|Year : 2021 | Volume
| Issue : 1 | Page : 282-287
An unknown chromosomal aberration in a patient with chronic lymphocytic leukemia: Extra isochromosome 4q
Emine Ikbal Atli1, Hakan Gurkan1, Ahmet Muzaffer Demir2
1 Department of Medical Genetics, Faculty of Medicine, Trakya University, Edirne, Turkey
2 Department of Haematology, Faculty of Medicine, Trakya University, Edirne, Turkey
|Date of Submission||01-Mar-2017|
|Date of Decision||18-Aug-2017|
|Date of Acceptance||26-Feb-2018|
|Date of Web Publication||17-Oct-2018|
|Date of Print Publicaton||12-Mar-2021|
Emine Ikbal Atli
Department of Medical Genetic, Faculty of Medicine, Campus of Balkan, Trakya University, Edirne
Source of Support: None, Conflict of Interest: None
The genetic characterization of chronic lymphocytic leukemia (CLL) has made significant progress over the past few years. Chromosomal abnormalities are detected in up to 80% of patients. Determination of new chromosomal disorders is important in the pathogenesis and treatment facilities. A patient was diagnosed with CLL Stage 2 on 2012 and followed since then by hematology clinic. She was 63 years old. Mature, small lymphocytes, and smudge cell was found in the patient's peripheral blood smear. Bone marrow (BM) biopsy made and hypercellularity showing infiltration of atypical cells with CD5+, CD20+, and CD23+ were determined. Hypoplasia is detected in myeloid/erythroid series, and Stage 2 reticular fibers proliferation were detected. The patient was followed up without medication. While follow-up of patient's white blood cell: 57300, hemoglobin: 5.36, and PLT: 99700 are determined in May 2014. According to the patient's flow results, CD5+, CD23+, and FMC7+ were detected. Mature, small lymphocytes and smudge cell was found in the patient's peripheral blood smear. In ultrasonography imaging, multiple laps were found in the abdomen and multiple neck lymph nodes were detected. The patient BM aspiration was performed in 2014, and hypercellularity was found to contain 54% of atypical lymphocytes in the BM. Fluorescence in situ hybridization (FISH) analysis made two times in 2014. At first, FISH analysis patient's rate of 18% in RB1/13q14.2/13qter revealed a deletion of the gene regions. Patient's FISH result was reported as normal (for RB1/13q14.2/13qter) after 5 months at second analysis. Cytogenetic analysis is made from the patient's BM at the same time. According to the results of karyotyping and FISH, 47, XX, isochromosome 4q (+i4q) is determined. According to literature, extra isochromosome 4q is reported by our case for the first time in CLL. She was diagnosed with Stage 4 CLL and FISH treatment was initiated. Our patient showed disease progression compared to previous results. Hence, we offer that this evidence can be considered regarding triggering the disease's progression or as a result of disease progression i4q was occurred.
Keywords: Chronic lymphocytic leukemia, cytogenetic, fluorescence in situ hybridization
|How to cite this article:|
Atli EI, Gurkan H, Demir AM. An unknown chromosomal aberration in a patient with chronic lymphocytic leukemia: Extra isochromosome 4q. J Can Res Ther 2021;17:282-7
|How to cite this URL:|
Atli EI, Gurkan H, Demir AM. An unknown chromosomal aberration in a patient with chronic lymphocytic leukemia: Extra isochromosome 4q. J Can Res Ther [serial online] 2021 [cited 2021 Apr 17];17:282-7. Available from: https://www.cancerjournal.net/text.asp?2021/17/1/282/244446
| > Introduction|| |
Chronic lymphocytic leukemia (CLL) displays a significant clinical heterogeneity that is included biological and genetic heterogeneity., Therefore, great efforts have been made toward the identification of biological markers that predict the tendency for disease progression at the time of diagnosis, thus assisting in accurate risk stratification and rational treatment design., Among a plethora of markers proven to be prognostically relevant in CLL, perhaps the most powerful and widely used relate to the patients' cytogenetic profile.
