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  Table of Contents  
ORIGINAL ARTICLE
Year : 2013  |  Volume : 50  |  Issue : 3  |  Page : 261-267
 

Clinico-pathological impact of cytogenetic subgroups in B-cell chronic lymphocytic leukemia: Experience from India


1 Cancer Cytogenetics Laboratory, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India
2 Hematopathology Laboratory, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India
3 Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India

Date of Web Publication23-Sep-2013

Correspondence Address:
PS Kadam Amare
Cancer Cytogenetics Laboratory, Tata Memorial Hospital, Parel, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.118730

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 » Abstract 

Background: The present study of 238 B-cell Chronic Lymphocytic Leukemia (B-CLL) patients were undertaken to seek the prevalence and to evaluate clinico-pathological significance of recurrent genetic abnormalities such as del(13q14.3), trisomy 12, del(11q22.3) (ATM), TP53 deletion, del(6q21) and IgH translocation/deletion. Materials and Methods: We applied interphase - fluorescence in situ hybridization (FISH) on total 238 cases of B-CLL. Results: Our study disclosed 69% of patients with genetic aberrations such as 13q deletion (63%), trisomy 12 (28%), 11q deletion (18%), 6q21 deletion (11%) with comparatively higher frequency of TP53 deletion (22%). Deletion 13q displayed as a most frequent sole abnormality. In group with coexistence of ≥2 aberrations, 13q deletion was a major clone indicating del(13q) as a primary event followed by 11q deletion, TP53 deletion, trisomy 12, 6q deletion as secondary progressive events. In comparison with del(13q), trisomy 12, group with coexistence of ≥2 aberrations associated with poor risk factors such as hyperleukocytosis, advanced stage, and multiple nodes involvement. In a separate study of 116 patients, analysis of IgH abnormalities revealed either partial deletion (24%) or translocation (5%) and were associated with del(13q), trisomy 12, TP53 and ATM deletion. Two of 7 cases had t(14;18), one case had t(8;14), and four cases had other variant IgH translocation t(?;14). Conclusion: Detail characterization and clinical impact are necessary to ensure that IgH translocation positive CLL is a distinct pathological entity. Our data suggests that CLL with various cytogenetic subsets, group with coexistence of ≥2 aberrations seems to be a complex cytogenetic subset, needs more attention to understand biological significance and to seek clinical impact for better management of disease.


Keywords: B-cell chronic lymphocytic leukemia, fluorescence in situ hybridization, group with coexistence of ≥2 aberrations, IgH aberrations, clinical impact


How to cite this article:
Amare PK, Gadage V, Jain H, Nikalje S, Manju S, Mittal N, Gujral S, Nair R. Clinico-pathological impact of cytogenetic subgroups in B-cell chronic lymphocytic leukemia: Experience from India. Indian J Cancer 2013;50:261-7

How to cite this URL:
Amare PK, Gadage V, Jain H, Nikalje S, Manju S, Mittal N, Gujral S, Nair R. Clinico-pathological impact of cytogenetic subgroups in B-cell chronic lymphocytic leukemia: Experience from India. Indian J Cancer [serial online] 2013 [cited 2019 Aug 18];50:261-7. Available from: http://www.indianjcancer.com/text.asp?2013/50/3/261/118730



 » Introduction Top


B-cell chronic lymphocytic leukemia (B-CLL) is a heterogeneous disease with respect to prognosis and clinical course of the disease. [1],[2],[3],[4],[5],[6] Over a period of time, clinical parameters including staging were not found to be strong prognostic predictors. [1],[3],[4],[5],[6],[7],[8],[9] The cytogenetic studies have disclosed various recurrent abnormalities such as 13q14.3 deletion, trisomy 12, 11q22.3 (ATM) deletion, 6q21 deletion, and TP53 deletion. [4],[5],[6],[9],[10],[11],[12],[13],[14],[15] These recurrent abnormalities proved clinico-pathological and independent prognostic significance as well. Besides these recurrent genetic aberrations, latest updates on IgH aberrations have shown IgH translocations/rearrangement and deletions in B-CLL. [16],[17],[18],[19],[20]

The present study was undertaken to score (a) the frequencies of the recurrent aberrations in our series of patients (b) to identify and categorize cytogenetic sub-groups on the basis of sole aberration and/or with coexistence of additional aberration/s (≥2 aberrations), and (c) to evaluate their clinico-pathological significance to identify the cytogenetic risk groups. In a separate group of 116 patients of B-CLL, we focused upon the frequency and characterization of IgH aberrations.


