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Year : 2016  |  Volume : 12  |  Issue : 3  |  Page : 1203-1206

Spectrum of complex chromosomal aberrations in a myelodysplastic syndrome and a brief review

1 MGM Center for Genetic Research and Diagnosis, MGM New Bombay Hospital, Navi Mumbai, Maharashtra, India
2 Department of Hematology, NRS Medical College, Kolkata, India
3 Department of Pediatrics, MGM Medical College, Navi Mumbai, Maharashtra, India

Date of Web Publication4-Jan-2017

Correspondence Address:
Dr. Bani Bandana Ganguly
MGM Center for Genetic Research and Diagnosis, MGM New Bombay Hospital, Vashi Sector 3, Navi Mumbai - 400 703, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.197563

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 > Abstract 

Myelodysplastic syndrome (MDS) is a heterogeneous premalignant condition characterized by cytopenia, ineffective hematopoiesis, dysplastic marrow, and risk of progression to acute myeloid leukemia. Cytogenetic abnormalities, including del(3q/5q/7q/11q/12p/20q), monosomy 5/7, trisomy 8/19, i(17q), and -Y, are the indicators of diagnosis and risk stratification. The present case with bicytopenia detected with highly complex chromosome rearrangements with variability in numerical and structural combinations. Chromosome analysis was carried out following unstimulated marrow culture and G-banding. In addition to known MDS-aberrations, der(9p), der(12) dic(12;?19), +15, −18, and ring and marker chromosomes were recorded having, at least, nine abnormal chromosomes/cell. To our knowledge, this is the first case with all MDS-aberrations in one single individual. The case has been discussed in relevance to current MDS research. In the present case, i(17q)/-17, der(12p), del(5q26), del(7q36), and del(20q11) indicate possible alterations in TP53, ETV6, IDH2, EZH2, and SRSF2 genes, which are responsible for pathomechanism, genetic instability, clonal evolution, and advancement of disease condition.

Keywords: Complex chromosome rearrangements, genetic mutations, myelodysplastic syndrome

How to cite this article:
Ganguly BB, Dolai TK, De R, Kadam NN. Spectrum of complex chromosomal aberrations in a myelodysplastic syndrome and a brief review. J Can Res Ther 2016;12:1203-6

How to cite this URL:
Ganguly BB, Dolai TK, De R, Kadam NN. Spectrum of complex chromosomal aberrations in a myelodysplastic syndrome and a brief review. J Can Res Ther [serial online] 2016 [cited 2022 Aug 8];12:1203-6. Available from: https://www.cancerjournal.net/text.asp?2016/12/3/1203/197563

 > Introduction Top

Myelodysplastic syndrome (MDS) represents heterogeneous clonal premalignant changes typically associated with blood cytopenia, ineffective hematopoiesis, and transformation to acute myeloid leukemia (AML). Conventional cytogenetic study is considered as the first line of diagnosis. Among the chromosomal rearrangements, del(3q/5q/7q/11q/12p/20q), monosomy 5/7, trisomy 8/19, i(17q), and -Y, have been frequently detected with variable frequencies.[1],[2] Therapeutic response and clinical evolution of chromosomal rearrangements are important for classification and risk-assessment.[3] We present an MDS case with complex heterogeneity and multiple clonal abnormalities with at least 10 aberrations/cell in 53% cells.

 > Case Report Top

A 71 years elderly was presented with a history of weakness/fatigability/exertional breathlessness/fever/jaundice/progressive pallor/wet purpura/petechial spots without lymphadenopathy/hepatosplenomegaly/any co-morbidity. Hemogram showed bicytopenia with hemoglobin 4.9 g%; total leukocyte count 9600/cu.mm; and platelet 60,000/cu.mm. In addition, atypical mononuclear cells, dysplastic neutrophils, <5% blast, Cabot rings, adequate megakaryocytes with dysplastic changes and high nucleo-cytoplasmic ratio were present in bone marrow.

The conventional cytogenetic analysis involved unstimulated culture of bone marrow in RPMI-1640 supplemented with fetal bovine serum at 37°C for 24 h and karyotyping and ISCN (2009) classification of 30 metaphases using IKAROS software (MetaSystems, Germany).

