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Bio-Technical Methods Section (BTS)

Is t(14;18)(q32;q21) a constant finding in follicular lymphoma? An interphase FISH study on 63 patients

Abstract

The translocation (14;18)(q32;q21) is the hallmark of follicular lymphoma (FL). However, conventional cytogenetics and PCR techniques fail to detect it in at least 10% of cases. In order to evaluate the true incidence of this translocation in FL, we analyzed 63 patients with FL, and 17 patients with diffuse large cell lymphoma (DLCL) corresponding to suspected FL transformations using interphase fluorescence in situ hybridization (FISH). Colocalized signals related to the translocation were observed in 19–92% of cells (median = 51%), corresponding to positivity over the threshold in all (63/63) cases. Similarly, 16/17 possibly secondary DLCL displayed the translocation. Although some cytogenetic changes might be missed by this FISH assay (such as rare insertion, or translocations with other chromosomal partners), our results stress t(14;18)(q32;q21) as an almost constant finding in FL. Our sensitive interphase FISH assay should be of great value to define FL more accurately, namely in patients included into therapeutic trials. Furthermore, this approach could be of interest in (re)defining some types of FL, especially the grade 3 FL which frequently lack t(14;18).

Introduction

Follicular lymphoma (FL) accounts for 20–25% of all non-Hodgkin's lymphomas (NHL)1 and is recognized as one single entity in the World Health Organization (WHO) classification.2 The hallmark of FL is a translocation involving the bcl-2 gene (B cell leukemia/lymphoma 2) and the IgH (immunoglobulin heavy chain) gene, leading to t(14;18)(q32;q21) and the overproduction of BCL2 protein, that prevents cells from undergoing apoptosis.

Besides histology, various methods have been proposed to ascertain diagnosis of FL. Overexpression of BCL2 protein is detected in >90% of cases using immunohistochemistry,3 but it is far from being specific for FL.3,4 Also, breakpoints at bcl-2 locus are not always located within either the major breakpoint region (MBR) or the minor cluster region (mcr), and PCR methods using such primers cannot demonstrate molecular rearrangement in all the cases, 10–15% of the cases lacking any specific amplification with these primers.5 Conventional cytogenetics is the best way to detect karyotypic changes in tumor samples but several limitations, including the need of fresh samples, lead to demonstrating t(14;18) in only 75% to 85% of FL.3 Interphase fluorescence in situ hybridization (FISH) is an alternative for the diagnosis of cytogenetic changes, and several sets of probes have been described to assess this translocation.6,7,8 Using these assays, bcl-2 rearrangements were observed in 85% to 100% of the cases. Thus, the exact incidence of t(14;18) in FL remains unknown.

In this report, we developed a colocalization-based FISH assay using a new set of probes, hybridizing to the centromeric part of IgH, and to the telomeric region of the bcl-2 loci, respectively, in order to detect t(14;18) whatever the breakpoints within the bcl-2 gene. This assay was applied to frozen samples from 63 histologically proven FL. Because a part of diffuse large B cell lymphomas (DLBCL) are reported as resulting from a preceding FL phase,9,10 we tested these probes in a limited number of DLBCL with a known or highly suspected previous history of FL, to determine the accuracy of that assay in such instances.

Materials and methods

Tissue samples

Retrospective interphase FISH study was performed on frozen samples (−80°C) from 63 FL and 17 DLBCL stored at the tissue libraries of the Pathology Departments from Nantes and Angers (France). Samples corresponded to biopsies of lymph nodes, tonsils, parotids, spleen, pleural effusion, bone marrow or peripheral blood, in 60, 2, 2, 1, 1, 9 and 5 cases, respectively.

Diagnosis of FL (n = 63) was performed according to the WHO classification criteria, including morphology (predominantly follicular pattern, without or with some diffuse areas, cleaved and noncleaved follicle center cells) and immunophenotype. Monotypic Ig light chain expression, negativity for CD5, positivity for CD20 (or CD19) and for CD10 was needed to include every case. Flow cytometry was performed at diagnosis on suspended cells (peripheral blood, bone marrow, or disruption of one part of the lymph node) to allow determination of tumor involvement in 40 cases. All cases that met the above mentioned diagnostic criteria and that had sufficient frozen material were included in the study.

