Cytogenetic abnormalities in myelodysplastic syndrome: an overview

Abstract

The myelodysplastic syndromes (MDS) are clonal disorders of haematopoietic stem cells characterized by ineffective haematopoiesis leading to blood cytopenias and by high incidence of progression to acute myeloid leukaemia (AML). These disorders generally arise de novo, but may also occur years after exposure to mutagenic chemotherapy. Clonal cytogenetic abnormalities are detected in about 30–50% de novo cases, whereas more than 80% of therapy-related forms harbour such markers. Although in the Western countries, MDS cases are mainly reported in the elderly population and rarely in the paediatric age group; this disease is increasingly seen in young adults in India. Cytogenetic study plays an important role in the diagnosis and is useful for prediction of individual prognosis using the international prognostic scoring system. Specific chromosomal abnormalities, such as −5/5q-, −7/7q-, and complex abnormalities, play an important role in the development of new therapeutic options and clinical management of MDS. In this review, we summarize the cytogenetic abnormalities in MDS from various parts of the world.

Keywords:

• Myelodysplastic syndrome
• Chromosomal aberrations
• Prognosis
• Complex translocations

Introduction

The myelodysplastic syndromes (MDS) are clonal disorders of haematopoietic stem cells characterized by ineffective haematopoiesis leading to blood cytopenias and by high incidence of progression to acute myeloid leukaemia (AML).1 These disorders generally develop de novo, but may also occur years after exposure to mutagenic chemotherapy.2 Primary and secondary MDS are recognized taking into account the previous history of the patients. In MDS patients, variability is seen in cytogenetics, which may influence the prognostic classification and understanding of the molecular background of the abnormalities seen in MDS. In MDS, cellular dysplasia of blood and marrow cells is linked to functional defects in both neutrophils and platelets, which contribute to infection and bleeding manifestations, even in the absence of substantial reduction in blood cell production. The variable risk of progression to AML which is characteristic of MDS appears to be driven by somatic genomic instability and epigenetic genomic modification. Allelic imbalances arising from structural or numerical chromosomal aberrations, defects in DNA repair,3,4 and linkage to genotoxic exposures including alkylating agents, topoisomerase 2 inhibitors, environmental poisons, or radiation.5,6 In this review, the frequency and type of chromosomal abnormalities found in different populations are considered, which may be helpful in the understanding the aetiology, current stratification, and management of MDS.

Classification of MDS

MDS has been recognized for the past 60 years and there have been attempts at classification. The French–American–British (FAB) classification which was revised and expanded in 1982 is based on the proportion of immature blast cells in the blood and bone marrow, and also on the presence or absence of ringed sideroblast or peripheral monocytosis.7 World Health Organization (WHO) created a new classification system based on FAB, but included new morphological features and cytogenetic abnormalities.8,9 Based on peripheral blood and bone marrow findings, the FAB cooperative group7 distinguishes fine morphological subtypes of MDS, which include refractory anaemia (RA), refractory anaemia with ringed sideroblasts (RARS), refractory anaemia with excessive blast in transformation (RAEB-t), and chronic myelomonocytic leukaemia (CMMoL). Controversies related to FAB classification were, for example, the heterogeneity of the refractory anaemias, the inclusion and definition of CMMoL, the definition of prognosis of patients with del(5q), and the observation that some groups of MDS patients with medullary blast counts above 20% generally have a prognosis similar to one with AML.5,10

The WHO classification has been more widely accepted by pathologists and clinicians, and was combined with the international prognostic scoring system,11 which utilizes the percentage medullary blasts, the number of cytopenic lines and cytogenetic abnormalities as prognostic factors, signifying an advance in the diagnosis and treatment of patients with MDS (Table 1)8.

