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 Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 5  |  Issue : 4  |  Page : 141-147

Prognostic value of 13q14 deletion and IgH 14q32 rearrangement by interphase fluorescence in situ hybridization in patients with multiple myeloma


1 Department of Clinical and Chemical Pathology, Ain Shams University, Cairo, Egypt
2 Department of Internal Medicine and Hematology, Ain Shams University, Cairo, Egypt

Date of Web Publication13-Dec-2014

Correspondence Address:
Prof. Mohamed M Moussa
Internal Medicine and Hematology, Ain Shams University, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1658-5127.146948

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  Abstract 

Background: Multiple myeloma (MM) is a clonal bone marrow (BM) disease characterized by the neoplastic transformation of differentiated B cells with the accumulation of malignant plasma cells in the BM compartment. In Egypt, its extrapolated prevalence is 17,630/76,117,421 with annual rate around 4,085/76,117,421. Chromosomal aberrations in MM are typically complex and represent a hallmark of the disease. The most frequent structural aberrations are 13q14 deletion detected in 33-50% of the cases and 14q32 IgH rearrangement detected in 60-70% of the cases with t (11;14) (q13;q32) being the most frequently detected 14q32 translocation seen in 15% of these patients. Aim: The aim was to detect both 13q14 deletion and 14q32 IgH rearrangement by interphase fluorescence in situ hybridization (I-FISH) on 100 newly diagnosed Egyptian myeloma patients and their relation to the patients' outcome and prognosis. Subjects and Methods: Patients were subjected to a complete history, clinical examination, and laboratory. We have also tested the expression of 13q14 deletion by locus-specific identifier (LSI) D13S319 probe assay and 14q32 IgH rearrangement by IgH dual color FISH break-apart assay on BM aspirates collected from the patients at diagnosis (before starting therapy). Staging and follow-up of the patients were carried out to detect the outcome of the disease. Results: We found that 65% of the examined myeloma patients showed genetic aberrations (13q14 deletion, 14q32 IgH rearrangement or both) by I-FISH. Of which, 40% were positive only for 13q14 deletion, 20% were positive only for 14q32 IgH rearrangement and only 5% were positive for both aberrations. 13q14 deletion was associated with more patients being resistant to chemotherapy or dying indicating its poor impact on patients' prognosis, whereas 14q32 IgH rearrangement was associated with more patients in remission indicating its good impact on patients' prognosis. Comparing myeloma patients who went into remission to those who died or were resistant to chemotherapy after receiving treatment, revealed highly statistical significance in these patients (P ≤ 0.001) as regards to their serum calcium, albumin, B2 microglobulin, and BM clonal plasma cell levels with P values (0.0009, 0.0001, 0.0001 and 0.0001, respectively). Moreover, a statistical significance (P ≤ 0.05) was found in these patients as regards to their total protein and serum M-component with P values (0.0288 and 0.0182, respectively). Summary/Conclusion: 13q14 deletion detected by LSI D13S319 FISH probe in myeloma patients was seen in 40% of the studied cases and was associated with patients being resistant to chemotherapy or dying. Whereas, 14q32 IgH rearrangement detected by IgH dual color break-apart FISH assay in these patients was seen in 20% of the studied cases and was associated with patients in remission.

Keywords: 13q14 deletion, multiple myeloma, Igh 14q32 rearrangement


How to cite this article:
Kassem NA, Elswefy DA, Eman NI, Mogy MI, Moussa MM, Ali RN. Prognostic value of 13q14 deletion and IgH 14q32 rearrangement by interphase fluorescence in situ hybridization in patients with multiple myeloma. J Appl Hematol 2014;5:141-7

How to cite this URL:
Kassem NA, Elswefy DA, Eman NI, Mogy MI, Moussa MM, Ali RN. Prognostic value of 13q14 deletion and IgH 14q32 rearrangement by interphase fluorescence in situ hybridization in patients with multiple myeloma. J Appl Hematol [serial online] 2014 [cited 2019 Sep 22];5:141-7. Available from: http://www.jahjournal.org/text.asp?2014/5/4/141/146948


