INTRODUCTION — The myelodysplastic syndromes (MDS) encompass a series of hematologic conditions characterized by chronic cytopenias (anemia, neutropenia, thrombocytopenia) accompanied by abnormal cellular maturation. As a result, patients with MDS are at risk for symptomatic anemia, infection, and bleeding, as well as progression to acute myeloid leukemia (AML), which is often refractory to standard treatment.
The pathobiology of MDS is complex and not fully understood; however, alterations in the function of the bone marrow microenvironment, or niche, as well as the hematopoietic stem cells have been implicated. The development of MDS involves a series of genetic changes in a hematopoietic stem cell. These changes alter normal hematopoietic growth and differentiation, resulting in an accumulation of abnormal, immature myeloid cells in the bone marrow and the impairment of normal hematopoiesis. Advances in the identification of recurring chromosomal abnormalities and gene alterations have provided insight into the pathobiology of MDS.
Specific cytogenetic abnormalities identified by karyotype analysis or fluorescence in situ hybridization (FISH) analysis have prognostic significance for patients with primary MDS and affect treatment planning. Certain gene mutations also confer prognostic significance in adult patients with MDS some of them influence treatment planning. Even those patients without obvious abnormalities detected by karyotypic analysis, FISH, or gene mutation analyses likely have abnormalities in gene expression profiles or have acquired copy number alterations that may help to identify genes important for the pathogenesis of MDS.
Characteristic chromosomal abnormalities have also been identified in patients who developed MDS or AML (often preceded by MDS) after chemotherapy and/or radiation therapy for an earlier disorder, such as Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), or a solid tumor, as well as non-malignant disorders, such as rheumatoid arthritis, or following organ transplantation (table 1). This subject is discussed separately. (See "Cytogenetic abnormalities in acute myeloid leukemia", section on 'Therapy-related myeloid neoplasms'.)
The cytogenetic and molecular genetic features of primary MDS and the use of genetic studies in predicting both progression to AML and survival will be reviewed here. An overview of cytogenetic abnormalities in hematologic malignancies (including definitions, methods of detection, the genetic consequences of chromosomal translocations) and a more detailed discussion of the prognosis of MDS are presented separately. (See "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults" and "General aspects of cytogenetic analysis in hematologic malignancies" and "Chromosomal translocations, deletions, and inversions".)
CHROMOSOMAL ABNORMALITIES — Patients with MDS may have single or multiple chromosomal changes at the time of diagnosis, or abnormal clones may appear during the course of the disease. Simple chromosome changes may involve a numerical change (ie, monosomy or trisomy), a structural abnormality involving only one chromosome (eg, inversion and interstitial deletion), or, less commonly, a balanced translocation involving two chromosomes. Ten to 15 percent of patients exhibit complex karyotypes with multiple abnormalities [1-4]. Additional chromosomal aberrations may evolve during the course of MDS, or an abnormal clone may emerge in a patient with a previously normal karyotype; these changes appear to portend progression to acute leukemia [5]. Notably, all of these common chromosome abnormalities observed in MDS are also frequently detected in other myeloid diseases (ie, acute myeloid leukemia and myeloproliferative neoplasms).
Recurring abnormalities — Clonal chromosomal abnormalities can be detected in bone marrow cells in approximately 50 percent of patients with primary MDS (table 1) [1,6-10]. This fraction is somewhat lower than the 70 to 80 percent detected in patients with acute myeloid leukemia (AML) de novo. The likelihood of chromosomal abnormalities is increased in patients with advanced MDS.
Although rates vary depending upon the technique used and the population studied, the most common chromosomal abnormalities seen in MDS are del(5q), -7 or del(7q), trisomy 8, del(20q), and loss of the Y chromosome (table 1 and table 2) [1]. As an example, the Revised International Prognostic Scoring System proposed a comprehensive cytogenetic scoring system based on an international data collection of 2902 patients. An abnormal karyotype was seen in 45 percent. The most common abnormalities were a complex karyotype, del(5q), -7/del(7q), +8, and del(20q) [1]. Loss of the Y chromosome is common in men, particularly older men, without hematologic disorders and is not thought to play a role in the pathogenesis of MDS [1].