 » Materials and Methods Top


A total of 238 patients (175 males and 63 females; age range: 24-89 years) were diagnosed between May 2008 and January 2012. The diagnosis of CLL was confirmed by clinical features like peripheral lymphocytosis of 5 × 10 9 /L, positivity for CD19, CD5, CD23, IgK, and IgL. Cases with mantle cell lymphoma (MCL) in leukemic phase and prolymphocytic leukemia were excluded.

Fluorescence in situ hybridization (FISH) studies were performed on interphase cells from bone marrow aspirate and/or peripheral blood with panel of probes consisting of LSI D13S319 (13q14.3)/LSI 13q34, LSI ATM (11q22.3)/CEP11, LSI TP53 (17p13.1)/CEP17, CEP 12, LSI 6q21/SE6, and LSI break apart IgH translocation probe (Vysis Abbott Molecular, Delkenheim, Germany and Kreatech Diagnostics, The Netherlands) according to the manufacturer's protocol. LSI dual color, dual fusion probes IgH/CCND1, IgH/BCL2 and C-MYC dual color break apart probe (Vysis Abbott Molecular) were applied for identification of t(11;14), t(14;18), and C-MYC translocation, respectively. In brief, cells affixed to glass slides and probes were co-denatured at 73°C and hybridized at 37°C by overnight incubation. In every specimen, 200 cells were analyzed for each probe by two observers.

The cut-off baseline values for each probe were 6% for 13q14.3 deletion, 2% for trisomy 12, 5% for ATM and 6q21 deletion, 7% for TP53 deletion, and 8% for IgH break. These values were established in bone marrow aspirate specimens from age and sex-matched normal individuals (BMT donors). Patients with ≥2 aberrations were grouped under "coexistence of ≥2 aberrations".

Statistical analysis was performed using the Statistical Product and Service Solutions (SPSS) program version 18. The significance of various cytogenetic subgroups such as 13q deletion, trisomy 12, ATM deletion, 6q deletion, TP53 deletion and group with coexistence of ≥2 aberrations with clinical variables was evaluated by Chi-square, Mann-Whitney U, and multiple logistic regression analysis.


 » Results Top


Among 238 patients, 164 (69%) had genetic aberrations, of which 115 (70%) revealed sole anomaly and 49 (30%) revealed coexistence of ≥2 aberrations. In the abnormal group, del(13q14.3) was most frequent (63%) followed by trisomy 12 (28%), TP53 deletion (22%), del(11q22.3): ATM deletion (18%), and del(6q) (11%) [Table 1], [Figure 1]. A biallelic (homozygous) deletion of 13q14.3 locus was observed in seven cases, of which five cases were at stage II-IV and two cases were at stage I. The 13q biallelic deletion was a sole abnormality in two cases and in combination with other abnormalities (coexistence of ≥2 aberrations) in five cases. The percentage of aberrant cells for 13q deletion was 8-100%, for trisomy 12: 5-90%, TP53 deletion: 8-96%, ATM deletion: 10-96%, and for 6q deletion: 6-96%. A clone of ≥50% cells was detected in 75% of the cases for del(13q), 60% of the cases for trisomy 12, 33% of the cases for TP53 deletion, 62% of cases for ATM deletion, and 65% of cases for 6q deletion. Among all the recurrent abnormalities, 13q deletion occurred most frequently as a sole anomaly (Freq. 41%) followed by sole trisomy 12 (15%), whereas ATM deletion, TP53 deletion and 6q deletion were most frequently associated with other aberrations [Table 1]. Of the 49 cases in the group with coexistence of ≥2 aberrations, 33 cases (67%) had two aberrations and 16 cases (33%) had three aberrations.
Table 1: Frequency of cytogenetic aberrations in a cohort 238 B-cell CLL patients

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Figure 1: (a) LSI 13S319 (13q14.3) probe shows monoallelic deletion of 13q14.3 locus (1 Red and 2 green signals); (b) LSI probe 13S319 (13q14.3) shows biallelic deletion of 13q14.3 locus (nil Red signals and 2 Green signals); (c) CEP 12 probe shows trisomy 12 (3 Red signals); (d) LSI ATM (11q22.3)/CEP11 probe shows monoallelic deletion of ATM (1 Red and 2 Green signals); (e) LSI TP53 (17p13.1)/CEP17 probe shows monoallelic deletion of TP53 (1 Red and 2 Green signals); (f) LSI 6q21/SE6 probe shows monoallelic deletion of 6q21 (1 Red and 2 Green signals)

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In the group with coexistence of ≥2 aberrations, 70% of cases had del(13q14.3) as a major clone and trisomy 12 (67% of cases), del(TP53) (67% of cases), ATM deletion (75% of cases), and 6q deletion (93% of cases) as secondary clones.