  Introduction Top


Multiple myeloma (MM) is a terminally differentiated clonal B-cell neoplasm characterized by monoclonal expansion and accumulation of the neoplastic/malignant plasma cells in the bone marrow (BM) compartment. It is also known as plasma cell myeloma (PCM), Myelomatosis, or Kahler's disease. The diagnosis of MM is based on a typical morphological finding in the BM (presence of >10% of clonal tumor plasmocytes), presence of monoclonal immunoglobulin in serum (most commonly types IgG and IgA) and/or urine (light chains) as well as typical skeletal damage by osteolytic lesions. [1] MM rarely involves the extramedullary sites such as blood, pleural fluid and skin. However, when plasma cells are seen in the blood at a proportion of >20% of the white blood cells, this is a condition known as plasma cell leukemia which is a very aggressive condition usually of poor prognosis. [2]

It accounts for approximately 1% of all malignant diseases, 10% of all hematological malignancies in whites and 20% in African Americans. [3]

Genetic mutations play a large role in the pathogenesis of MM. [3] Genetic damage occurs in the developing B lymphocyte at the time of isotype switching from IgM to IgG or IgA producing plasma cells, thus transforming the normal plasma cells into a malignant MM cell. These malignant cells multiply in the BM and produce large quantities of monoclonal immunoglobulin (M) protein leading to stimulation of osteoclasts. [4]

Chromosomal aberrations in MM are typically complex and represent a hallmark of the disease, involving many chromosomes that are altered both numerically and structurally. The most frequent structural aberrations are 13q14 deletion detected in 33-50% of the cases and 14q32 IgH rearrangement detected in 60-70% of the cases with t (11;14) (q13;q32). [1]

The low proliferative activity of the tumor cells early in the disease is an important limitation of conventional cytogenetics (karyotyping) since only dividing cells can be analyzed. This limitation has been overcome by the use of molecular cytogenetic techniques as fluorescence in situ hybridization (FISH), multicolor-FISH, CGH, gene expression profiling, and single nucleotide polymorphism arrays. Nowadays, the standard diagnostic work up for myeloma includes both interphase-FISH (I-FISH) and traditional metaphase chromosomal studies as a surveillance to monitor the therapeutic response and at relapse to help direct therapy. [3]

Therefore, the aim of this study was to detect 13q14 deletion and IgH 14q32 rearrangement by I-FISH and their impact on prognosis in MM patients.


  Subjects and Methods Top


The present study was carried out on 100 newly diagnosed patients with MM from February 2011 to December 2011. They were selected from Ain Shams University Hematology/Oncology clinics. They were all adults, 55 (55%) males and 45 (45%) females with a male to female ratio 1.2:1. Their ages ranged from 18 to 70 years with a mean of 50.1 ± 11.59 standard deviation (SD) patients were then diagnosed based on the WHO (4 th edition/2008) and International Myeloma Working Group (IMWG) diagnostic criteria for symptomatic PCM. [5]

All patients were followed-up for 12 months.

All patients in this study were subjected to complete history and clinical examination, laboratory investigations including; complete blood count, examination of leishman-stained peripheral blood smears, BM aspiration/biopsy and examination, protein and urine protein, electrophoresis and immunofixation, β2 microglobulin, lactate dehydrogenase (LDH), creatinine, blood urea nitrogen (BUN), calcium and uric acid levels. Furthermore, radiological skeletal bone survey: Computed tomography or magnetic resonance imaging to indicate the presence and extent of lytic bone lesions. Detection of 13q14 deletion and IgH 14q32 rearrangement by I-FISH technique which was only done at the time of diagnosis using the Vysis locus-specific identifier (LSI) D13S319 (13q14.3) probe for 13q14 gene deletion and LSI IgH dual color, break apart rearrangement probe (14q32) for 14q32 gene rearrangement.