Table 1. WHO classification for the myelodysplastic syndromes

Category	Peripheral blood	Bone marrow
RA	Anaemia	Erythroid dysplasia
	Blasts <1%	Blasts <5%
	Monocytes <1000/μl	Ring sideroblasts <15%
RARS	Anaemia	Dysplasia only in the erythroid line
	Blasts <1%	Ring sideroblasts ⩾15%
	Monocytes <1000/μl	Blasts <5%
RCMD	Cytopenias (bi- or pancytopenia)	Dysplasia ⩾10% of the cells
	Blasts <1%	Blasts <5%
	Monocytes <1000/μl	Ring sideroblasts <15%
RCMD-RS	Cytopenias (bi- or pancytopenia)	Dysplasia ⩾10% of the cells
	Blasts <1%	Blasts <5%
	Monocytes <1000/μl	Ring sideroblasts ⩾15%
RAEB-I	Cytopenias	Dysplasia uni- or multilines
	Blasts <5%	Blasts 5–9%
	Monocytes <1000/μl
RAEB-II	Cytopenias	Dysplasia uni- or multilines
	Blasts 5–19%	Blasts 10–19%
	Monocytes <1000/μl	Auer rods ±
	Auer rods ±
5q- syndrome	Anaemia	Megakaryocytes hypolobulate normal or increased
	Blasts <5%	Blasts <5%
	Normal or increased platelet counts	del(5q) alone
MDS without classification	Cytopenias	Single-line dysplasia of the granulocytes or megakaryocytes
	Blasts <1%	Blasts <5%

Note: RA, refractory anaemia; RARS, refractory anaemia with ring sideroblasts; RCMD, refractory cytopenia with multiline dysplasia; RCMD-RS, refractory cytopenia with multiline dysplasia with ring sideroblasts; RAEB, refractory anaemia with excess blasts; MDS, myelodysplastic syndrome.

The main changes of WHO classification refined the definitions of low-grade subtypes (RA and RARS) as being strictly erythrocytic, and added a new category, refractory cytopenia with multilineage dysplasia. The lower limit for the percentage blasts for the diagnosis of AML, in peripheral blood or bone marrow, was reduced from 30 to 20%, which resulted in the elimination of subtype RAEB-t from the WHO classification. Other changes included in WHO classification included RAEB-I with 5–9% medullary blasts, RAEB-II with 10–19% and MDS without classification, and the specific genetic subtype, 5q- syndrome.8 The FAB guidelines for RA and RARS are somewhat ambiguous and result in different interpretations by different research groups. Bennet et al.7 state that, in RA and RARS, morphological abnormalities in the granulocytic and megakaryocytic series identical to those present in the other subtypes of MDS may occasionally be found in varying degrees. They also noted that the erythroid series are mainly affected and the granulocytic and megakaryocytic series almost always appear normal.

Incidence

The precise incidence of de novo MDS is not known; however, there are estimates that it exceeds the incidence for acute myeloid leukaemia in the elderly, the risk increasing with the age. In one study, the annual incidence per 100,000 was estimated at 0·5 for people less than 50 years of age compared to 5·3 for the ages 50–59 years, 15 for ages 60–69 years, 49 for ages 70–79 years, and 89 for ages older than 80 years.12 Aul et al.13 reported a crude annual incidence of 4·1/100 000 for MDS. The mean age in most series is approximately 65 years, and in the majority of the cases, there is a male predominance.14 Onset of the disease before the age of 50 years is unusual with the specific exception of mutagen-induced MDS.15

Cytogenetic Features in MDS

The chromosomal aberration frequency varies with the geographic and ethnic changes (Table 2). Chromosomal aberrations are present in half of all de novo MDS patients. There are various cytogenetic abnormalities observed in MDS that are also seen in AML, thus supporting a common origin for a proportion of these two diseases.16 Some karyotypic abnormalities are more frequently associated with MDS than AML, mainly del(5q) and del(20q).16 A loss of genetic material in the form of deletions and monosomies is frequently observed in MDS and gain of genetic material in the form of total or partial trisomies is not frequently observed. In consideration into loss or gain of genetic material, it is assumed that main molecular mechanism in MDS is the inactivation of tumour suppressor genes in the form of loss as compared to the activation of oncogenes. Difference between the primary and secondary MDS is complexity of abnormal karyotypes as single chromosomal abnormalities typical for primary MDS, while complex chromosomal abnormalities are seen in secondary MDS.17