Correlation of cytogenetic groups with clinical and hematopathological parameters

Of 238, 151 patients with proper clinical and laboratory parameters were enrolled for statistical analysis to evaluate the relationship of cytogenetic groups with clinical variables. Overall, frequencies of total genetically abnormal patients as well as individual frequency of del(13q14.3), trisomy 12, TP53 deletion, del(11q22.3), and del(6q21) were almost similar in both groups of 151 and 238 patients. Since ATM and 6q21 deletion were a part of the group with coexistence of ≥2 aberrations and TP53 as a sole aberration was a very small group (five cases), the abnormal cytogenetic group was divided into three categories: Sole 13q deletion, sole trisomy 12, and group with coexistence of ≥2 aberrations. We evaluated clinical significance of these cytogenetic groups, sole 13q deletion, +12 and group with coexistence of ≥2 aberrations by Pearson Chi-square analysis. It revealed significant association of 13q deletion, trisomy 12, and cases with coexistence of ≥2 aberrations with higher age group (P < 0.000, P < 0.03, P < 0.000, respectively) and male patients (P < 0.000, P < 0.03, P < 0.000, respectively) [Table 2]. In comparison with 13q deletion and trisomy 12, group with coexistence of ≥2 aberrations was associated with higher leukocyte count (P < 0.01) [Table 2]. Although not statistically significant, the involvement of lymph node at multiple sites was common in patients with coexistence of ≥2 aberrations (P < 0.06). Patients with sole del (13q) (57%) and trisomy 12 (71%) were at Rai stage 0, I, II. Except two cases at stage I, 42 (95%) patients with coexistence of ≥2 aberrations were at stage II, III, and IV. In comparison with group with coexistence of ≥2 aberrations, group with sole 13q deletion and sole trisomy 12 were associated with normal Hb (≥ 10 g/dL) (P < 0.002) [Table 2].
Table 2: Correlation of cytogenetic groups with clinical and hematopathological parameters in a cohort of 151 B-CLL cases

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We also compared cytogenetic groups with clinical parameters by Mann Whitney U test. When the trisomy 12 group was compared with group with coexistence of ≥2 aberrations, significant differences were observed for stage (P < 0.048), hyperleukocytosis (P < 0.017), and Hb (P < 0.037) [Table 3]. The comparison of various clinical parameters in the group with coexistence of ≥2 aberrations and group with no cytogenetic abnormality showed association of hyperleukocytosis (P < 0.01) in the former group. The multiple lymph node involvement was also noted in the group with coexistence of ≥2 aberrations, although borderline (P < 0.050) [Table 3].
Table 3: Clinical and hematopathological significance of cytogenetic subgroups

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IgH Aberrations

In a separate group of 116 cases (Males: 88, Females: 28, age range: 27 to 87 years) of B-CLL which were not a part of 238 cohort of patients, IgH translocation/deletion by FISH on interphase cells was evaluated. We identified IgH aberrations in 29% (34/116) of cases, of which 5% (7/116) had translocation (1R 1G 1Y) [Figure 2]a, 21% (25/116) of cases had deletion in variable region of IgH (1R1Y/1RdimG1Y) [Figure 2]b, and 3% (4/116) of cases had deletion in 3' IgH region (1G1Y (three cases), 2G2Y (one case) [Figure 2]c). The IgH translocation was the sole abnormality in two cases and was associated with del(13q) in three cases and trisomy 12 in one case. Application of IgH-CCND1, IgH-BCL2, and C-MYC probes identified IgH-BCL2: t(14;18) (1R1G2Y) in two cases, and t(8;14) involving C-MYC (1R1G1Y) and IgH (1R1G1Y) in one case [Table 4] and [Figure 3]. Of seven cases with IgH translocation, four cases were categorized as Atypical CLL based upon immunophenotype and morphology (Atypical CLL: CD 5 +ve, CD23 -ve, CD 20 strong +ve, FMC 7 +ve, lymphoplasmacytic differentiation and/or presence of cleaved cells). Additional concurrent abnormalities were found in 73% (25/34 cases) of cases with IgH aberrations (translocation and deletion). These included del(13q) at incidence of 38% (13/34 cases), trisomy 12: 26% (9/34 cases), del(17p13.1): 18% (6/34 cases), and del (11q): 15% (5/34 cases). Presence of additional abnormalities (≥ 2) apart from IgH was found in 21% (7/34) of cases, in which del(13q), del(17p) and trisomy 12 were most frequent aberrations. The analysis of clone size by screening of interphase cells revealed IgH deletion as a secondary clone (30-70% of cells) with major clones of del(13q), +12, del(11q) and del(17p13.1) (50-95% of cells) in majority (16/28) cases.
Table 4: Characterization of IgH translocation positive CLL cases