All our patients were subjected to vincristine-adriamycin-dexamethasone (VAD) protocol for three cycles (A 4 days cycle every 28 days). Then complete evaluation was done. VAD treatment protocol is considered the standard of care for Egyptian patients under insurance cover of ministry of health for economical point of view.

To determine the response to VAD treatment, all our patients were later classified into two major categories according to the IMWG:

  • Those who went into complete remission (<5% plasma cells in BM, disappearance of the original monoclonal proteins, disappearance of soft tissue plasmacytomas and no increase in number or size of lytic bone lesions)
  • Those who were resistant to treatment (>25% increase in plasma cells in BM, >25% increase in the level of serum M protein, development of new bone lesions or soft tissue plasmacytoma and development of hypercalcemia).


Methods

Sample


Two ml of BM aspirate was collected. A volume of 1 ml was collected on EDTA for morphological analysis. The remaining one ml was collected in sterile preservative free heparin-coated Vacutainer tube for culture and FISH technique. A clotted sample is needed for chemical analysis.

Fluorescence in situ hybridization detection of 13q14 deletion and IgH 14q 32 rearrangement.

Principle

This technique is based on the ability of specific DNA or RNA sequences indirectly or directly labeled with fluorochromes to anneal to their complementary denatured sequences in metaphase or interphase cells which are then subsequently visualized by fluorescent microscope. [6]

Detection of 13q14 deletion gene

By using the Vysis LSI D13S319 (13q14.3) probe, normal cells show 2 red signals corresponding to the normal 13q14 gene. In positive cells with 13q14 deletion gene, only one red signal corresponding to the deletion in the long arm of chromosome 13, region 1 band 4 is seen [Figure 1] and [Figure 2].
Figure 1: Fluorescence in situ hybridization analysis negative for 13q14 deletion identified by the presence of two red signals

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Figure 2: Fluorescence in situ hybridization analysis positive for 13q14 deletion identified by the presence of one red signal only

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Detection of IgH 14q32 rearrangement

By using the LSI IgH dual color fusion break apart rearrangement probe, normal cells show two yellow fusion signals (juxtaposed red and green signals) denoting normal IgH 14q32 gene rearrangement. In positive cells for IgH 14q32 gene rearrangement, one red and one green signal corresponding to IgH 14q32 gene rearrangement and one yellow fusion signal corresponding to normal IgH 14q32 gene rearrangement are seen [Figure 3] and [Figure 4].
Figure 3: Fluorescence in situ hybridization negative for 14q32 rearrangement on lymph node biopsy

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Figure 4: Fluorescence in situ hybridization positive for 14q32 rearrangement on lymph node biopsy

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Analytical Statistics

The collected data were revised, coded, and tabulated then introduced to a PC using Statistical Package for Social Science (SPSS 15.0.1 for windows; SPSS Inc., Chicago, IL, 2001). Data were presented, and suitable analysis was done according to the type of data obtained for each parameter. Descriptive statistics (mean, ±SD, minimum and maximum values [range] for numerical data, frequency, and percentage of nonnumerical data) and analytical statistics (independent-samples t-test and the one-way ANOVA test were used to assess the statistical significance of the difference between two study group means, and Chi-square test and Fisher exact test used to examine the relationship between two qualitative variables).


  Results Top


This study was carried out on 100 newly diagnosed MM patients, 55 (55%) males and 45 (45%) females with a ratio of 1.2:1. Their ages ranged from 18 to 70 years old with a mean of 50.1 ± 11.59 SD, and median age was 50 years old.

13q14 Deletion and 14q32 IgH Rearrangement as Regards to the Patients' outcome

13q14 deletion was found in 40/100 (40%) of the patients, of which 10 (25%) went into remission, and 30 (75%) were resistant to the VAD treatment or died. 55/100 (55%) of the patients were negative for 13q14 deletion, of which 45 (81.8%) went into remission, and 10 (18.2%) were resistant to the VAD treatment or died.

13q14 deletion abnormality was found to be of statistical significance (P ≤ 0.05) as regards to the patients' outcome as shown in [Table 1].

