|Year : 2016 | Volume
| Issue : 2 | Page : 87-93
CKS1B/CDKN2C (P18) amplification/deletion as prognostic markers in multiple myeloma patients
Amira Y Abd El-Naby1, Amr M Gawaly MD 2, Samah A Elshweikh2
1 Department of Clinical Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt
2 Department of Internal Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt
|Date of Submission||28-Jan-2016|
|Date of Acceptance||05-Mar-2016|
|Date of Web Publication||15-Jul-2016|
Amr M Gawaly
8 Bader Street, El-Mahalla El-Kubra
Source of Support: None, Conflict of Interest: None
Introduction Multiple myeloma (MM) is neoplasia of plasma cells characterized by clonal proliferation of malignant plasma cells in the bone marrow. Amplification of 1q21 (CKS1B) is the most common recurrent chromosomal aberration in myeloma. Overexpression of the CKS1B gene upregulates cell cycle processes and leads to a more proliferative malignant plasma cell. This is related to an unfavorable clinical course with poor prognosis and disease progression. Also the deletions of CDKN2C have been identified in 40% of the studied MM cases and hence inactivation of CDKN2C may be an important step in the initiation and progression of MM and could be an important prognostic factor.
The aim of the work The aim of the study was to assess the prognostic significance of CKS1B gain and CDKN2C gene deletion in MM patients.
Patients and methods This prospective cohort study was carried out on 40 newly diagnosed MM patients who were submitted to routine laboratory investigations, including complete blood count, bone marrow aspiration, blood urea nitrogen, creatinine, calcium, albumin, plasma protein electrophoresis, 24 h urine for total protein, and β2-microglobulin, and to detection of CKS1B/CDKN2C (P18) amplification/deletion by fluorescence in-situ hybridization technique.
Results On using fluorescence in-situ hybridization, we found that 25% (10 out of 40) of patients showed CKS1B gain and 20% (eight out of 40) showed positive deletion of the CDKN2C gene. All these patients showed inferior outcome and short survival.
Conclusion MM patients with CKS1B/CDKN2C (P18) amplification/deletion had a more aggressive disease with adverse impact on survival, which makes CKS1B and CDKN2C genes valuable prognostic indicators in MM patients.
Keywords: CKS1B/CDKN2C (P18) amplification/deletion, fluorescence in-situ hybridization, multiple myeloma
|How to cite this article:|
Abd El-Naby AY, Gawaly AM, Elshweikh SA. CKS1B/CDKN2C (P18) amplification/deletion as prognostic markers in multiple myeloma patients. Egypt J Haematol 2016;41:87-93
|How to cite this URL:|
Abd El-Naby AY, Gawaly AM, Elshweikh SA. CKS1B/CDKN2C (P18) amplification/deletion as prognostic markers in multiple myeloma patients. Egypt J Haematol [serial online] 2016 [cited 2020 Apr 10];41:87-93. Available from: http://www.ehj.eg.net/text.asp?2016/41/2/87/186412
| Introduction|| |
Multiple myeloma (MM) is a mature neoplastic B cell characterized by clonal proliferation of plasma cells in the bone marrow associated with elevated urine and serum monoclonal para-protein resulting in end-organ complications. MM is the second most frequent hematological malignancy in the USA, after non-Hodgkin's lymphoma. MM is classically preceded by an age-progressive-related condition called monoclonal gammopathy of undetermined significance (MGUS) that presents in 1% of adults above the age of 25 and progresses to myeloma at a rate of 0.5-3% each year . MM continues to remain an incurable disease despite the introduction of high-dose chemotherapy and autologous stem cell transplantation in recent times .
The most common structural cytogenetic aberration in MM includes abnormalities involving chromosome 1, found in up to 48% of abnormal metaphase karyotypes ; amplification of 1q21 (CKS1B) is one of the most frequent recurrent chromosomal aberrations in myeloma. Overexpression of the CKS1B gene upregulates the cell cycle process and leads to a more proliferative disease . In a study of MM patients, it was discovered that 30% of chromosomal abnormalities were related to chromosome 1; most upregulated genes related to chromosome 1q and downregulated genes to chromosome 1p6. Gains of the long arm 1q are one of the most frequent genetic abnormalities in myeloma disease , and duplications of the chromosome 1q band are commonly associated with disease progression .
