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ORIGINAL ARTICLE  
Year : 2012  |  Volume : 55  |  Issue : 3  |  Page : 347-351
Fluorescence in situ hybridization patterns of BCR/ABL1 fusion in chronic myelogenous leukemia at diagnosis


1 Cytogenetics Unit, Christian Medical College, Vellore, Tamilnadu, India
2 Department of Cytogenetics,Tata Medical Centre, Kolkata, West Bengal, India
3 Department of Hematology, Christian Medical College, Vellore, Tamilnadu, India

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Date of Web Publication29-Sep-2012
 

   Abstract 


Background : Chronic myelogenous leukemia (CML) is characterised by the t(9;22)(q34;q11.2) which results in the formation of the BCR/ABL1 fusion gene. Occasionally, the t(9;22) may be associated with submicroscopic deletions of chromosomes 9 and/or 22 which appear to be associated with a worse prognosis. Three or four-way variant t(9;22) may also occur. All these changes as well as gain of the Philadelphia chromosome which represents disease progression can be detected by fluorescence in situ hybridization (FISH) analysis. FISH analysis at presentation is used to determine the number of cells with BCR/ABL1 fusion and establish whether the patterns are typical or atypical. Response to therapy can then be monitored by serial testing. Patients and Methods : The study group consisted of all patients diagnosed or suspected to have CML who had interphase FISH analysis at presentation on peripheral blood/bone marrow using a commercially available BCR/ABL1 dual colour, dual fusion probe. The study was performed at a tertiary hospital in India between 2004 and 2010. Results: There were 1076 diagnostic samples which were positive for BCR/ABL1 fusion. Typical dual fusion signals (two fusions, one red and one green, 2F1R1G) were seen in 801 cases (74 %). Atypical signal patterns were seen in 275 cases (26%). These were: 1F1R2G (4%), 1F2R1G (2.5%) and 1F1R1G (11%) representing deletions of the derivative 9 involving chromosome 9 sequences, chromosome 22 sequences, or both respectively; 3F1R1G (6.5%) usually representing gain of an additional Philadelphia chromosome and 1F2R2G (1%) representing a three- or four-way variant translocation. More than one signal pattern was seen in 1%. Conclusions: Our findings were similar to the literature with respect to the distribution of signal patterns except that we had a lower number of patients with variant translocations. While each signal pattern is typically associated with a particular abnormality, there can be more than one explanation for each pattern. Hence, metaphase FISH analysis is the "gold standard" for the interpretation of signal patterns.

Keywords: Chronic myelogenous leukemia, BCR/ABL1 fusion, atypical FISH signals

How to cite this article:
Jain PP, Parihar M, Ahmed R, Abraham A, Vishwabandya A, George B, Mathews V, Srivastava A, Srivastava VM. Fluorescence in situ hybridization patterns of BCR/ABL1 fusion in chronic myelogenous leukemia at diagnosis. Indian J Pathol Microbiol 2012;55:347-51

How to cite this URL:
Jain PP, Parihar M, Ahmed R, Abraham A, Vishwabandya A, George B, Mathews V, Srivastava A, Srivastava VM. Fluorescence in situ hybridization patterns of BCR/ABL1 fusion in chronic myelogenous leukemia at diagnosis. Indian J Pathol Microbiol [serial online] 2012 [cited 2014 Apr 23];55:347-51. Available from: http://www.ijpmonline.org/text.asp?2012/55/3/347/101742



   Introduction Top


The reciprocal t(9;22)(q42;q11.2) is diagnostic of chronic myelogenous leukemia (CML) and juxtaposes the ABL1 gene on chromosome 9 to the BCR locus on chromosome 22 resulting in the formation of a BCR/ABL1 fusion gene which has constitutive tyrosine kinase activity. [1] It is also seen in acute lymphoblastic leukemia, although the molecular breakpoint on chromosome 22 is different in the majority of patients. [2] Conventional cytogenetic analysis (karyotyping) of bone marrow is the most commonly used method for confirming the presence of the t(9;22). However, this requires familiarity with chromosome morphology and cell culture techniques and is labour-intensive. Therefore, fluorescence in situ hybridization (FISH) using a commercially available locus specific dual colour, dual fusion probe may also be used for confirmation of the t(9;22). [3] In individuals lacking the t(9;22), two green and two red signals are seen on the normal chromosomes 9 and 22. [4] This pattern is altered when the t(9;22) is present. FISH analysis at presentation can confirm that the t(9;22) is present and show whether the signal patterns are typical or atypical. The latter usually represent deletions on the derivative (translocated) chromosome 9, three-or four-way variant t(9;22) or an additional Philadelphia chromosome. [4],[5] Response to therapy can then be monitored by serial testing. A change in signal pattern, especially gain of the derivative chromosome 22 (Philadelphia chromosome) signifies that there is disease progression. [6],[7],[8] There are only a few studies describing the patterns of BCR/ABL1 fusion FISH signals in unselected patients with CML. [4],[5] We describe the FISH patterns observed in a large cohort of patients with CML at presentation.