14q32 IgH rearrangement was found in 20/100 (20%) of the patients. All of the 20 patients (100%) went into remission, whereas 75/100 (75%) were negative for 14q32 IgH rearrangement, of which 35 (46.7%) went into remission and 40 (53.3%) were resistant to VAD treatment or died.

14q32 IgH rearrangement abnormality was found to be statistically insignificant (P > 0.05) as regards to the patients' outcome as shown in [Table 2].

Both 13q14 deletion and 14q32 IgH rearrangement were only found in 5/100 (5%) of the patients included in this study. These 5 patients were resistant to VAD treatment, whereas 35/100 (35%) of the patients were found negative for both aberrations, of which 25 (71.4%) went into remission and 10 (28.6%) were resistant to VAD treatment or died.

Statistical Comparative Analysis Between the Laboratory Findings of Patients who went into Remission and Those who were Resistant to Vincristine-adriamycin-dexamethasone Treatment or Died after Receiving Chemotherapy

There were highly statistical significant differences (P ≤ 0.001) found in this study between the patients who went into remission and those who were resistant to VAD treatment or died as regards to their serum Calcium, serum Albumin, B2 microglobulin, and BM clonal plasma cell levels P values (0.0009, 0.0001, 0.0001, 0.0001, respectively). It was noticed that patients who went into remission in this study showed lower Calcium, B2 microglobulin and BM clonal plasma cell levels, but higher Albumin levels when compared to those who were resistant to VAD treatment or died which favors a better outcome. Whereas, there were statistical significant differences (P ≤ 0.05) found between the patients who went into remission and those who were resistant to VAD treatment or died as regards to their total protein level and serum M-component P values (0.0288 and 0.0182, respectively). It was also noticed that patients who went into remission showed lower total protein levels and serum M-component when compared to those who were resistant to the VAD treatment or died which also favors a better outcome. Yet there were no statistical significant differences (P > 0.05) found between the patients who went into remission and those who were resistant to VAD treatment or died as regards to their total lymphocyte count (TLC), Hb concentration, platelets count, serum creatinine, BUN, uric acid, and LDH levels.


  Discussion Top


Multiple myeloma cells are characterized by high genetic instability, resulting in a complex set of numerical and structural chromosomal abnormalities. [7] Recent researches have proved that the detection of these chromosomal aberrations is of crucial importance not only because of their association with clinical prognosis, but also because they can be used as measurable targets for response to treatment. [8]

The most significant structural chromosomal changes commonly seen in myeloma patients are rearrangements involving the switch regions of the immunoglobulin heavy chain gene at 14q32 position as well as chromosome 13q14 deletion. Owing to the hypo-proliferative nature, and the low mitotic index of BM myeloma cells, conventional cytogenetics (Karyotyping) has become of limited value in the detection of these aberrations. 50% of 13q14 deletions and the majority of IgH translocations were easily missed producing normal karyotypes in these patients. [9]

However, with the use of modern molecular-based techniques such as I-FISH, chromosomal aberrations have been detected in >90% of PCM patients [10] about 3 times more frequently than karyotyping. [11] I-FISH is now considered the method of choice for the detection of both 13q14 deletion and 14q32 IgH rearrangement. [9]

The present study was planned to determine the incidences of both 13q14 deletion and 14q32 IgH rearrangement by I-FISH performed in 100 newly diagnosed Egyptian myeloma patients as well as their prognostic significance and relation to the patients' clinical outcome. Such evaluation of prognostic factors and risk stratification are important to define treatment strategies, compare the outcome of therapeutic trials and predict survival from diagnosis. [12]

In this study, LSI D13S319 (13q14.3) and LSI IgH dual color break apart rearrangement probes were applied on 100 BM aspirates collected from Egyptian adult myeloma patients at the time of diagnosis (before receiving treatment) for the detection of 13q14 deletion and 14q32 IgH rearrangement, respectively.

In our study, 40/100 (40%) of the examined myeloma patients were only positive for 13q14 deletion by I-FISH, 20/100 (20%) were only positive for 14q32 IgH rearrangement, whereas 5/100 (5%) were positive for both aberrations.