G-banded metaphases revealed multiple complex abnormalities, including monosomy of 5/7/18/19; loss of Y; deletion of 5q/7q/20q; +(15, markers, small and large rings, minutes); and der(9p) and der(12) dic(12p;?19p), with aneuploidies of different numerical combination of 45, 46, and 47 chromosomes [Figure 1]. The detail raw data are presented in [Table 1a] (presence: √; absence: -). Del(5q/20q), dir(9p/12p), -(18/19/Y), and, at least, one marker was consistently present in 88% of the cells evaluated. The remaining showed more monosomies resulting in more complex rearrangements leading to increase in marker chromosomes.
Figure 1: The metaphases show complex rearrangements with 46,X,-Y,del(5q),−7,der(12)dic(12;19),+15,−18,−19,del(20q),+mar,+ring(?)

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Table 1a: Description of chromosomal aberrations observed in 30 individual cells

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All cells had abnormalities of five and seven as deletion or monosomy with the prevalence of deletion in 93% and 80% for the two chromosomes, respectively. One chromosome 9 appeared as a derivative with the addition of chromosomal material in “p” arm and was observed in all cells [Figure 2]a]. Der(12) was a dicentric chromosome wherein 19 is the partner, which has resulted in monosomy 19 [Figure 2]b. Monosomy 17 and i(17q) were noticed in low frequencies. In addition to identified chromosomes, every cell had, at least, one marker chromosome [Figure 2]c and rings of small to large sizes [Figure 2]d. Loss of 18/19/Y was observed in 100% cells, except one cell with two 19s and der(12) [Figure 2]e. The rings and markers had variability in structure where some of the markers could be classified as ring. Altogether, 314 aberrations were recorded in thirty cells [Table 1b], with a range of 9–12 aberrations/cell [Table 1c]. Numerical alteration was observed with 45 (77%) and 47 (6%) chromosomes; however, cells with 46 chromosomes (17%) had a minimum of ten aberrations. Overall, ten aberrations were noticed in 53.3% cells followed by 26.7%, 13.3%, and 6.7% cells with 11, 12, and 9 aberrations, respectively [Table 1c]. In fact, a great deal of variabilities of aberrations was observed, even among cells with 45 chromosomes.
Figure 2: Additional karyotypes to support suspected aberrations (abnormal chromosome placed on right of the pair). (a) Der(9), (b) der(12) dic(12;?19), (c) marker chromosomes, (d) ring chromosomes, (i) suspected rings, (ii) confirmed rings, and (e) the cell with two 19s and der(12) dic(12;?19)

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Table 1b: Distribution of aberrations in different chromosomal make up of the cells

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Table 1c: Complex aberrations versus total number of chromosomes per cells

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 > Discussion Top

Cytogenetic information is important in risk stratification according to the International Prognostic Scoring System-Revised (IPSS-R) and WHO classification-based prognostic scoring system.[3],[4] The prognostic division of del(7q) from −7 and the importance of double and complex aberrations has classified 91% of chromosomal lesions into five prognostic subgroups with the scoring of “very good” to “very poor” in IPSS-R. However, the remaining abnormalities with unknown significance pose two major problems, viz., risk of profound heterogeneity of acquired cytogenetic alterations and associated risk of designing a comprehensive therapy that predicts the prognostic impact of rare abnormalities.

Cytogenetic finding of monosomal karyotypes of one or more autosomes and/or structural abnormality in association with one monosomy, which are often detected in AML, also have significant importance on prognostication of MDS.[4] However, independently monosomal karyotypes have not been considered in IPSS-R classification, due mainly to the fact that the missing chromosome can be present as a marker or rearranged on seemingly normal chromosomes. Though the independent effect of monosomal karyotype on MDS-risk is not streamlined, such abnormal status leads to genomic instability when it appears in a complex karyotypic scenario.[5],[6] The present case showed a heterogenic chain of monosomy, including −7, −17, −18, and −19, some of which could be rearranged and appeared as rings and markers.