   Patients and Methods Top


All samples at initial presentation from patients diagnosed or suspected to have CML based on peripheral blood and bone marrow findings evaluated at a tertiary care centre in India between April 2004 and December 2010 were included in this analysis. Post treatment samples and those with myeloproliferative neoplasms other than CML and acute lymphoblastic leukemia were excluded.

A total of 3537 BCR/ABL1 FISH tests were performed on blood and bone marrow during the period of study of which 1400 were post treatment samples. Interphase FISH analysis was performed using fixed cell suspensions obtained by direct or unstimulated overnight cultures of peripheral blood or bone marrow using standard protocols. [9] A dual colour, dual fusion BCR/ABL1 translocation probe (Abbott Molecular-Vysis Inc., Des Plaines, IL, USA) was used. At least 200 interphase cells and any available metaphases were analysed from each sample at 1000× magnification by two independent observers using a Zeiss Axioimager or Axioskop 2 mot microscope and Isis software (Meta Systems, GmBH, Altlussheim, Germany). Results were recorded using the International System for Human Cytogenetic Nomenclature (ISCN) 2005 and 2009. [10],[11]

Description of FISH Signal Patterns

With the dual colour, dual fusion BCR/ABL1 probe [Figure 1], the normal signal pattern consists of two red and two green signals (2R 2G) on the normal chromosomes 9 and 22 respectively [[Figure 2], first row]. When the t(9;22) is present, the typical BCR/ABL1 fusion pattern (2F 1R 1G) consists of two fusions (2F), one red (1R) and one green (1G) signal [Table 1]; [Figure 2], second row]. The fusion signals are seen on the chromosomes 9 and 22 derived from the balanced t(9;22) while the red and the green signals are seen on the non-rearranged chromosomes 9 and 22, respectively. An untreated patient was considered to be positive for BCR/ABL1 fusion if more than 2 % of interphase cells (or at least two metaphases, if present) showed typical dual fusion signals.
Figure 1: Diagrammatic representation of the dual colour, dual fusion probe

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Figure 2: BCR/ABL1 fusion signal patterns by FISH analysis. First row: Normal, second row: 2F 1R 1G, third row: 1F 1R 2G, fourth row: 1F 2R 1G, fifth row: 1F 1R 1G, sixth row: 3F 1R 1G, seventh row: 1F 2R 2G. *variable partner chromosome

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Table 1: BCR/ABL FISH signal patierns and their interpretation

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There are five commonly recurring atypical fusion patterns: 1F 1R 2G, 1F 2R 1G, 1F 1R 1G, 3F 1R 1G and 1F 2R 2G [Table 1]; [Figure 2], third to seventh row].

Three of these patterns-the 1F 1R 2G, 1F 2R 1G and 1F 1R 1G-all represent a deletion of the derivative chromosome 9. The 1F 1R 2G is seen when the deletion involves only the chromosome 9 sequences 5' of the ABL1 breakpoint [[Figure 2], third row] while the 1F 2R 1G represents a deletion involving only the chromosome 22 sequences 3' of the BCR breakpoint [[Figure 2], fourth row]. The 1F 1R 1G signal pattern is seen when the deletion involves chromosome 9 sequences, 5'of the ABL1 breakpoint as well as chromosome 22 sequences, 3' of the BCR breakpoint [[Figure 2], fifth row].

The other two atypical patterns are the 3F 1R 1G which usually represents gain of an additional Philadelphia chromosome [[Figure 2], sixth row] and the 1F 2R 2G which usually represents either a three-way or a four-way variant t(9;22) [[Figure 2], seventh row]. The signal patterns and their usual interpretations are summarized in [Table 1] and [Figure 2].