On the contrary, Gao et al. [13] and Becze [14] detected different incidences of both 13q14 deletion and 14q32 IgH rearrangement. Where, Gao et al. showed that among the 60 examined Chinese myeloma patients included in their study, 63.3% of these patients revealed positive only for 13q14 deletion by I-FISH and 70% revealed positive only for 14q32 IgH rearrangement which was considered the most frequent chromosomal abnormality detected among their patients in that study.

On the other hand, Yuregir et al. [15] who was studying chromosomal aberrations including 13q14 deletion and 14q32 IgH rearrangement by both FISH and conventional cytogenetics in 36 myeloma patients at the time of diagnosis, revealed an incidence of 13q14 deletion among their patients somehow close to the results of our study (30.5% vs. 40% in our study) yet, the incidence of 14q32 IgH rearrangement revealed to be much higher than that in our study (58.3% vs. 20% in our study).

The observed differences in the previous results may be explained by the use of different scales of patients examined in different researches and different techniques adopted by different researchers.

Variations in the size of the IgH probe signals can also occur as a result of normally occurring deletions and rearrangements within the IgH gene leading to problems in the interpretation of both positive and negative results. In addition to various genetic, cultural, environmental, social, and racial differences noted among different population.

However, the incidence of 13q14 deletion by I-FISH reported in our study, coincided with that detected by Hu et al., [16] Zhan et al. [17] and Chiecchio et al. [18] with reported incidences (47.2%, 50% and 47%, respectively).

As regards to the prognostic impact of 13q14 deletion, we found a statistical association between the chromosomal aberration 13q14 deletion and the patients' outcome, in which the majority of the patients who tested positive only for 13q14 deletion (75%) were resistant to VAD treatment or died. Whereas the majority of those who tested negative only for this deletion (81.8%) went into remission. Thus, we postulated that 13q14 deletion detected by I-FISH has an adverse prognostic outcome on the patients.

In accordance to the previous mentioned results, Deng et al. [19] who studied the clinical significance of cytogenetic aberrations detected by both I-FISH and chromosomal banding analysis in 100 Chinese myeloma patients, found that chromosome 13 abnormalities including 13q14 deletion detected by I-FISH were associated with significantly shorter overall survival (OS) and time to progression and was considered the only independent adverse prognostic factor.

Similarly, Moreau et al. [20] in the analysis of the prognostic value of chromosomal rearrangements in 168 newly diagnosed MM patients receiving intensive chemotherapy found that 13q14 deletion by I-FISH conferred a similarly poor prognosis and shorter OS even in patients treated with intensive chemotherapy.

Similar findings were also found by Zhan et al. [17] who were studying the role of cytogenetics by FISH and conventional cytogenetics (Karyotyping) in myeloma patients. They showed that the inferior prognosis of patients with FISH deletion 13 was entirely due to the one-third of patients with abnormal metaphase cytogenetics.

As regards to the prognostic impact of 14q32 IgH rearrangement, although no statistical significance was found between 14q32 IgH rearrangement and the patients' outcome, yet it was noticed that all the patients (100%) who tested positive only for 14q32 IgH rearrangement went into remission, whereas those who tested negative only for this aberration (53.3%) were resistant to VAD treatment or died. We thus postulated that 14q32 IgH rearrangement detected by I-FISH has a favorable prognostic outcome in these patients.

Previous studies have demonstrated the prognostic value of specific translocations involving the 14q32 region. Gao et al. [13] found that patients with t (4;14) (p16;q32) had significant higher B2 microglobulin level predicting a poor outcome as found by the study done by Hu et al. [16] Moreover, Zhan et al. [17] in their study showed that patients with t (4;14) and t (14;16) as analyzed by FISH had an inferior outcome.