For DLBCL (n = 17), diffuse growth pattern, centroblasts or/ and immunoblasts, and immunophenotype of B cell lineage were used as diagnosis criteria. Preceding history of FL or part of the tumor sample showing remnant architecture of FL (hypothesizing evolution from a previously undiagnosed FL) were present in 12 and five cases, respectively.

Reactive lymph nodes (10 cases), bone marrow and peripheral blood mononuclear cells from normal donors (10 cases) were used as negative controls.

DNA probe description

The first set of probes corresponded to cos Ig10 and PAC 210c12, labeled by nick translation with SpectrumGreen-dUTP and SpectrumOrange-dUTP, respectively (Vysis, Voisins-le-Bretonneux, France). Cos Ig10 (T Rabbits; MRC, Cambridge, UK) hybridizes the Cα2 and Cε IgH sequences, located at the centromeric border of the IgH gene on chromosome 14, as previously reported.11 PAC 210c12 maps at the 5’ end of the bcl-2 gene, downstream from the FVT-1 locus12 on chromosome 18, as previously published6 (Figure 1).

Figure 1
figure1

The IgH/bcl-2 molecular rearrangement. Breakpoint clusters are indicated (arrows), as well as sequences hybridizing the cos Ig10/PAC 210c12 set of probes.

The second set of probes used was LSI IGH/BCL2 Dual Color, Dual Fusion Translocation Probe (Vysis), a mixture of SpectrumGreen-labeled LSI IGH and Spectrum Orange-labeled LSI BCL2 probes. LSI IGH contains sequences homologous to the whole IgH locus, and sequences extending about 300 kb beyond the 3’ end. LSI BCL2 covers the whole bcl-2 gene region and sequences extending approximatively 250 kb both distal and proximal to the gene. Cos Ig10, PAC 210c12, LSI IGH and LSI BCL2 probes span approximately 60 kb, 120 kb, 1.5 Mb and 750 kb, respectively.

Centromeric (a satellite) CEP 18 and CEP 8 DNA probes (Vysis) were used in some cases, in order to better ascertain polysomy or polyploidy in some patients.

Fluorescence in situ hybridization

Interphase FISH was performed on nuclei isolated from uncultured frozen biopsies or suspended cells, as follows. After fast thawing, each biopsy was mechanically disrupted in a few milliliters of 1X PBS (phosphate buffer saline), in order to obtain an homogeneous cell suspension. After incubation in an hypotonic solution (KCl 0.075 M/37°C/30 min), cells were fixed (methanol/cold acetic acid, 3 vol/1 vol) and dropped on slides. Nuclei were denaturated for 3 to 5 min in formamide 70%/2 X SSC, pH 7, and then dehydrated in gradient alcohol baths. Denatured probes (10 μl) were dropped on the slides, covered with a coverslip and sealed with rubber cement. An overnight hybridization was performed at 37°C in a humid chamber. After washes for 5 min at 73°C in 2 X SSC baths and a quick rinse for 2 min in 2 X SSC 0.1% Triton bath, nuclei were counterstained with DAPI and mounted in an antifade solution. Slides were analyzed on an epifluorescence microscope (Axioplan 2; Zeiss, Jena, Germany), and hybridization signals were evaluated on 100 to 200 nuclei on each slide.

R banding analysis and PCR

Cytogenetic analysis was performed in 21 patients, according to Bastard et al13 Karyotypes were described according to the International System for Human Genetic Nomenclature (ISCN, 1995). Thirty-three patients were studied at diagnosis for PCR-MBR rearrangement, as previously described.14 All patients corresponded to FL at diagnosis.

Results

PCR and R banding analysis

PCR demonstrated a MBR-bcl2 rearrangement in 19/33 FL samples (58%) (mcr not tested). Cytogenetic study was performed in 21 cases and demonstrated t(14;18) in most (at least 80%) or in a few (5 to 40%) metaphases analyzed in 14 and three cases, respectively. One case showed 18q− only (14q+ undetected), one case (AJ) presented with a complex karyotype, as follows: 50,XX,der(1)t(1;2)(p36;?),del(6)(q22),+7,der (11)t(11;12)(p15;q12), der(12) t(1;12)(q25;p13),+del(12)(q21),+14,add(18)(q21),+21 [15], and the last two samples presented with a normal karyotype.