Table 2. The frequency of chromosomal abnormalities reported in MDS

Author (year)	Total no. of patients studied	Percentage of abnormal karyotype (%)
Knapp et al. (1985)	174	38
Horiike et al. (1988)	83	60
Geddes et al. (1990)	124	36
Toyama et al. (1993)	401	50
Haase et al. (1995)	179	51·4
de Souza Fernandez pet al. (1997)	50	32
Borgonovo et al. (2005)	93	69
Solé et al. (2005)	968	51
Dakshinamurthy pet al. (2005)	52	64·5
Panani et al. (2006)	239	26·36
Haase et al. (2007)	2072	52·3
Gmidène et al. (2008)	224	51
Pozdnyakova et al. (2008)	1029	45
Li et al. (2009)	351	67·5
Skonieczka et al. (2009)	58	43·1
Wang et al. (2009)	424	38·7
Vundinti et al. (2009)	145	54·48

Primary MDS and cytogenetics

Most frequent chromosomal abnormalities in MDS

Monosomy 5/del(5q)

Monosomy 5 or deletion of long arm of chromosome 5(5q-) was the most frequent chromosomal abnormality found across the world and have been reported in various populations, including Tunisian 13%, Brazilian 12·5%, USA 5·9%, India 42%, and Germany 30% groups. The chromosome 5q region contains many genes that are involved in the regulation of haematopoiesis, including cytokines and their receptors, cell cycle regulators, transcription factors, and signalling mediators. The haematological genes between 5q13 and 5q33 suggest a significant correlation between the genetic abnormality and the clinical features of 5q- syndrome and other del(5q) MDS subtypes.18^–20 More than 50% of patients with MDS present with cytogenetic aberrations at diagnosis. Partial or complete deletion of the long arm of chromosome 5 is the most frequent abnormality. Isolated del(5q) is generally associated with refractory anaemia without excess of blasts, macrocytic anaemia, thrombocytosis, and typical mononucleated megakaryocytes, features characteristics of the 5q- syndrome.21 In 5q- syndrome, there are characteristic clinical features, in addition to the above, including mild leukocytopenia, and elevated platelets with less than 5% blasts in bone marrow smears with or without the presence of erythroid and granulocytic dysplasia. Sole 5q- deletion in MDS is of favourable prognosis. In MDS with 5q-, the deletion is always interstitial but is of variable extent. A commonly deleted segment involving 5q31 and 5q32 bands was detected using cytogenetic analysis.22 Boultwood et al.21,23 has described a small commonly deleted segment at 5q31–32 of only 1·5 Mb.

On the basis of haploinsufficiency, it is shown that 41 candidate genes in the critical region of chromosome 5q have been reported and gene for ribosomal subunit protein (RPS41) seems to be a relevant gene in 5q- syndrome.24 In 5q31 region, there are two distinct deleted regions, which is located more centromeric, possibly associated with high risk, complex abnormalities, poor prognosis as well as secondary MDS. Another area which is more telomeric near 5q32 is supposed to be associated with good prognostic 5q- syndrome.25^–27 Supportive care with red blood cell transfusion is the main option in majority of patients with non complex del(5q-).28^–30 The use of recombinant erythropoietin and granulocyte colony-stimulating factor has yielded poor results in 5q- syndrome compared to non-5q- MDS.31,32 Modern therapeutic options, such as the immunomodulating agent lenalidomide, give a good response in 5q- syndrome patients.33 Chromosome 5 abnormalities were significantly associated with exposure to inorganic gases and fumes which include exhaust gases, ammonia fumes, hydrogen peroxide, and mineral acids.34

Monosomy 7/del(7q)

Along with −5/5q- abnormality, chromosome 7 abnormalities are also frequently observed in MDS patients.35 The frequency of chromosome 7 abnormalities in various countries such as Tunisia, Brazil, and India were 8, 14, and 32·2%, respectively. Monosomy 7 is characterized by a severe refractory cytopenias, and susceptibility to major infections. Allelotyping studies have identified three distinct loci, 7q22, 7q31·1, and 7q31·3, which are frequently deleted, and a region between 7q22 and 7q36 has been identified as a region harbouring more than one tumour suppressor genes which are inactivated in AML and MDS.36^–38 No significant prognostic relevance has been observed in monosomy 7/7q-. The German–Austrian study group39 reported 36% where monosomy 7 was the sole abnormality, 14% with one additional abnormality and 50% as part of complex chromosomal abnormalities. It can be assumed that there must be a cluster of genes with tumour suppressor features present in 7q region associated with MDS.40 Molecular background of the monosomy 7 in MDS is associated with cytogenetic subgroup with RAS mutation, AML1 mutations, and hypermethylation of P15INK4B.41,42

