive cells for the deletion had a statistically significant association with advanced clinical Rai staging, lymphocyte doubling time less than 12 months, lower Hb level, higher total leucocytic count and lower platelet count. Follow-up of all patients showed that 30/76 (39.5%) patients showed a good therapeutic response; 28/30 (93.4%) of the patients were positive for 13q14 (BCMS) deletion, with a percent of cells ranging from 12 to 67%. The remaining 46/76 (60.5%) patients showed a poor therapeutic response; 12/46 (26.1%) of these patients were 13q14 (BCMS) positive, with a percent of positive cells ranging from 84 to 96%. Deletions in 17p13 were detected in 8/76 (10.5%), trisomy 12 was found in 10/76 (13.1%) and 11q23 rearrangements were found in 12/76 (15.7%) patients.
The prognostic significance of del 13q14 is dependent on the percentage of positive cells for this deletion. A high number of losses in 13q14 are associated with a poor prognosis.
Keywords: 13q14 deletion, BCMS gene, chronic lymphocytic leukaemia, prognosis
|How to cite this article:|
Shalaby NA, Fouad DA, Eissa DG, Ibrahim RI. The percentage of deletion of the B-cell neoplasia-associated gene with multiple splicing ( an indicator for the prognosis of CLL). Egypt J Haematol 2012;37:257-61
|How to cite this URL:|
Shalaby NA, Fouad DA, Eissa DG, Ibrahim RI. The percentage of deletion of the B-cell neoplasia-associated gene with multiple splicing ( an indicator for the prognosis of CLL). Egypt J Haematol [serial online] 2012 [cited 2020 Mar 31];37:257-61. Available from: http://www.ehj.eg.net/text.asp?2012/37/4/257/134974
| Introduction|| |
A variety of cytogenetic abnormalities have been described in B-chronic lymphocytic leukaemia (B-CLL). Deletion of the long arm of chromosome 13 (13q14.3) is, however, the most common, occurring in greater than 50% of B-CLL and mantle cell lymphoma, indicating the localization of a tumour suppressor gene involved in the pathomechanism of these diseases. Within a 400 kb recurrently deleted segment, at least two minimally deleted subregions have been reported 1,2.
Previously, the deleted gene maps to 13q14 were suggested to be the retinoblastoma gene (Rb), an unknown gene in close proximity to the Rb gene. Recently, Haferlach et al. 3 have reported the B-cell neoplasm of multiple splicing site (BCMS) to be a critical gene located on chromosomal band 13q14 and composed of at least 50 exons spanning at least 560 kb of genomic DNA, and expressed in more than 20 RNA splicing variants. The alignment of the gene with all critical subregions provides a strong argument for BCMS being the most likely candidate for the tumour suppressor gene in 13q14 involved in the leukemogenesis of B-CLL.
For the two genes residing in the proximal subregion, initially named LEU1 and LEU2, a pathogenic role has not been established. LEU1 is only a small portion of a large gene, which spans all previously reported critical subregions including the distal subregion 4. This gene, designated B-cell neoplasia-associated gene with multiple splicing (BCMS), is composed of at least 50 exons spanning at least 560 kb of genomic DNA and is expressed in more than 20 RNA splicing variants 5.
Among patients with B-CLL, those with the 13q14 deletion have a favourable outcome. However, recent studies have reported that increased percentage of cells with 13q- may lead to a poor prognosis or may adversely affect the biological characteristics of this disease 6. For these reasons, this work aimed to investigate patients diagnosed with B-cell and deletion in 13q14 (BCMS gene) as the sole cytogenetic abnormality and to assess the clinical characteristics including outcome and the biological characteristics of the patients with different degrees of positive malignant cells for del 13q.
| Patients and methods|| |
This study included 76 patients from the Ain-Shams University Hematology Oncology Department, diagnosed with B-CLL during a period of 1 year. There were 46 men and 30 women, with a male to female ratio of 1.5 : 1. The diagnosis of B-CLL was made according to the WHO classification 7 and the Working Group of National Cancer Institute (NCI) criteria 8. Evidence of persistent lymphocytosis and a compatible immunophenotype were required for the diagnosis. In all cases, an immunophenotype analysis was carried out by flow cytometry, including at least the following monoclonal antibodies: CD19, CD5, CD23, FMC7, CD22, CD79b, CD38, and surface immunoglobulins κ or the &lgr; light chain.
Fluorescence in-situ hybridization analysis
Locus-specific identifier (LSI) probes (Vysis, Abbott molecular diagnostics, USA): 13q14 (BCMS), LSI 17P13 (p53), 11q23 (MLL), and centromeric 12 (CEP 12), were applied for all patients for the detection of the common cytogenetic aberrations according to the study conducted by Liso et al. 9. Two healthy volunteers were used as controls to check the signals of the probes used. The study protocol was approved by the ethical committee and written consent was obtained from the patients.