Interphase FISH

Controls: In non-malignant nuclei, the expected pattern was the same with both sets of probes: two Orange and two Green separated signals (2O2G pattern). Using cos Ig10 and PAC 210c12 probes, t(14;18) led to the colocalization of one Orange and one Green signal leading to a yellow (or Orange/Green) fusion signal (1O1G1F pattern). Using LSI IGH/BCL2 probes, the most common pattern was as follows : one Orange signal, one Green signal representing the normal chromosomal homologs, respectively, and two Orange/Green (yellow) fusion signals, corresponding to both derivative chromosomes (1O1G2F pattern). In normal patients and reactive lymph nodes some fusion signals were observed, corresponding to random colocalization of bcl-2 and IgH regions. Using Ig10/PAC210c12 probes, an average of 6.7% nuclei showed one fusion signal, and the threshold to ascertain translocation was defined over 11% (mean + 3 s.d.)-positive cells. Using LSI IGH/BCL2 probes, an average of 0.5% nuclei showed two fusion signals, and threshold was defined over 1%. Depending on the level of condensation of DNA and on the cycle phase, a few cells could exhibit up to three or four signals of the same color: random colocalization led to two fusion signals in some of such cells.

Using Ig10/210c12 probes, 63 of the 63 (100%) FL tested presented with at least one fusion signal in a number of cells over the threshold (19 to 92% (mean 51%)). In 56/63 cases, the expected pattern corresponding to 1O, 1G, and 1F signal, respectively, was observed. In seven cases, atypical patterns could be observed, corresponding to an increased number of O and G signals: the use of centromeric probes (and karyotype if performed) led to an explanation in each instance (Table 1). All samples demonstrating atypical patterns were selected and studied using the LSI IGH/BCL2 probes.

Table 1 Atypical patterns observed using Ig10/210c12 and/or LSI IGH/BCL2 probes

Using LSI IGH/BCL2 (Vysis) probes, 39/40 FL tested presented with two colocalized fusion signals over the threshold (8 to 90% (mean 49%)). The expected 1O1G2F pattern was observed in 30 cases and atypical patterns in the other nine cases (Table 1). Comparison of the results obtained using both sets of probes (40 cases) demonstrated discrepancies in two cases (Table 2). In one case LSI IGH/BCL2 failed to detect any abnormality although MBR rearrangement was demonstrated after PCR study. In the last case, the translocation was ascertained using both Ig10/210c12 and LSI IGH/BCL2 probes, but the respective numbers of positive nuclei differed (30% and 8%). In that latter case, clear-cut positivity was observed using Ig10/210c12 probes whereas green signals corresponding to IgHhybridization of Vysis probe were very faint. As V(D)J rearrangements (within the variable region) or class-switch deletions (within the constant region) may occur on one or both the translocated or non-translocated IgH alleles in FL,15 the green probe signal intensity from the relevant IgH region (on one or both alleles) may be diminished as a result of the LSI IGH probe target deletion.

Table 2 Comparison of results obtained in 40 FL using both cos Ig10/PAC 210c12 and LSI IGH/BCL2 sets of probes

Flow cytometry using CD10 and CD19 allowed determination of tumor infiltration in 26 lymph nodes, five peripheral blood and nine bone marrow samples, ranging from 19% to 100% (median 52%). Results are reported in Table 2.

In DLBCL, among the 17 cases tested using Ig10/210c12 probes, only one presented with colocalized signals below the threshold (one fusion signal in 8% of cells), whereas the 16 other specimens presented with the classical 1O1G1F pattern (25 to 85% of nuclei (mean 54%)). The negative sample was tested using the LSI IGH/BCL2 probes and was also negative.

Discussion

The translocation (14;18)(q32;q21) is the hallmark of FL, discovered in up to 85% of patients after conventional cytogenetic study.3,9 If breakpoints at 14q32 always lay within IgHJ(D) segments,16 breakpoints are much more scattered at 18q21: although mainly located within MBR or mcr regions (50–75% and 5–25% of cases, respectively),9,10 various other breakpoints, scattered between MBR and mcr, or at the 5’ side in VCR (variant cluster region) or FVT-1 (follicular variant translocation) have been reported.12,17,18 The interphase FISH assay that we have developed here uses a set of probes hybridizing to DNA sequences located at distance from all breakpoints reported in the literature to date: PAC 210c12, mapping to the telomeric region (or 5’) of all the 18q21 breakpoints, and Ig10, mapping to the centromeric part (or 3’) of all reported 14q32 breakpoints (Figure 1). This set of probes allowed us to ascertain t(14;18) in 63/63 (100%) FL tested. Conventional cytogenetic study was performed in only one part of our cases, but results were in agreement with literature data (eg 85% positive cases).3,9 Several explanations dealing with normal karyotypes in FL have been suggested, including complex karyotypes masquerading the translocation (case AJ), fully balanced cryptic translocations (under the resolution of banding), low tumor cell infiltration, or low proliferative index of tumor cells.3,7 The latter two hypotheses cannot be ruled out in some of our cases, and we found a good relationship between the number of cells exhibiting positive fluorescent signal and the number of tumor cells infiltrating the sample, in each case studied using flow cytometry (table 2).