There is no favoured therapeutic option available in the monosomy 7 subgroup. Allogeneic stem cell transplantation can be done if age and clinical conditions are adequate,40 but in monosomy 7 there is a high risk of early relapse. Chromosome 7 abnormalities were significantly associated with exposure to organics, inorganic dusts, and inorganic gases.35 According to Raj et al.,43 MDS and AML patients treated with 5- azacytidine shows a good response in monosomy 7 with continuous complete remission for 10-month follow-up.

Other chromosomal abnormalities in primary MDS

Other chromosome abnormalities have also been frequently observed in MDS after −5/5q- and −7/7q-. The variant chromosome rearrangements such as trisomy 4, trisomy 8, trisomy 9, trisomy 11, trisomy 13, trisomy 14, trisomy 17, trisomy 18, trisomy 19, trisomy 21, −8, −10, −16, −22, −X, −Y, monosomy 19, monosomy 21, del(1)(q32), del(2)(q33-ter), del(8q), del(9)(q31), del(12)(p12p13), del(13q), del(17)(q23), del(18p), del(20q), +1q, +3q, +mar, 11q23 rearrangements, t(6;14)(q23;q32), inv(1)(p22q24), i(1q), i(14)(q11), i(17q), dup(1)(q21q32), t(1;1)(q41;q43), t(1;8)(q21;p12), derivative(1;7)(q10;p10), t(1;11)(q11;q25), t(1;11)(q11;p15), t(1;12)(q10;q10), t(1;19)(q23;p13), t(3;9)(p21;p23), t(5;13)(q21;q31), t(5;16)(q14;p13), t(5;19)(q22;q13), t(1;7)(q10;p10), t(1;17)(q10;q10), t(7;17)(p15;q11), t(X;6)(p10;p10), t(X;11), t(9;12)(q12;q24·3), t(1;2)(q13;q12), t(11;14)(q13;q32), dic(1;16)(q21;p13·3) t(1;22),t(9;12;22)(q34;q15;q11), t(10;14)(q31;q21), der(4)t(1;4)(q21;q35), t(7;13), t(1;X)(p21;q31), t(2;11)(p21;q23), and t(3;3)(q21;q26) were observed to date. These aberrations are reported to be associated with poor prognosis.