Our current study also showed that there were highly statistical significant differences found between the myeloma patients who went into remission and those who were resistant to VAD treatment or died as regards to their serum Calcium, serum Albumin, B2 microglobulin, BM clonal plasma cell levels with P values (0.0009, 0.0001, 0.0001 and 0.0001, respectively). It was noticed that patients who went into remission in this study showed lower Calcium, B2 microglobulin, BM clonal plasma cell levels, but higher Albumin levels when compared to those who were resistant to VAD treatment or died which favors a better outcome. Whereas there were statistical significant differences found between the patients who went into remission and those who were resistant to VAD treatment or died as regards to their total protein and serum M-component with P values (0.0288 and 0.0182, respectively), as it was noticed that patients who went into remission showed lower total protein and serum M-component when compared to those who were resistant to VAD treatment or died. However, there were no statistical significant differences found in these patients as regards to their TLC, Hb concentration, platelets count, serum creatinine, BUN, uric acid, and LDH levels.

These results coincided with those obtained by Yang et al. [8] who found that patients with elevated B2 microglobulin (≥3.5 mg/l) at diagnosis were independently associated with poor survival.

Hu et al. [16] also found that patients with high B2 microglobulin >5.5 mg/l had a worse outcome with median progression-free survival = 5 months versus 8 months in those lacking high B2 microglobulin levels. Similar results were also obtained by Munshi and Avet-Loiseau [12] who also found that genetic abnormalities characteristic of poor outcome at diagnosis may suggest poor outcome if detected at the time of relapse where high serum B2 microglobulin and low Albumin were considered to predict high risk disease.

In our study, no statistical association was found between the patients' outcome and the Ig isotype of their serum M-component. Although it was noticed that slightly more patients with IgG kappa M-band went into remission when compared to those who were resistant to the VAD treatment or died (53.8% vs. 46.2%). Kuiper et al. [21] found that genes associated with the immune response, cell cycle control, and apoptosis induction were up-regulated in the IgG MM demonstrating that IgG isotype is significantly associated with longer survival and a better outcome. Whereas genes associated with the inhibition of differentiation and apoptosis were up-regulated in IgA MM and those associated with immune response, cell cycle control, and apoptosis induction were down-regulated in this subgroup demonstrating that IgA isotype is significantly associated with shorter survival and a worse outcome.


  Conclusion Top


Molecular cytogenetic aberrations including 13q14 deletion, 14q32 IgH rearrangement or both detected by I-FISH occur in a high incidence (65%) among the Egyptian myeloma patients included in this study. 13q14 deletion is considered more prevalent among these patients when compared to 14q32 IgH rearrangement.

13q14 deletion was found to be associated with more patients being resistant to VAD treatment or dying indicating its adverse prognostic effect, whereas 14q32 IgH rearrangement was found to be associated with more patients in remission indicating its good impact on patients' prognosis.

Low serum calcium, B2 microglobulin, BM clonal plasma cell level, serum M-component, and total protein levels, but high Albumin levels are associated with a good prognosis and patients going in remission after receiving treatment.

 
  References Top

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Yang SH, Teng HW, Hong YC, Liu CY, Yu YB, Yang CF, et al. International Staging System predicts prognosis of Chinese patients with multiple myeloma across different calendar periods with application of novel agents. Ann Hematol 2012;91:93-102.  Back to cited text no. 8
    
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Avet-Loiseau H, Attal M, Moreau P, Charbonnel C, Garban F, Hulin C, et al. Genetic abnormalities and survival in multiple myeloma: The experience of the Intergroupe Francophone du Myélome. Blood 2007;109:3489-95.  Back to cited text no. 11
    
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Munshi NC, Avet-Loiseau H. Genomics in multiple myeloma. Clin Cancer Res 2011 15;17:1234-42.  Back to cited text no. 12
    
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Gao X, Li C, Zhang R, Yang R, Qu X, Qiu H, et al. Fluorescence in situ hybridization analysis of chromosome aberrations in 60 Chinese patients with multiple myeloma. Med Oncol 2012;29:2200-6.  Back to cited text no. 13
    
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Becze E. Cytogenetics helps determine diagnosis and prognosis for multiple myeloma. ONS Connect 2012;27:18-9.  Back to cited text no. 14
    
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