There are two features that distinguish the cytogenetic changes in primary MDS from those in de novo AML:
●Although +8, del(5q), -7/del(7q), and del(20q) are common in both disorders, the specific structural rearrangements (balanced translocations) that are closely associated with distinct subsets of de novo AML are not commonly seen in MDS [1,4]. Exceptions include the t(3;21), inv(3)/t(3;3), and t(11;16), which are observed in primary MDS and in AML with myelodysplastic features, as well as in therapy-related myeloid neoplasms (t-MN) and in rare cases of chronic myeloid leukemia (CML) during accelerated and blast phases. (See "Cytogenetic abnormalities in acute myeloid leukemia".)
●Deletions of chromosomes 5 and -7/del(7q) are particularly characteristic (up to 70 percent) of therapy-related MDS/AML induced by alkylating agents and/or radiation therapy. How these deletions might promote myeloid leukemogenesis is described elsewhere. (See "Cytogenetic abnormalities in acute myeloid leukemia".)
●With occasional exceptions (such as the 5q- syndrome/MDS with isolated del(5q)), chromosomal abnormalities in MDS have not correlated with specific clinical or morphological subsets using the WHO classification system (table 2). (See '5q- syndrome/MDS with an isolated del(5q)' below.)
Deletions of chromosome 5 — Deletion of the long arm of chromosome 5 (5q) is the most common chromosomal abnormality seen in MDS, occurring in approximately 15 percent of cases overall [1,11-13]. The identification of an isolated del(5q), or del(5q) plus one other abnormality with the exception of -7/del(7q), is used in the World Health Organization (WHO) classification system of MDS to define the 5q- syndrome (table 2) [4]. (See "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)", section on 'MDS with isolated del(5q)'.)
Although the deletions are large and interstitial (two breaks occur in the long arm, with loss of the intervening segment), cytogenetic and molecular analysis has led to the identification of two small commonly deleted regions [12,13]:
●5q32-33.1 – Deletion of this locus is most commonly associated with the 5q- syndrome and a good prognosis, and all patients with the 5q- syndrome have this region deleted. (See '5q- syndrome/MDS with an isolated del(5q)' below.)
●5q31.2 – Deletion of this locus is more commonly seen with high risk MDS or therapy-related MDS and is associated with a complex karyotype, TP53 loss or mutation, and more aggressive disease.
In each case, these deletions occur on a single chromosome resulting in a heterozygous (haploinsufficient) state with retention of one normal allele of all of the genes contained within the deleted segment. As yet, mutations in the non-deleted alleles have not been detected by gene sequencing nor have cases of acquired uniparental disomy (also known as copy-neutral loss of heterozygosity) of 5q been identified [11]. Uniparental disomy ordinarily is a genetic phenomenon that occurs during early embryogenesis where a mitotic recombination event results in homozygosity of both copies of a chromosome or chromosome segment. In contrast, acquired uniparental disomy occurs as a result of a mitotic recombination event in a hematopoietic stem or progenitor cell resulting in homozygosity of a chromosome or chromosome segment, followed by clonal hematopoiesis. Because most patients have very large deletions, these regions are not exclusive and most cases will have a deletion that spans both regions. In addition, del(5q) is commonly accompanied by other chromosomal abnormalities.
The long arm of chromosome 5 contains numerous genes that have been implicated in the pathogenesis of MDS and/or sensitization to specific therapies [13]. Gene expression profiling, knock-down experiments using RNA interference, and forced expression studies have implicated the RPS14 protein, required for the maturation of 40S ribosomal subunits, in the genesis of the 5q- syndrome, particularly in abnormalities of erythropoiesis [12,13]. Of interest, the ribosomal processing defect caused by haploinsufficiency of RPS14 in the 5q- syndrome is highly analogous to the functional ribosomal defect seen in Diamond-Blackfan anemia. (See "Overview of causes of anemia in children due to decreased red blood cell production", section on 'Diamond-Blackfan anemia'.)