With hindsight, evidence for the complicated genetic landscape of CLL was already available by conventional cytogenetic studies from the early 1990s., Here, it should be noted that though considerably more laborious, and hence, superseded by fluorescence in situ hybridization (FISH) for routine diagnostics, classic cytogenetic analysis offers the opportunity to globally assess the karyotype of the malignant clone that is beyond the scope of FISH screening with probes for selected chromosomal regions. Conventional and molecular cytogenetic analysis became a significant tool for individual risk prediction. Unlike any other approaches, cytogenetic monitoring reflects the genetic heterogeneity and clonal growth dynamics during the course of the disease. Today, more than 80% of CLL patients show one or more cytogenetic defect, identified by FISH analysis. The most common chromosomal aberrations are deletion 13q14 (50%–60% of CLL cases). Deletion 14q32.33 (12%–15% of the samples) and deletion 13q14 associated with a good prognosis. trisomy 12 (15%–25%) is associated with intermediate prognosis. Deletion 11q22–23 (10%–20%) and deletion 17p13 (5%–10%), and/or recurrent balanced translocations go together with adverse prognosis. Less frequently observed aberrations in CLL are deletions in 6q associated with intermediate prognosis, 9p21 and 10q23, total or partial trisomies of chromosomes 3, 8, 18, or 19, and duplications in 2p24, the prognostic significance for these aberrations is unknown. Different chromosomal abnormalities detected in karyotype may be important for the progression. Therefore, it cannot be skipped in CLL cytogenetic maintains its position as a stepping stone.
| > Case Report|| |
Our patient was diagnosed with CLL Stage 2 on 2012 and followed since then by hematology clinic. BM biopsy made, and hypercellular BM showing infiltration of atypical cells with CD5+, CD20+, and CD23+ were determined. Hypoplasia is detected in myeloid/erythroid series, and Stage 2 reticular fibers proliferation were detected. Moreover, patients were followed up without medication. While follow-up of patient's white blood cell: 57300, hemoglobin: 5.36, and PLT: 99700 are determined in May 2014. According to the patient's flow results, CD5+, CD23+, and FMC7+ were detected. Mature, small lymphocytes, and smudge cell was found in the patient's peripheral blood smear. In ultrasonography imaging, multiple laps were found in the abdomen and multiple neck lymph nodes were detected. Patient BM aspiration was performed in May 2014, and hypercellularity was found to contain 54% of atypical lymphocytes in the BM. FISH analysis is made from the patient's BM.
| > Materials and Methods|| |
Cells were obtained from BM for diagnostic purposes. A comprehensive set of commercially available probes (Cytocell by Oxford Gene Technology (OGT)) was used as follows: ATM (11q22.3), RB1/13q14.2, 13qter, p53(17p13.1)/CEP17, and CEP 12 (D12Z3) (12p11.1-q11) for FISH technique. A minimum of 100 interphase nuclei was evaluated per probe. FISH results in the patient's rate of 18% in RB1/13q14.2/13qter revealed a deletion of the gene regions. She was diagnosed with Stage 4 CLL, and FISH treatment was initiated. Five months later, FISH analysis is made from the patient's BM again, and cytogenetic analysis was done. Bone marrow specimen was examined directly or was cultured for 24 h in Roswell Park Memorial Institute (RPMI) 1640 supplemented with %15 fetal calf serum before karyotyping. After cell culture, chromosome banding of metaphases was performed using a Trypsin-Leishman technique.
| > Results|| |
A comprehensive set of commercially available probes (Cytocell by OGT) was used, as follows: ATM (11q22.3), RB1/13q14.2, 13qter, p53(17p13.1)/CEP17, and CEP 12 (D12Z3) (12p11.1-q11) for FISH technique. A minimum of 100 interphase nuclei were evaluated per probe region. FISH results were evaluated as normal for the regions viewed.