   Results Top


There were 1076 diagnostic samples of CML in which FISH analysis showed BCR/ABL1 fusion. These included 988 peripheral blood and 88 bone marrow samples.

We found the typical 2F 1R 1G signal pattern in 801 cases (74 %). Atypical fusion patterns were seen in the remaining 275 cases (26%), the commonest among which was the 1F 1R 1G seen in 112 patients (10%). There were 81 patients who had more than one type of signal. The majority (70, 86 %) had typical dual fusions associated with gain of a Philadelphia chromosome (2F 1R 1G and 3F 1R 1G). The remaining 11 had: Dual fusions with atypical single fusions (2F 1R 1G with 1F 1R 1G or 1F 1R 2G or 1F 2R 1G); two types of atypical single fusions (1F 1R 1G with 1F 1R 2G or 1F 2R 1G); dual or single fusions associated with gain(s) of the ABL1 and/or BCR loci. These gains could represent either isochromosome(s) 9q or 22q or complete/partial trisomy or tetrasomy of these chromosomes (2F 3R 3G, 2F 4R 4G, 1F 3R 3G, 1F 4R 4G). See [Table 2] for details of these 11 patients. The median age of our patients was 37 years (range: 3 to 83 years) and the M:F ratio was 2.39:1. There were 49 patients below 15 years of age.
Table 2: Cases with more than one FISH signal patiern

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   Discussion Top


Our data shows that the majority (74%) of our patients showed the typical BCR/ABL1 dual fusion (2F1R1G) pattern at presentation. This is similar to the reported incidence of 71% to 88%. [4],[5],[12],[13],[14] Atypical FISH signal patterns were seen in 26% of our patients. The atypical single fusion patterns 1F 1R 1G, 1F 1R 2G and 1F 2R 1G represent submicroscopic deletions on the derivative chromosome 9 which may involve chromosome 9 sequences or chromosome 22 sequences, or both; such deletions have been reported in 10-15% of patients. [4],[15] Deletions of the derivative chromosome 9 appear to occur when the t(9;22) is formed, rather than during disease progression. [13],[16] Derivative 9 deletions were reported to be associated with a poor prognosis in all disease phases of CML. [13],[14],[15],[17],[18] However, more recent studies have shown that the adverse effect of derivative chromosome 9 deletions can be mitigated by Imatinib therapy at least in early chronic phase CML. [18],[19] Awareness of the different patterns associated with derivative 9 deletions will enable accurate interpretation of signals. It is important to note that this group of patients cannot be identified by karyotyping which will usually only show a reciprocal t(9;22) similar to those without such deletions. [5],[8] Morphological assessment of blood and bone marrow is also not useful to differentiate between those with and without such deletions.

We noted deletions of the derivative chromosome 9 in 17.5% of our patients. In this group, deletions of chromosome 9 sequences alone were seen in 4%, deletions of chromosome 22 sequences alone in 2.5% and deletions of sequences from both chromosome 9 as well as chromosome 22 in 11%. This is similar to the findings of Huntly et al. [20]

The most common atypical fusion signal pattern was the 1F 1R 1G. This pattern has to be interpreted with caution if it is seen in<20% of cells as it may be a false positive due to artefactual co-localisation of the normal red and green signals. We report positivity for 1F 1R 1G in our laboratory only if more than 20% of interphase cells (mean+2 SD based upon study of normal samples of peripheral blood and bone marrow, unpublished observations) or at least two metaphases show this abnormality (based upon the definition of clonality as defined by the International System for Human Cytogenetic Nomenclature). The position of each signal can be confirmed by using single band pass filters that detect each fluorochrome. Use of an extra signal (ES) or tricolour fusion probe would also help to exclude artefactual co-localisation of signals [4],[12] . However, the tricolor fusion probe is considerably more expensive and requires an additional excitation filter in the fluorescence microscope. Rarely, this pattern may also be seen when there is loss of the entire derivative chromosome 9. The other atypical single fusion patterns associated with derivative 9 deletions (1F 1R 2G and 1F 2R 1G) are easier to interpret; however, the caveats described above must be followed. Our cut-off values for each of these two patterns are: >10% of interphase cells or at least two metaphases with this abnormality.