The present case demonstrated a wide spectrum of acquired rearrangements with a minimum of ten aberrations/cell, including del(5q/7q/20q), -(18/19/Y), der(9p/12p), ring, and marker in over 53% cells. The present case with three times of IPSS-R complex aberrations is expected to exhibit very poor prognosis and faster transformation to AML. However, such magnitude of aberrations and its prognostic classification have not been reported in IPSS-R, which requires a large database for risk management of such isolated class. The present case would be informative in the proposed scoring system with 19 cytogenetic categories based on 2801 cytogenetically evaluable untreated MDS patients.[2]

Employment of aCGH, SNP-array, and sequencing technologies have described a number of random genetic mutations (”passengers”) in hematopoietic stem cells before acquisition of the initiating nonrandom founder mutations.[7],[8] The presence of TET2 mutations in hematologically normal older individuals forms the understanding of such random genetic events prior to disease initiation. Multiple genetic mutations of RNA-splicing machinery are believed to be the driving factors of MDS. In the present case, i(17q)/-17, der(12p), del(5q26), del(7q36), and del(20q11) indicate possible alterations in TP53, ETV6, IDH2, EZH2, and SRSF2 genes.

Molecular aCGH/SNP-array/sequencing techniques collect genome-wide information on CNV on cases with normal or abnormal karyotypes and also in unsuccessful cytogenetics, at much higher resolution without utilizing metaphases.[9] However, data analysis with low frequency or noncoding mutations and cost and time required are the limiting factors for routine clinical work-up. Conventional karyotyping enables genome-wide detection of balanced translocations and complex rearrangements, which otherwise cannot be detected by molecular techniques. A combined approach of molecular karyotyping and conventional cytogenetics showed convincing results on independent predictor of survival.[10] Therefore, it is clear that cytogenetic study is mandatory for every new MDS and also for patients having differential diagnosis with persistent unexplained cytopenias. The present case highlights the necessity of classification and risk-assessment of isolated rare abnormalities for MDS management and targeted drug development. Till date, this is the first case with all MDS-specific abnormalities of different prognostic implications.

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Conflicts of interest

There are no conflicts of interest.

 > References Top

Haase D, Germing U, Schanz J, Pfeilstöcker M, Nösslinger T, Hildebrandt B, et al. New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: Evidence from a core dataset of 2124 patients. Blood 2007;110:4385-95.  Back to cited text no. 1
Schanz J, Tüchler H, Solé F, Mallo M, Luño E, Cervera J, et al. New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge. J Clin Oncol 2012;30:820-9.  Back to cited text no. 2
Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood 2012;120:2454-65.  Back to cited text no. 3
Patnaik MM, Hanson CA, Hodnefield JM, Knudson R, Van Dyke DL, Tefferi A. Monosomal karyotype in myelodysplastic syndromes, with or without monosomy 7 or 5, is prognostically worse than an otherwise complex karyotype. Leukemia 2011;25:266-70.  Back to cited text no. 4
Heim S, Mitelman F. Cancer Cytogenetics. 3rd ed. Hoboken, NJ: Wiley-Blackwell; 2009.  Back to cited text no. 5
Schanz J, Tüchler H, Solé F, Mallo M, Luño E, Cervera J, et al. Monosomal karyotype in MDS: Explaining the poor prognosis? Leukemia 2013;27:1988-95.  Back to cited text no. 6
Kulasekararaj AG, Mohamedali AM, Mufti GJ. Recent advances in understanding the molecular pathogenesis of myelodysplastic syndromes. Br J Haematol 2013;162:587-605.  Back to cited text no. 7
Nybakken GE, Bagg A. The genetic basis and expanding role of molecular analysis in the diagnosis, prognosis, and therapeutic design for myelodysplastic syndromes. J Mol Diagn 2014;16:145-58.  Back to cited text no. 8
Bejar R, Lord A, Stevenson K, Bar-Natan M, Pérez-Ladaga A, Zaneveld J, et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood 2014;124:2705-12.  Back to cited text no. 9
Noronha TR, Rohr SS, Chauffaille Mde L. Identifying the similarities and differences between single nucleotide polymorphism array (SNPa) analysis and karyotyping in acute myeloid leukemia and myelodysplastic syndromes. Rev Bras Hematol Hemoter 2015;37:48-54.  Back to cited text no. 10


  [Figure 1], [Figure 2]

  [Table 1a], [Table 1b], [Table 1c]


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