According to the results of karyotyping, 30 metaphases were evaluated, and 47, XX, isochromosome 4q (+i4q) is determined. The nomenclature used to describe the karyotype was that established by the International System for Human Cytogenetic Nomenclature (ISCN). Moreover, FISH tests were conducted to verify the results. We used FIP1 L1/CHIC2/PDGFRA deletion/fusion probe (4q12) and detected four copy of the genes in interphase; three copy was seen in metaphase because probe region is so close on chromosome 4q12 [Figure 1].
|Figure 1: Karyotype and fluorescence in situ hybridization image of case. Up: karyotype of image, down: four red and green signal on chromosome 4q (Commercial fluorescence in situ hybridization probe location near the picture; in interphase nucleus two separated signal for 4q12 region on isochromosome 4q and only one big signal was seen because two signals are too close each other on metaphase spread for 4q12 region)|
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| > Discussion|| |
Changes in chromosome 4 have been identified in several types of human cancer. These genetic changes are somatic, which means they are acquired during a person's lifetime and are present only in certain cells. For example, rearrangements (translocations) of genetic material between chromosome 4 and several other chromosomes have been associated with leukemias, which are cancers of blood-forming cells t(4;11)(q35;q23) KMT2A/SORBS2 in acute myeloid leukemia (AML), t(4;11)(q21;p15) NUP98/RAP1GDS1 in T-cell acute lymphoblastic leukemia (ALL), and t(4;11)(q21;q23) KMT2A/AFF1 in ALL mainly, t(4;12)(q12;p13) CHIC2/ETV6 in AML and therapy-related ALL cases with t(4;12)(q11-12;p13). B-cell ALL cases seem to have a more distal breakpoint in 4q13 or 21. t(4;10)(q12;q23) PDGFRA/TNKS2 in myeloid neoplasm with eosinophilia, t(4;16)(q26;p13) interleukin 2 (IL2)/TNFRSF17 in T-cell lymphoma of the small intestine of low-grade malignancy, t(4;17)(q12;q21) FIP1 L1/RARA in Juvenile myelomonocytic leukemia and acute promyelocytic leukemia, and t(4;22)(q12;q11) BCR/PDGFRA reported in three cases; myeloproliferative disorder: Atypical chronic myeloid leukemia (aCML) (Philadelphia chromosome-negative) and +4 or trisomy 4 in AML. +4 as the sole anomaly is a rare chromosomal abnormality associated with a specific subtype of primary AML and secondary (treatment related) AML with myelomonocytic morphology; it has been found with the same frequency in the M1-M2 and M4 French–American–British phenotypes. +4 has been described in two cases of T-cell ALL as the sole chromosomal anomaly [Table 1].
There are many genes that are important also in CLL on chromosome 4. IL2 on 4q26-q27, the protein encoded by this gene, is a secreted cytokine that is important for the proliferation of T and B lymphocytes. IL2 is a potent inducer of T-cell proliferation. FBXW7, F-box and WD repeat domain containing 7(4q31.3), encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif the F-box. Mutations in this gene are detected in ovarian and breast cancer cell lines implicating the gene's potential role in the pathogenesis of human cancers. Multiple transcript variants encoding different isoforms have been found for this gene. An analysis of 1160 untreated CLL patients. Jeromin et al.(2014) reported 2.5% of cases had FBXW7 mutations. FBXW7 mut was associated with CD38 positivity and CLL/prolymphocytes. They were more frequent in patients with trisomy 12 and rare in del(13q) sole. NOTCH1 and FBXW7 are part of the same signaling pathway. NOTCH1 mut was associated with higher percentages of cells with a CLL phenotype. ADAM metallopeptidase domain 29 (ADAM29)(4q34), this gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Patients expressing ADAM29 had shorter disease-free survival and overall survival. ADAM29 gene expression associated to IGHV mutational status for predicting the clinical outcome of patients treated by oral fludarabine + cyclophosphamide and could be considered for treatment strategies.
According to literature, it was reported isochromosome 4q in studies with malignant melanoma cell lines and head/neck squamous cell carcinoma lines. Moreover, these samples exhibited metastatic behavior.
| > Conclusion|| |
Extra isochromosome 4q is reported with our patient for the first time in CLL. The number of copies of genes located on 4q increase as a result of this anomaly occurred [Table 2]. Patient showed disease progression compared to previous results. Hence, we offer that this evidence can be considered regarding triggering the disease's progression or as a result of disease progression i4q was occurred. This anomaly has not been previously reported in the literature. Therefore, any information on the importance of progression is absent from the literature.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]