We observed two cases with normal karyotype although tumor infiltration was high (80% and 85% tumor cells). As molecular study failed to detect MBR rearrangement in either case, this led to question about the presence of t(14;18). However, in both cases, interphase FISH assays (using Ig10/210c12 and LSI IGH/BCL2 probes) were positive in a number of cells similar to tumor infiltration rate. That led to hypothesize in both cases low tumor cell proliferation rate, although a cryptic translocation could not be fully ruled out, but the lack of associated cytogenetic abnormalities does not support the hypothesis of FL with a cryptic translocation.

LSI IGH/BCL2 dual fusion translocation probe (Vysis) also detects t(14;18) in FL, but comparison with our set of probes demonstrated discrepancies in two of 40 cases tested (Table 2). In one instance, discrepancy was related to a difference in the respective numbers of cells exhibiting positive signal, LSI IGH/BCL2 probes underestimating the level of the tumor cell infiltration as compared to both results using our probes and immunological methods. In one instance, low intensity of fluorescent signal corresponding to the IgH probe might correspond to a large deletion within the IgH loci, as reported.15

Other interphase FISH assays were reported to study FL, and a segregation-based interphase FISH assay using two probes flanking bcl-2 breakpoint regions was described by Vaandrager et al.6 Thirty-five out of 35 (100%) samples with bcl-2 rearrangement were detected. As the partner chromosome could not be identified using that interphase FISH assay, the same authors proposed either the study of metaphase nuclei or to develop a three-color FISH assay, using two probes flanking the breakpoint region on one chromosome and a third one for the partner chromosome, both proposals difficult to apply in routine conditions. Using YAC yA153A6, spanning the whole bcl-2 region, and J1.3, hybridizing within the C region of the IgH gene, a colocalization-based interphase FISH assay was described by Poetsh et al:7 a fusion signal was detected in 30/30 FL. However, threshold for positivity was quite low, that led to ascertain positivity for all FL tested but also for one part of normal controls. Moreover, subsequent studies failed to confirm that low threshold using both identical probes,6,8 and a recent study showed that this set of probes was unable to detect some cases of FL,8 and the proposed explanation was that the bcl-2 probe used did not map at a sufficient distance of all possible breakpoints.

In a preliminary study, we applied our interphase FISH assay in DLBCL cases following a FL: 16 of 17 cases tested were found to bear t(14;18), showing that our assay is also suitable to identify such a subgroup of patients within DLBCL.

Cytogenetic studies reported some chromosomal rearrangements in FL other than t(14;18)(q32;q21), including translocations between bcl-2 gene and Igκ at 2p12 or Igλ at 22q11, or double rearrangement on the same allele (5’end transferred to the Igλ locus,6 VCR deletion19). All the above mentioned cytogenetic changes cannot be detected using both our assay and the commercially available one. However, as we demonstrated t(14;18)(q32;q21) in all patients from a series of 63 FL cases tested, incidence of such abnormalities is certainly low. Moreover, several reports described FL cases lacking any bcl-2 rearrangement, especially in grade 3 FL.20,21,22 These cases frequently display bcl-6 rearrangements and may correspond to special forms of DLBCL. Stringent criteria are needed to include patients into clinical trials: our interphase FISH assay could be used in order to ascertain histological diagnosis of FL, namely for those cases negative after cytogenetic or molecular studies. That will certainly lead to define more accurately patients into prospective therapeutic trials.

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Godon, A., Moreau, A., Talmant, P. et al. Is t(14;18)(q32;q21) a constant finding in follicular lymphoma? An interphase FISH study on 63 patients. Leukemia 17, 255–259 (2003). https://doi.org/10.1038/sj.leu.2402739

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Keywords

  • interphase FISH
  • follicular lymphoma
  • t(14;18)(q32;q21)
  • bcl-2
  • diffuse lymphoma

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