CKS1B helps cell cycle progression by promoting degradation of p27 with release of the cyclin-dependent kinases and the entry into mitosis. This increased level of expression is associated with a copy number gain of chromosome 1 at band q21 in a subset of patients . Also band 1p32.3 CDKN2C (p18) is a tumor suppressor gene responsible for promoting apoptotic cell death and DNA. It is upregulated by the expression of the cytokine IL-6 in MM, and deletion of the gene is associated with a more proliferative disease. Although p18 deletions have been reported to be rare in human cancers, cytogenetic analysis has shown abnormalities of 1p32-36 in 16% of human MM cases .
Cyclin-dependent kinase inhibitors (CKIs) are a group of low-molecular-weight proteins that associate with cyclin-CDK complexes or CDKs alone and inhibit their activity. G1 progression is regulated by the balance between positive (CDKs and cyclins) and negative (CKIs) regulators, and not by the level of any single cell cycle regulator per se. Alternatively, as we know that CDKN2C is required for negative cell cycle control during the differentiation of B cells to plasma cells, it could be expressed in cycling normal plasma cell precursors and does not imply a resistance to CDKN2C. To gain further insight into these potential mechanisms, we looked at the expression patterns of these genes, finding that the proliferating cases with overexpression of CDKN2C had a high level of expression of CDK4 consistent with the possibility that the inhibitory effects of CDKN2C could have been over-ridden by either deregulated cyclin D or CDK4/6expression in some cases of myeloma .
In addition to CDKN2C, a number of other molecules are important in controlling the G1-S transition point. Because of the global nature of the mapping and expression analysis carried out in this study, in addition to analyzing CDKN2C, we were able to analyze changes impacting the other CKI loci affecting this transition point. This analysis showed relatively frequent loss of CDKN1B, but the number of cases was insufficient to show an association between deletion and expression. Looking at the role of this gene further and whether its loss may interact with CDKN2C loss, we observed that CDKN1B copy number was normal in all cases with homozygous deletion of CDKN2C.
Functionally, we know that CDKN2C has an important role in end-stage phosphatidylcholine differentiation, and consequently the loss of one copy of CDKN1B would not be predicted to affect G1 progression in plasma cells in the presence of both copies of CDKN2C. In contrast, loss of one copy of CDKN2C, even in the presence of both copies of CDKN1B, would be predicted to significantly alter G1 progression consistent with our results and a report that CDKN2C is haploinsufficient in mediating tumor suppression .
| Patients and methods|| |
This prospective cohort study included 40 newly diagnosed patients with MM selected from Clinical Pathology, Internal Medicine Department (Hemato-oncology Unit), Tanta University Hospital and Tanta Cancer Institute from March 2013 to March 2015.
Patients with hereditary diseases, congenital anomalies, and severe comorbidity such as cardiovascular disease or other malignancy were excluded from the study.
All patients gave their written informed consent before participation and after full explanation of the benefits and risks of the study. The study protocol was approved by the Institutional ethics committee and was in accordance with the principles of the Declaration of Helsinki II.
The patients were subjected to detailed history and thorough clinical examination. The skeletal bone survey for detection of any lesions and laboratory investigations including complete blood count, bone marrow aspiration, creatinine, blood urea nitrogen (BUN), lactic dehydrogenase, calcium, albumin, serum protein electrophoresis, 24 h urine for total protein, serum β2-microglobulin (β2-M), detection of CKS1B/CDKN2C (P18) amplification/deletion by fluorescence in-situ hybridization (FISH) technique, and Kaplan-Meier curve were used to detect the overall survival (OS) of patients for 2 years.
Venous blood was collected from each patient by sterile venipuncture under complete aseptic conditions and divided as follows: 1 ml venous blood was collected on 1.5 mg/ml potassium 3 EDTA for complete blood count, 3 ml blood was collected in a vacationer tube (plain) to separate serum for renal function assessment, serum protein electrophoresis, and serum β2-M, and 2 ml venous blood or 1 ml bone marrow sample was collected on non-preservative Sodium Heparin for the study of CKS1B/CDKN2C (P18) amplification/deletion by FISH.