In a Tunisian population, chromosome abnormalities in MDS patients were found in 51% and the most frequent karyotypic abnormalities found was del(12p) in 4%, del(20q) and trisomy 8 in each 3%, i(17q) in 21%, and −Y in 0·4% cases. In this population, patients are classified according to prognostic significance as good risk cytogenetics, whose median survival was 30 months, if they possessed specific single chromosomal abnormalities, such as del(5q), del(20q), −Y, and normal karyotype. Poor risk patients, whose median survival was 10 months, possessed −7 and complex karyotypes. Intermediate prognosis is observed with various abnormalities, such as trisomy 8, trisomy 21, del(12)(p12p13), i(17q), t(2;11)(p21;q23), t(3;3)(q21;q26), del(12)(12p13), i(14)(q11), trisomy 19, monosomy 19 +mar, del(5q) del(13q), t(6;14)(q23;q32), +13, and +21.44 In a Brazilian population,45 the frequency of chromosomal alterations was 69% of the patients with primary MDS, and the most frequent chromosomal abnormalities were 11q23 rearrangements in 12·5%, del(12p) in 12·5%, trisomy 8 in 9·4%, and del(20q) in 7·8%. Among the abnormalities detected in adults, the most frequent were rearrangements of 11q23 (16·23%) and del(12p) (14·3%). In paediatric patients, del(5q) (20%) and monosomy 7 (20%) were the most frequent alterations detected. In these studies, some structural aberrations involved rare breakpoints such as 1q24, 1q32, 1q41, 1q43, 9q31, and 17q23 in inv(1)(p22q24), del(1)(q32), t(1;1)(q41;q43), del(9)(q31), and del(17)(q23), respectively. One more study in de Souza Fernandez et al.46 reported lower (32%) chromosomal aberration frequency compared to other studies. The most frequent chromosomal abnormalities found in this series were +8, dup(1)(q21q32), del (20q), t(1;8)(q21;p12), and −8. A large group (968) with primary MDS were studied in a Spanish population and 45% chromosome aberrations were detected. The most common abnormalities found were trisomy 8, rearrangement of 11q, del(12p), i(17q), del(20q), and loss of Y. Complex karyotypes were observed in 107 patients, 23·6% among those patients with abnormal karyotypes. Single chromosomal abnormalities were found to be gain of 1q, involvement of 3q, trisomy 8, trisomy 9, del, or t(11q), trisomy 11, del(12p), rearrangement of 13q, i(17q), trisomy 17, trisomy 18, trisomy 19, del(20q), trisomy 21, monosomy 21, and loss of X and Y chromosomes.47 Pozdnyakova et al.48 conducted a study in the USA on a series of 1029 patients with primary MDS which showed various cytogenetic abnormalities with a frequency of chromosomal aberrations found to be 45% (458 patients) of the single chromosomal abnormalities, including del(20q), −Y, +8, 3q rearrangement, +9, del(11q), +11, del(12p), 13q rearrangements, isochromosome 17q[i(17q)], +17, +18, +19, +21 and −21, −7, del(7q), and derivative(1;7)(q10;p10). The most frequent single chromosomal aberrations in there series were +8 (3·7%) and del(20q) (2·7%). A complex karyotype (mostly chromosome 5 and chromosome 7 or both) was observed in 39·5% among the patients with abnormal karyotype.48

Recently, a multicentre study was carried out in Chinese population and high frequency (67·5%) of chromosomal aberrations was detected. Ninety-nine had copy number changes alone (41·7%), 70 had structural abnormalities alone (29·5%), and 68 displayed both of these changes (28·8%). Chromosomal abnormalities frequently detected in these series were +8,−20/20q-/del(20)(q11–13), −18, −11/11q-/del(11)q23–25), +21, −Y, −21, −10, −16, −22, +9, and del(12)(p12). Besides these aberrations, they also found some rare chromosomal translocations such as t(1;11)(q11;q25), t(1;11)(q11;p15), t(1;12)(q10;q10), t(1;19)(q23;p13), t(3;9)(p21;p23), t(5;13)(q21;q31), t(5;16)(q14;p13), t(5;19)(q22;q13), t(1;7)(q10;p10), t(1;17)(q10;q10), t(7;17)(p15;q11), and t(X;6)(p10;p10).49 Panani et al.50 carried out a study on Greek population on 239 primary MDS patients and 63 (26·36%) cases were found with an abnormal karyotype. Among the cytogenetically abnormal cases, 46 patients presented single chromosomal abnormalities (73·01%). These aberrations were according to frequency +8 (28·57%), +14 (6·35% each), i(17q) and del(11)(q13) (4·76% each), +11, −Y, i(1q), del(8q), del(18p), and t(X;11) (1·59% each). The incidence of chromosomal abnormalities in Greek MDS patients was lower (26·36%) than that reported in the literature.50