Interpretations of fluorescence in-situ hybridization
The results were interpreted by scanning most of the metaphases and interphases using the chromoscan (CytoVision 2.7, Santa Clara, California, USA) in order to detect the target abnormalities. The sample was considered negative for the 13q14 deletion if two red signals representing BCMS genes and two green centromeric control signals were detected, positive for heterozygous deletion if one red signal and two green signals were detected, and positive for homozygous deletion if no red signals and two green signals were detected.
Indications for treatment were consistent with published guidelines 7 and the classic FCR (Fludarabine and Cyclophosphamide, Rituximab) protocol for all the patients, notably troublesome lymphadenopathy or hepatosplenomegaly, constitutional symptoms or developing cytopenias. Response to treatment was assessed by the received NCI criteria 8. Follow-up of all patients was carried out throughout the period of this study. Complete remission was indicated by the resolution of systemic symptoms, lymphadenopathy and hepatosplenomegaly with the normalization of blood counts. These criteria must be maintained for more than 2 months, after which a bone marrow aspiration and biopsy must show less than 30% lymphocytes and no lymphoid nodules. Those who fulfilled the previous criteria after therapy were considered responders 10.
The data were determined using SPSS 15 (IBM, New York, USA) and NCSS 2007 software packages under Windows 7 operating system. Qualitative data were presented as frequency (number and %). The χ2-test and Fisher’s exact test (F) were used for comparison of qualitative data. A P value less than 0.05 and less than 0.01 was considered significant and highly significant, respectively. Survival analysis was carried out according to Kaplan–Meier survival curve and analysis.
| Results|| |
Fluorescence in-situ hybridization
Fluorescence in-situ hybridization (FISH) analysis for all patients showed cytogenetic abnormalities in 70/76 (93.3%). Deletions involving the (BCMS) 13q14 region as a sole anomaly were positive in 40/76 (52.6%) patients [Figure 1]. Of all patients, 8/76 patients (10.5%) were positive for P53 del, 12/76 patients (15.7%) were positive for the 11q23 rearrangement and 10/76 patients (13.1%) were positive for trisomy 12. Patients positive for 13q14 deletion showed a statistically highly significant association in terms of Hb, lymphocyte doubling time and FMC7 expression; a significant association was found in total leucocytic count, platelets, CD38 expression, Rai clinical staging and splenomegaly [Table 1].
|Table 1: Comparison between the parameters studied in patients with 13q14 deletion versus negative patients|
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|Figure 1: Interphase FISH analysis positive for 13q14 deletion (one red signal represents one allele of BCMS (13q14); two green signals represent the centromeric control of chromosome 13). FISH, fluorescence in-situ hybridization.|
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During follow-up of the patients, they were classified according to good and poor outcome on the basis of the response to therapy. Of the 38 patients, 30/76 (39.5%) patients achieved a good response; 28/30 (93.4%) of these patients were positive for the 13q14 (BCMS) deletion, with a percent of cells that ranged from 12 to 67%, and 2/30 (5.6%) patients were negative for 13q14. The remaining 46/76 (60.5%) patients showed a poor outcome; 12/46 (26.1%) of these patients were 13q14 (BCMS) positive, with a percent of positive signals ranging from 84 to 96%, and 34/46 patients (73.9%) were (BCMS) 13q14 negative [Table 2].
|Table 2: Characteristics of positive patients for the 13q14 deletion classified according to the percentage of positive cells by FISH|
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Receiver operating characteristic curve showed that a cut-off of 84% was the best value above which patients with positive 13q14 deletion were characterized to have a poor outcome with 100% sensitivity and 100% specificity. On the basis of this cut-off value, patients positive for the 13q14 deletion were divided into two groups and compared in terms of demographic, clinical and laboratory data. Comparative study showed that patients with a cut-off value higher than 84% showed a statistically significant association with advanced clinical Rai staging, lymphocyte doubling time less than 12 months, lower Hb level, higher total leucocytic count and lower platelet count [Table 2].
| Discussion|| |
In the present study, cytogenetic abnormalities were detected in 70/76 patients (92.1%). This was in agreement with Stilgenbauer et al. 11, who found that during the initial analysis, 92% of the patients had genomic aberrations. Haferlach et al. 12 found that cytogenetic aberrations were detected in 85.2% cases either by metaphase cytogenetics and/or by interphase FISH. More recently, Parker and Strout 13 reported that ∼80% of individuals with CLL had acquired chromosomal abnormalities within their malignant clone.