Cell culture for cytogenetic studies
Separation of chromosomes from blast cells of the bone marrow depends on allowing the cells to proliferate in culture media, followed by treatment with a mitotic arrest agent such as colcemid, which obstructs the formation of spindle fibers and arrests cell proliferation at the metaphase. The cells must then be treated with hypotonic solution for swelling of the cells and adequate spreading of the chromosomes. The cells must be fixed in this state using fresh fixative solution and stored until used for FISH .
The culture medium was RPM1 1640 with glutamax-1 (cat. # 21875-042; GIBCO BRL, Paisley, UK). A volume of 100 ml in a bottle was supplemented with antibiotic (penicillin, streptomycin, 5000 IU/ml, 5000 μg/ml, GIBCO BRL cat. # 15140-122; (Life Technologies, Grand Island, NY, USA), and fetal calf serum (cat. # S0113; Biochrom KG, Berlin, Germany) was added.
Colcemid (10 μg/ml) (cat. # L6221; Biochrom KG) was used to arrest the cells in metaphase. Hypotonic KCI [potassium chloride (5.59 g/1)] was dissolved in distilled water, autoclaved, and used at 37°C. Thereafter the cells were fixed with freshly prepared fixative solution consisting of methanol (three parts) and glacial acetic acid (one part).
| Methods|| |
FISH technique for detection of CKS1B/CDKN2 (P18) amplification/deletion
FISH probe : Structural abnormalities of chromosome 1 are frequently detected in MM and have been correlated with more advanced disease .
CDKN2C (p18), located in band 1p32.3, is a tumor suppressor gene responsible for inducing apoptotic cell death and DNA fragmentation . CKS1B is located on chromosome 1q21.
The CKS1B/CDKN2C product consists of a 180 kbp probe, labeled in red, covering the entire CKS1B gene and flanking regions, including the PYOG2 and ZBTB7B gene, and a green probe covering a 168 kbp region, including the entire CDKN2C(P18) gene, the D1S1661 marker, and the centromeric end of the FAF1 gene: CKS1B, 1q21, red; CDKN2C (P18), 1p32.3, green ([Figure 1]).
|Figure 1 Probe specification CKS1B, 1q21, red CDKN2C (P18), 1p32.3, green.|
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Codenaturation of specimen DNA and probe hybridization: Probe (10 μl) was added to the target area on the slide. The slide was then covered immediately with a coverslip and sealed with rubber cement. The specimen slide was placed on the Hybrite surface (Vysis No). The hybrite was set at 76°C for 10 min (for denaturation) and at 37°C overnight for hybridization for CDKN2C (P18).
Posthybridization washes: The first jar (containing 0.4× SSC/0.3% NP-40) was placed in a 73 ± 1°C water bath at least 30 min before use. The slides were washed in this jar for 2 min, after which they were immediately placed in the second jar (containing 2× SSC/0.1% NP-40) for 2 min at room temperature, protected from light. The slides were air-dried in the dark, and 10 μl DAPI (4, 6-diamidno-2 phenyl indol) counterstain was added at the marked area of the slide, after which a clean coverslip was applied and sealed well.
The slide was placed in a dark box in a fridge for 20-30 min before screening.
Interpretation of result and image capture: The slides were evaluated with an epifluorescence Olympus BX60 microscope (New York, USA) equipped with selective filters for fluorescent, and DAPI. The images were captured with a progressive scan IAI camera fitted with PC Applied Image System (Pittsburgh, USA) analysis software.
FISH analysis using CKS1B/CDKN2C (P18) probe was used on either metaphase spreads whenever possible or in interphase nuclei. In case of interphase FISH at least 200 interphase nuclei were scored. Different areas of the slide were examined and only interphases with clear signals, with no overlapping or splitting, were analyzed.
Statistical analysis of the present study was conducted using mean and SD in univariate analysis, and the Student t-test and χ2 -analysis of variance in multivariate analysis, with SPSS, version 17 (Chicago, IL, USA). P values less than 0.05 were considered significant.
| Results|| |
The present study included 40 newly diagnosed MM patients selected from Clinical Pathology and Internal Medicine (Hemato-oncology Unit) Departments of Tanta University Hospital. Their ages ranged from 50 to 70 years with a mean value of 61.150 ± 6.620.