In Cardiff, UK clonal karyotype abnormalities in 124 patients with MDS were reviewed which found that 45(36·3%) showed chromosomal abnormalities. Trisomy 8 represented the second most frequent abnormality in all subtypes but most commonly in RAEB; chromosome 7 abnormalities like −7, +der(1)t(1;7), del(20q), and trisomy 21 were also observed. They carried out sequential studies in 77 patients of whom 12 showed karyotypic evolution. Leukaemic transformation most commonly occurred in patients with an abnormal karyotype, particularly those with multiple abnormalities, and in patients with evolving karyotype.51 In China,52 chromosomal analysis was successfully carried out in 424 patients, of which 164 (38·7%) were found to have clonal chromosomal abnormalities. The greatest frequency of abnormal karyotypes was found in RAEB subtypes. The most common chromosomal abnormality was trisomy 8 occurring either singly or in combination with other abnormalities. Various other chromosomal abnormalities are also observed, such as −5/5q-, −7/7q-, 20q-, 9q-, 11q, 12p-, 17p, −Y, translocations, and complex karyotypes.52 In Germany, Haase et al.53 carried out sequential study on 2124 myelodysplastic syndrome patients which reveals clonal chromosomal abnormalities in 1084 (52·3%) patients. Other frequent chromosomal abnormalities including −7/7q-, +8, −18/18q-, 20q-, −5, −Y, −17/17p- [including isochromosome (17q)], +mar, +21, inv/t(3q), −13/13q-, +1/+1q, −21, +11, 12p-, t(5q), 11q-, and t(7q) were present in various proportions in German populations.53

The position in India in MDS appears quite different from the rest of the world as revealed by a number of studies. One study54 showed chromosomal abnormalities in 64·5% of patients. The most frequent chromosomal abnormalities were del(5q/5-) (42%), −7/7q- (32·2%), +8, and 20q- (19·3%) each and i(17)(q10), −Y, trisomy 4, and trisomy 14 (3·2%) each. A further study conducted from India reported 54·48% of chromosomal abnormalities including novel chromosomal aberrations,55 frequency of chromosomal abnormalities was increased with the advancing age (>30 years) and chromosomal abnormalities are significantly associated with pesticide exposure. Chromosomal deletions (19%) are more frequent as compared to other chromosomal aberrations (12%). Novel chromosomal abnormalities such as t(9;12)(q12;q24·3), t(1;2)(q13;q12), and t(11;14)(q13;q32) in RA, dic(1;16)(q21;p13·3), t(1;22), t(9;12;22)(q34;q15;q11), and t(10;14)(q31;q21) in RAEB-t. der(4)t(1;4)(q21;q35) +mar, t(7;13), t(8;21)(q22;q22), t(1;X)(p21;q31), and −7 in RA with RAEB-t, del(2)(q33-ter) in CMMoL), and trisomy 14 in RA with RARS have been reported.55

Secondary MDS

Therapy-related myelodysplasia and myeloid leukaemia (t-MDS/t-AML) is a distinctive clinical syndrome occurring after exposure to chemotherapy or radiotherapy. Most patients with t-MDS/t-AML have clonal chromosomal abnormalities in their bone marrow cells at diagnosis. In Chicago, clonal chromosomal abnormalities observed in 282 (92%) patients having one or two detectable abnormal clones and 24 (8%) patients were karyotypically normal. The most common abnormalities involved loss of a whole chromosome 5, 7, or both (−5 and −7) or a deletion of the long arm of these chromosomes [del(5q) or del(7q)] in 214 (70%) patients. Monosomy 7 (−7) was present in 102 (33%) patients and monosomy 5 (−5) in 36 (12%) patients. The most common structural chromosomal abnormality was a del(5q) in 59 (19%) patients.56 Increasing copy number of chromosome 8/8q may be a marker of advanced clonal evolution and toxic-exposure myelodysplasia, and both these features were associated with a poor prognosis. In one such therapy, related MDS due to cyclophosphomide therapy for fibrosing alveolitis showed complex karyotype: 45–47,XX,der(5)t(5;12)(q14;q13)[21],del(5)(q13)[3],i(8)(q10)[20],+i(8)(q10)[20], inv(9)(p13q13)[20],−12[20],+r[2][cp21] with a normal clone of 46,XX[3].57

Impact of fluorescence in situ hybridization (FISH) in detection of chromosomal aberrations in MDS

FISH may add value to karyotype non-informative results and occasionally reveals cryptic aberrations not recognized by conventional cytogenetics. According to Yang et al.,58 FISH testing is informative only in those cases with karyotype failure and intermediate–high grade MDS with normal karyotype and has limited utility in cases that have normal G-band karyotypes and morphological features of low-grade MDS or in cases with abnormal G-band karyotypes. G-banded karyotyping has limited resolution power in the range of few megabases of DNA. FISH has a much higher resolution power and can detect chromosomal aberrations in the order of few hundred kilobases of DNA.59 Hence, FISH is more sensitive in detecting chromosomal aberrations in clones with low mitotic index, in detecting cryptic or submicroscopic chromosomal aberrations, and in detecting minor clones.