Out of cytogenetic aberrations detected in this work, aberrations in the 13q14 region were found in 52.6% patients as the sole cytogenetic aberration. This was in agreement with the study conducted by Parker and Strout 13, who reported 13q14 deletions as the most common abnormality in CLL, being present in 55% of patients at the initial diagnosis. Other studies have shown a wide variability in results. Using the FISH technique, del 13q14 was detected in 66% of patients by Bacher et al. 14, 45.8% by Reddy 15, 46% by Aoun et al. 16, 42.1% by Ripollés et al. 17 and 42.2% by Xu et al. 18. However, much lower incidence for del 13q14 was detected by others including 18% by Jarosova et al. 19, 25.3% by Durak et al. 20, 31% by Mittal et al. 21 and 35% by Quijano et al. 22, and this can be attributed to the specificity of the targeted base sequence.
Considering the epidemiological and clinical characteristics of 13q14 positive patients, the present work found no significant association of the 13q14 deletion with age, sex, hepatomegaly or lymphadenopathy. Similar results were obtained by Ripollés et al. 17, except for age. They reported that when genetic abnormalities were correlated with age, the most frequent abnormality in the older patients (>60 years) was 13q14del. There was a significant association between staging and 13q14 deletion. Similarly, Dőhner et al. 5 and Karacosta et al. 23 have reported that 13q14 is usually found in patients with stage A according to the Binet system, indicating an early clonal aberration in which the loss or the inactivation of a tumour suppressor gene may be crucial for the development of CLL. In addition, Ripollés et al. 17 found that the majority of patients in the initial stages (Rai stages 0–I) showed 13qdel, and a significant association was also detected between 13q14 del and high white blood cell count (P<0.001). The same finding has been reported previously by Cuneo et al. 24.
In the present study, we found a significant association between 13q14 del and negative CD38 expression. The same findings have been reported previously by Krober et al. 25 and Hayat et al. 26, who found CD38-negative expression to be associated with 13q14 deletion, whereas Haferlach et al. 12 and Dicker et al. 27 found that a low CD38 expression was correlated with 13q deletions as the sole abnormality.
The percent of malignant cells with the 13q14 deletion ranged from 12 to 96%. A similar range was obtained by Durak et al. 20, who found that the percentage of cells ranged from 10 to 97%, whereas Xu et al. 18 reported that the percentage of cells with del 13q14 ranged from 22 to 93%. Interestingly, in this work, focusing on patients with loss of 13q as the sole cytogenetic aberration, we found that the number of malignant cells carrying this genetic lesion influences the disease outcome. Thus, according to the percentage of cells with 13q deletion, two prognostic groups could be established: the patients with a high proportion (≥84%) of 13q deletion cells had a statistically significantly poor outcome than that of patients with less than 84% 13q deletion cells. This was in agreement with Hernández et al. 6, who reported that the number of malignant cells with the 13q deletion can influence the outcome of B-CLL patients in whom the 13q deletion is the single genetic abnormality. Cases with a high number of cells with 13q deletion, as quantified by FISH, are associated with short overall survival and time to progression, which indicates that it is the most malignant clones in CLL, but these results need to be confirmed by additional studies.
Other specific genomic abnormalities are encountered in CLL in addition to 13q14, such as 11q22 (ATM) and 17p13 (P53) deletions, trisomy chromosome 12, and loss of the 13q14 region, that provide clinically meaningful prognostic information 28. They are known to be associated with prognostic impact in CLL patients, which is important for deciding on the therapeutic protocol 29. In our work, FISH detected p53 deletion in 4/38 (10.5%) of patients. This was in agreement with Dohner et al. 30, Dickinson et al. 31 and Abdel Salam et al. 32, who detected p53 deletion in 10% of CLL patients, and with other investigators: 8.7% Ripollés et al. 17, 6.6% Mittal et al. 21; however, a lower incidence (3.4%) was detected by Reddy 15. Many studies using the FISH technique have shown a wide variability in results, such as Berkova et al. 33 and Xu et al. 34, who documented the P53 gene deletion in 17 and 16.8% of CLL patients, respectively. Overall, 5/38 patients (13.1%) were positive for +12 as the sole anomaly by FISH, a finding that was in agreement with previous studies: 15% by Dohner et al. and Oscier 30,35; 16% by Dőhner et al. and Stilgebauer et al. 5,36; 19% by Dewald et al. 37; higher values have been obtained in other studies: 21, 23, and 30% 16, 22, 32. Moreover, FISH detected 11q23 deletion in 6/38(15.7%) of our patients. This was in agreement with a previous study carried out by Dewald et al. 37, who detected this in 15% of their patients; higher values have been obtained in other studies: 20 and 18% 30,36. The discrepancy observed between the present results and those of other studies can be attributed to different sample sizes and/or the various ethnic groups studied.
| Conclusion|| |
Quantification of the percentage of malignant cells with 13q14 deletion as the sole anomaly can be used as an indicator for the prognosis and monitoring of therapy in B-CLL patients. According to this percentage, patients can be subcategorized into patients with a poor prognosis, with 84% or more of cells with del 13q, and those with a favourable prognosis, with less than 84% of cells with del 13q.
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[Table 1], [Table 2]