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Figure 2: (a) Dual color IgH break apart probe on interphase cells shows normal IgH allele (yellow signal) and residual IgH (1 Red and 1 Green signal); (b) Dual color IgH break apart probe on interphase cells shows normal IgH allele (1 Yellow signal), Residual IgH (1Red signal); (c) Dual color IgH break apart probe on interphase cells shows 2 copies of normal IgH allele (2 Yellow signals), and 2 copies of residual IgH (2 Green signals)

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Figure 3: (a) IgH/BCL2 dual fusion probe shows IgH-BCL2 fusion (2 Yellow signals), 1 normal IgH allele and 1 normal BCL2 allele (1 Green and 1 Red signal, respectively); (b) C-MYC break apart probe on interphase cells shows C-MYC allele (1 Yellow signal) and residual MYC (1 Red and 1 Green signal)

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 » Discussion Top


Frequency of recurrent aberrations (69%): del(13q), +12, del(11q), del(17p), and del(6q) by interphase - FISH in our series was in the range (50-80%) of reported studies which once again proved that FISH is a very efficient technology to detect various types of chromosomal abnormalities like deletion, translocation/partial deletion, and aneusomy. [4],[5],[6],[9],[10],[11],[12],[21] The incidence of del(13q14.3) (63%), trisomy 12 (28%), ATM deletion (18%), and del(6q21) (11%) was not deviated from that of previously reported studies except incidence of TP53 deletion (22%) was comparatively higher in our series than that in the reported literature (4-15%). [5],[7],[9],[10],[11],[13],[15],[21],[22],[23] Since the distribution of patients with TP53 deletion at different stages of disease was almost equal, the higher incidence of TP53 does not seem to be due to high frequency of advanced disease in our series.

Del(13q14.3) was the most common sole abnormality as observed by other studies. The homozygous loss of 13q14 has been reported in other series. [3],[5],[14],[24] Parker et al.,[6] in their studies showed that 13q deletion in B-CLL affects variable regions and patients with large deletions on 13q were significantly associated with disease progression. The significance of large 13q14 deletions was emphasized by involvement of multiple gene loci such as miR15a/16-1 micro RNA, RB1 genes involved in key biological pathways like cell cycle control, NF-KB signaling. [25],[26],[27],[28]

In a group with coexistence of ≥2 aberrations, 13q deletion always displayed as a major predominant clone, and del(11q22.3), del(6q21), TP53 deletion, and trisomy 12 as secondary clones. The co-existence of 13q deletion with other aberrations in significant proportion of cases is consistent with previous observations that 13q deletion could be a primary, initiating event, whereas del(11q), TP53 deletion and 6q deletion could be secondary events necessary for progression of the disease. Except studies by Dewald et al.,[10] which reported 45% of B-CLL patients with coexistence of ≥2 aberrations, the frequency of patients with coexistence of ≥2 aberrations was 30% in our series as observed in the range 7-29% of reported series. [5],[9],[10],[15],[21],[22],[23],[29]

In consistent with previous findings, del(13q) and patients with coexistence of ≥2 aberrations were more common in old age group. On the other hand, trisomy 12 seems to be associated with variable age groups.