Cytogenetics and prognostic significance

Karyotype plays an important role in the prognosis of patients with MDS which is helpful for the development of therapeutic strategies based on individual risk assessment. According to World Health Organization classification-based prognostic scoring system, cytogenetics is of immense importance (Table 3).60

Table 3. Chromosome aberrations and prognosis in MDS

Good prognosis	Intermediate prognosis	Poor prognosis
Normal	+8	−5
Isolated 5q-		−7
Isolated 20q-		7q-
		Inv(3)(q21q26)
		t(6;9)p23;q34)
		Complex

Good prognosis

According to Knapp et al.,61 cytogenetic findings with a normal karyotype is favourable and complex abnormalities are linked to a poor prognosis, in contrast to the AML patients where a normal karyotype is associated with intermediate prognosis. Isolated del(20q) as the sole abnormality had improved outcome.10,62 A recent study reported most MDS patients had complex abnormalities with del(20q) as part of abnormal karyotype, and associated with poor prognosis.63 Altogether del(20q) as sole abnormality is associated with favourable outcome, but less favourable when present with a part of complex chromosomal abnormalities. This phenomenon is similar with the del(5q). According to a few studies, loss of Y- chromosome is also of good prognosis, but this abnormality has been noted in bone marrow samples from haematologically normal elderly men.64

The Spanish group identified new cytogenetic abnormalities with a good prognosis (12p- and 11q-)47 according to German–Austrian study; the following abnormalities linked with good prognosis are t(1q), 5q-, t(7q), 9p-, 12q-, t(15q), t(17q), 20q-, +21, −21, −X, and −Y. Prognosis was favourable only when there are not more than one additional abnormality present.53

Intermediate prognosis

Patients with trisomy 8 represent an intermediate clinical course. Data presented by the Spanish group on more than 900 patients give new abnormalities which are associated with an intermediate clinical course, such as 3q abnormalities, trisomy 9, 11q translocations, and 17p deletions.47 Recently, a German–Austrian study group revealed several infrequent abnormalities with an intermediate prognosis. In trisomy 8 and 11q-, a median survival time of 23–26 months was observed which is termed as intermediate 1, and with 11q23 translocations, chromosome 3q aberrations, trisomy 19, 7q deletions, and complex abnormalities with three different chromosomal alterations and monosomy 7 are associated with worse prognosis with a median survival time between 20 and 14 months, which is termed as intermediate 2.65

Poor prognosis

Complex chromosomal abnormalities in MDS are associated with a bad prognosis and median survival time significantly below 1 year.66 Median survival in MDS is significantly reduced only when more than three cytogenetic abnormalities are present.53 Most of the publications feature two to three abnormalities as ‘complex’, but in the Medical Research Council AML trials, poor prognosis was associated to cases with five or more abnormalities.67 The monosomy 5 and chromosome 7 abnormalities have been associated with poor prognosis in MDS and AML.68,69 The cytogenetic findings of Toyama et al. who observed unfavourable outcome in trisomy 8 and del(20q) were not confirmed by other group study.

Conclusions

Cytogenetic study plays an important role in diagnosis and prognosis of MDS patients. Although common chromosome aberrations −5/5q- and −7/7q- are reported worldwide, MDS shows considerable heterogeneity in karyotypic pattern. The complex chromosome abnormalities are seen in significant number of MDS and associated with a poor prognosis. FISH investigation has a major impact on identification of common chromosome aberrations; however, conventional cytogenetics has its own position in identification of complex karyotypic abnormalities. The advancement in cytogenetic technology using multicolour FISH or spectral karyotyping essentially helps in identification of unidentified cytogenetic abnormalities or complex translocations. The identification of complex gene rearrangements may help in the development of new therapeutic options for the management of the disease.