In most instances the 3F 1R 1G pattern (6.5%) represents gain of an additional Philadelphia chromosome (derivative chromosome 22) which indicates that there is disease progression. [7],[21] Rarely, the third fusion signal may be due to gain of the derivative chromosome 9. [4] The incidence of this pattern is also similar to that reported in the literature. [5]

The incidence of the 1F 2R 2G pattern appears to be lower (1%) in this study than the reported incidence of 9% to 10% in other Asian studies. [5],[22] This pattern must also be interpreted with caution as it may represent either a three-or a four-way variant translocation or a typical dual fusion. This is because the widely-used commercially available BCR/ABL1 probe (Abbott Molecular-Vysis Inc.) is designed with a 300 kb gap on chromosome 22. Therefore, if the degree of DNA condensation in a particular cell is low, one fusion signal will appear to be split. This can result in the 1F 2R 2G pattern even in patients with a typical reciprocal t(9;22). However, in such instances, careful analysis will detect a second (sometimes small) population of interphase cells with the typical 2F 1R 1G pattern. If metaphases are present in the sample, the distinction between a reciprocal t(9;22) and a three-or four-way variant t(9;22) can be made easily. Variant translocations account for 2-10% of cases with chromosomes 1, 6, 7, 12 and 19 being the most commonly involved partner chromosomes. They do not appear to have an adverse impact on outcome. [22],[23]

The presence of more than one type of BCR/ABL1 fusion pattern in the same patient suggests that more than one clone is present. The concurrent presence of 2F 1R 1G as well as 3F 1R 1G represents clonal evolution which signifies disease progression.

Conventional cytogenetic analysis and/or reverse transcriptase polymerase chain reaction (RT-PCR) are used to follow-up patients with CML. Conventional cytogenetic analysis helps in identifying the characteristic t(9;22) in about 95% of cases of CML but cannot detect cryptic translocations or other rearrangements of the BCR or ABL1 loci. [4],[5] The technique is also labour-intensive and based on morphology; therefore, it requires significant skills in pattern recognition without which errors in interpretation are likely to occur in difficult cases. FISH techniques are easier to standardize. In our institution, the cost of FISH is marginally more than karyotyping, but considerably less than RT-PCR. FISH has the shortest turn-around time. The results of bone marrow interphase FISH have been shown to correlate well with conventional cytogenetic analysis for the diagnosis and follow-up of CML. [24],[25],[26] Several studies have also shown that there is no difference between the results of interphase FISH on blood and bone marrow in CML. [3],[27],[28] Therefore, peripheral blood FISH could replace karyotyping for initial monitoring of response to tyrosine kinase inhibitors. This will not only result in a shorter turn-around time but will also reduce the need for repeated bone marrow aspirations on these patients reducing cost and discomfort. RT-PCR for BCR/ABL1 fusion transcripts will continue to be used to define molecular remission and can be performed on peripheral blood after FISH shows very low levels or negativity for BCR/ABL1 fusion.

We have described the commonly seen interphase FISH patterns among our patients with CML at initial presentation using a commercially available dual colour, dual fusion probe for the BCR and ABL1 loci. Typical fusion patterns seen in the common recurring t(9;22) can be interpreted fairly easily. To be certain that an atypical fusion pattern is not due to co-localization of signals, it must be present in adequate numbers of cells as described earlier. The presence of more than one signal pattern in a patient could represent clonal evolution. Although the recurring patterns are fairly well-defined, there can be more than one interpretation for each pattern. Therefore, metaphase FISH analysis remains the "gold standard" for confirmation of these changes.

In conclusion, interphase FISH using a commercially available dual colour, dual fusion BCR/ABL1 probe is a sensitive, specific, efficient and cost-effective way to establish the initial diagnosis of CML. It reveals submicroscopic abnormalities that are not detectable by conventional cytogenetic analysis or by morphological examination of blood or marrow. It can also detect additional small clones or gain of a Philadelphia chromosome which provide evidence of disease progression, as well as variant t(9;22). However, it cannot reveal additional abnormalities of other chromosomes that would also indicate disease progression. Therefore in selected cases, FISH can be combined with karyotyping, particularly if response to treatment is not as expected or if there is evidence of disease progression. A combination of karyotyping and FISH analysis would, of course, give the maximum information in a particular case when required.

 
   References Top

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Correspondence Address:
Vivi M Srivastava
Cytogenetics Unit, Christian Medical College, Vellore - 632 004. Tamilnadu
India
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DOI: 10.4103/0377-4929.101742

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