Overall three abnormal cytogenetic sub-groups, del(13q), +12, and coexistence of ≥2 aberrations indicated that cytogenetic group with coexistence of ≥2 aberrations was significantly associated with hyperleukocytosis with substantial number of cases at an advanced stage of the disease. The clinical significance of patients with coexistence of ≥2 aberrations is not yet clear except Quijano et al., [5] who found significant increase in the percentage of cycling tumor cells in patients with simultaneous occurrence of del(13q) and del(17p).

The IgH translocation frequency (5%) observed in our series falls in the range of general incidence 4-9% of reported studies in B-CLL. [17],[24],[30] High incidence of IgH translocation (19%) was reported by Flanagan et al., [26] in the lymph node tissue. We could characterize two cases with t(14;18) and one with t(8;14). The remaining four IgH translocation positive cases indicated involvement of partner chromosome other than 8, 11, and 18. Heterogeneity of IgH translocations such as t(2;14)(p13;q32) affecting BCL11A, t(6;14)(p21;q34) affecting CCND3, t(7;14)(q21;q32) affecting CDK6, t(11;14) affecting CCND1 has been reported in CLL. [17],[31] However, recent updates have shown the association of t(14;19)(q32;q13) affecting BCL3 gene with B-CLL. [17],[19],[31],[32] In other reported studies of B-CLL, clinico-pathological characterization of IgH/14q32 translocation showed association with clinical features and unfavorable prognostic factors such as unmutated IgVH, expression of ZAP-70, CD38 positivity, atypical immunophenotype and trisomy 12/complex cytogenetics. [17],[19],[32],[33] In our group of IgH translocation positive cases, only one patient had trisomy 12 as an additional aberration, whereas del(13q) was comparatively more frequent as an additional abnormality. Cavazani et al., [24] found coexistence of t(14;19), del(13q), and trisomy 12.

Recently, few studies have disclosed IgH deletions in B-CLL with incidence 9-33% which matches with incidence (24%) in our series. [18],[20],[34],[35],[36] As reported in other studies, the most frequent target region of IgH deletion was variable region in our cases. [18],[20] As observed in IgH translocation positive cases, patients with IgH deletions in our series frequently showed coexistence of 13q deletion, followed by trisomy 12, TP53, and ATM deletion. On the other hand, trisomy 12 was most frequently observed as an additional aberration in B-CLL patients with IgH deletion in other reported series. [19],[20],[35],[36] The biological and clinical significance of IgH deletion of variable region is a controversial issue. IgH deletion with ≥2 aberrations in substantial number of patients was an interesting observation in our series. The co-existence of IgH abnormalities (IgH translocation and/or deletion) with other recurrent aberrations in our series indicated that IgH aberrations may frequently occur in association with other aberrations. IgH aberration (translocation/deletion) positive cases included both typical and atypical CLL based upon immunophenotype and morphology. [37] IgH deletion cases were typical CLL and four out of seven cases with IgH translocation had atypical CLL. Association of IgH translocation: t(14;19) with atypical morphology and immunophenotype in B-CLL has been reported by Huh et al., [19] and Martin-Subero et al.[32] Prognostic impact of IgH aberrations as a sole or in association with other recurrent aberrations was not clear in our series due to unavailability of clinical data in some cases. Detail characterization of IgH aberrations and clinical correlation in a large prospective study is essential to understand the biological and clinical significance which can help ensure that IgH aberration in B-CLL is a distinct pathological entity.

In conclusion, our study supported the importance of interphase-FISH as a sensitive and efficient technique to detect prevalence of various recurrent abnormalities such as del(13q), trisomy 12, del(11q), TP53 deletion, del(6q), and IgH aberrations which are known to have diagnostic and prognostic significance. The higher frequency of TP53 deletion may reflect population difference. The study also supported the earlier observation that 13q deletion as a sole aberration could be a primary event followed by development of 11q deletion, 6q deletion, and TP53 deletion as secondary progressive changes responsible for progression of the disease. In comparison with sole del(13q), sole trisomy 12, group with coexistence of ≥2 aberrations was indicative of a high risk group. The IgH aberration +ve group was found to be another sub-class associated frequently with other additional aberrations. Hematopathological picture of IgH translocation group inclined towards atypical CLL. Detail characterization and clinical impact are essential to ensure that IgH aberrations in B-CLL is a distinct pathological entity.


 » Acknowledgment Top


Our thanks to Ms. Arti Kanujia, Statistician for her help in the statistical analysis.

 
 » References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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