[Table 1] shows the demographic data of MM patients enrolled in this study. There is a highly significant decrease in hemoglobin level and significant decrease in serum albumin in MM patients with chromosome 1 abnormalities compared with patients with normal genes (P < 0.001 and 0.003, respectively). Further, there was a significant increase in plasma cell percentage in bone marrow, in creatinine level, and in BUN in these patients (P = 0.046, 0.008, and 0.034, respectively) and also a highly significant increase in the β2-M level (P < 0.001) ([Table 2]). There was a significant increase in mortality in patients with chromosome 1 abnormalities compared with patients have normal chromosomes (P = 0.005) ([Table 3]).
|Table 2 A comparison between laboratory data of MM patients with normal CDKN2C gene and MM patients with Chromosome 1 abnormalities (CDKN2C gene deletion or CKS1B gene gain) |
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|Table 3 A Comparison between mortality in MM patients with normal Chromosome 1 and MM patients with deleted CDKN2C gene or CKS1B gene gain within the period of this study (24 months) |
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Eight MM patients out of 40 (20%) showed CDKN2C gene deletion and 10 MM patients out of 40 (25%) showed CKS1B gene gain, whereas only four MM patients out of 40 (10%) showed combined CDKN2C gene deletion and CKS1B gene gain ([Figure 2]).
|Figure 2 Number of multiple myeloma patients according to CKS1B/CDKN2C (P18) amplification/deletion detection by fluorescence in-situ hybridization.|
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[Figure 3] and [Figure 4] show an MM patient with CKS1B gene gain and normal CDKN2C gene and [Figure 5] and [Figure 6] show a case with normal CKS1B gene and deleted CDKN2C gene, as observed through FISH. There was a highly significant (P < 0.001) decrease in OS among MM patients with CDKN2C gene deletion when compared with patients with normal gene and also a significant decrease (P = 0.014) in OS among MM patients with CKS1B gene gain when compared with patients with normal gene, as shown in [Figure 7].
|Figure 3 A case of multiple myeloma show interphase cell with two orange signals and two green signals, that is, two normal (CKS1B) and two normal (CDKN2C) genes|
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|Figure 4 A case of multiple myeloma show interphase cell with CKS1B gene gain (three or four orange signals) and normal CDKN2C gene (two green signals).|
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|Figure 5 A case of multiple myeloma show interphase cell with two orange signals only whereas no green signals, that is, CKS1B gene gain and deleted CDKN2C gene|
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|Figure 6 A case of multiple myeloma show interphase cell with CKS1B gene gain (three or four orange signals) and deleted CDKN2C gene (no green signals).|
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|Figure 7 Kaplan-Meier of overall survival of the studied myeloma patients in relation to CDKN2C (normal or deleted) and CKS1B (normal or gain).|
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| Discussion|| |
FISH identified genomic aberrations that recently emerged with disease progression in myeloma patients receiving chemotherapy or stem cell transplantation. The initial study showed valuable prognostic significance of chromosome 1 abnormalities (CDKN2C gene deletion and CKS1B gain) in MM patients, although this genomic instability has been controversial.
In our study we had 10 patients out of 40 (25%) with CKS1B gain, which is in agreement with the observation made by Fonseca et al. , who stated that gain of 1q21 is seen in about 30-37% of patients depending on the method of detection. Chang et al.  also found that CKS1B amplification (three to eight CKS1B signals) was detected in 31 of 99 (31%) patients and was associated with deletions of p53 (P = 0.003) and 13q (P = 0.039), but not with translocation t(11;14) or t(4;14).
Shaughnessy and colleagues stated that chromosome 1q21 abnormalities have been associated with genomic instability in MM. Chromosome 1q21 gain may be a marker of more clonally advanced tumor. In addition to that, the subsequent overexpression of candidate oncogenes or genes regulating cell cycle progression and proliferation, including CKS1B, located on the genome region of interest, may explain the greater prognostic significance associated with 1q21 gain. The effect of CKS1B gain on progression of disease may be due to its strong correlation with p53 deletion .
Chang and colleagues has demonstrated a significant increase in CKS1B amplification from MGUS to newly diagnosed MM, to relapsed MM, and to plasma cell leukemia. Although further investigation is required for the understanding of the molecular mechanism and functional consequence of CKS1B amplification, an increased copy number of CKS1B may be regarded as a surrogate marker of genetic instability and may play a role in the disease progression of plasma cell dyscrasias .
Bahmanyar et al.  stated that anaplastic multiple myeloma was associated with significantly higher prevalence of CKS1B amplification (91 vs. 34%, P < 0.001), 17p (p53) deletion (45 vs. 11%, P = 0.006), and t(4, 14) (36 vs. 14%, P = 0.015) compared with nonanaplastic MM, which may have resulted in the genetic instability and more aggressive clinical course.
Stellaa and colleagues detected significant CKS1B mRNA levels in MM compared with MGUS cases (P = 0.048). In MM, the frequency of 1q21 (CKS1B) copy gain was significantly higher in cases with abnormal karyotype compared with patients with normal karyotype (P = 0.021). Global analysis showed a positive correlation between CKS1B expression and 1q21 copy number (P < 0.001). No association between CKS1B mRNA expression and clinical parameters was found. However, a significantly higher level of β2-M in cases with 1q21 gains compared with those without (P = 0.0094) was observed .
OS was shorter in cases with 1q21 gain compared with those with normal 1q21 (P = 0.0082). Stellaa and colleagues suggested a role for CKS1B in the multiple step process of progression of MGUS to MM and showed that CKS1B copy gain has a more significant prognostic value than its overexpression. This adverse impact on survival probably reflects the genetic instability associated with chromosome 1q alterations resulting in a more aggressive behavior of the disease .
The study also shows that 20% (eight out of 40) of the patients having deletion of the CDKN2C gene are 50 to 68 years old, and all of them are male. These patients with the deleted gene showed significant decrease in hemoglobin level, and significant increase in creatinine level, clonal plasma cell in bone marrow, β2-M, and in OS compared with those with normal gene.
Kevin and colleagues found in a study on MM patient that the CDKN2C gene was deleted in 11.2% of the cases. They found that mapping of the homozygous deletion in newly presenting myeloma patients identified two regions of potential importance, 1p32.3 and 1p12. Although CDKN2C seemed to be the target of homozygous deletion of 1p32.3, it remains unclear whether the adverse survival seen in patients with homozygous deletion was mediated through CDKN2C dysregulation, or whether other genes played a role in the observed clinical outcome .
In agreement, Walker and colleague found in a study that the region with a prognostic impact on OS includes Del (1p) (FAF1, CDKN2C) . Also Leone et al.  found in their study that 15.7% of MM patients showed a deleted CDKN2C gene, which is associated with adverse OS.
Leone and colleagues in their study on MM patients suggest that deletions of CDKN2C are important in the progression and clinical outcome of myeloma. By FISH they identified deletion of 1p32.3 (CDKN2C) in three of 66 MGUS (4.5%), four of 39 SMM (10.3%), and 55 of 369 MM cases (15%). They examined the impact of copy number change at CDKN2C on OS, and found that the cases with either hemizygous or homozygous deletion of CDKN2C had a worse OS compared with cases that were intact at this region (22 vs. 38 months; P = 0.003) .
A recent study regarding the importance of these data for clinical application performed by Huang and colleagues demonstrates that cells with elevated CKS1B expression are resistant to bortezomib but sensitive to MLN4924 and offers a mechanism through the stabilization of p21. These findings provide rationale for targeting the NEDD8 pathway in MM patients exhibiting elevated expression of CKS1B. The NEDD8 inhibitor MLN4924 selectively targets SCFSkp2 activation and offers a more specific approach to protein degradation inhibition than to total proteasomal inhibition .
| Conclusion|| |
MM patients with CKS1B/CDKN2C (P18) amplification/deletion had a short survival during the time of the study compared with patients with normal gene. Thus, we can use the CKS1B and CDKN2C genes as a prognostic indicator in MM patients and apply that in clinical practice for targeted personalized therapy.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2], [Table 3]