Studies have shown that haploinsufficiency of two micro-RNAs (miRNAs) that are abundant in hematopoietic stem/progenitor cells (HSPCs), miR-145 and miR-146a, are encoded by sequences near the RPS14 gene, and cooperate with loss of RPS14. The Toll-interleukin-1 receptor domain-containing adaptor protein (TIRAP) and tumor necrosis factor receptor-associated factor-6 (TRAF6) are respective targets of these miRNAs, implicating inappropriate activation of innate immune signals in the pathogenesis of the 5q- syndrome [12]. Studies in a mouse model suggest that a Tp53-dependent mechanism underlies this syndrome [12], perhaps due to activation of the innate immune system and induction of S100A8-S100A9 expression, leading to a Tp53-dependent erythroid differentiation defect [14,15]. In one report, the low expression of RPS14 in 23 patients with the 5q- syndrome was not due to promoter hypermethylation, suggesting that the use of hypomethylating agents (eg, azacitidine, decitabine) is unlikely to benefit this MDS subset [12].
Animal studies and retrospective analyses have implicated loss of the CSNK1A1 gene within the deleted 5q region in the development of the 5q- syndrome. CSNK1A1 encodes casein kinase 1A, a component of the APC destruction complex that regulates WNT signaling via degradation of beta-catenin (CTNNB1). In a mouse knockout and transplantation study, heterozygous deletion of CSNK1A1 led to a proliferative advantage for hematopoietic stem cell and progenitor cells, and CTNNB1 activation [16]. CSNK1A1 was also shown to be crucial for clonal expansion in MDS with del(5q), based on comparing various genes on 5q by genetic barcoding experiments [17]. TP53 activation was also observed in mice with homozygous deletions of CSNK1A1. In a retrospective study, mutations in CSNK1A1 were detected in seven of 39 patients with MDS and del(5q) [18]. These missense mutations are associated with disease progression and poor response to treatment with lenalidomide. In rare patients, mutations in CSNK1A1 coexist with TP53 mutations, implicating cooperation of these genes in the pathogenesis of MDS with a del(5q). Of interest, lenalidomide induces the ubiquitination of CSNK1A1 by the E3 ubiquitin ligase CRL4 (CRBN), resulting in CSNK1A1 degradation and subsequent upregulation of the WNT pathway; haploinsufficient loss of CSNK1A1 sensitizes cells to lenalidomide therapy, providing a mechanistic basis for the therapeutic window of lenalidomide in del(5q) MDS [19].
Other genes located on 5q that are deleted in MDS, AML, or therapy-related MDS/AML with a del(5q) include EGR1 and APC. Loss of function of Apc (the mouse homolog of the adenomatosis polyposis coli gene [APC] tumor suppressor gene) results in MDS with dyserythropoiesis in animal models [13,20,21]. Loss of function of EGR1 cooperates with mutations induced by alkylating agents to induce myeloid neoplasms in mouse models. These results support the model that haploinsufficiency of multiple genes on 5q cooperates in the pathogenesis of myeloid disorders with a del(5q). This cooperativity is illustrated by a report that haploinsufficiency for both Egr1 and Apc on 5q together with knockdown of Tp53 in bone marrow cells induced AML in a low percentage of mice; treatment with a single dose of the alkylating agent, N-ethyl-N-nitrosourea, resulted in MDS/AML with dysplasia in 80 percent of mice [20,21].
Cases of MDS where del(5q) is the sole chromosomal abnormality have a relatively good prognosis and good chance of responding to treatment with lenalidomide (table 3). In comparison, monosomy 5 (now known to result from structural rearrangements of chromosome 5, rather than actual chromosome loss) or del(5q) with other chromosomal changes is associated with advanced MDS and a worse outcome [10,12]. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Chromosome 5q deletion'.)
Monosomy 7 and deletions of chromosome 7 — Approximately 10 percent of patients with de novo MDS and up to half of patients with therapy-related MDS demonstrate -7/del(7q), either alone or as part of a complex karyotype [1]. Approximately 90 percent of cases have loss of a whole chromosome 7 (-7), and 10 percent are del(7q) (ie, deletion of the long arm of the chromosome).
Several genes located in the minimally deleted regions (MDRs) of 7q have been identified that are implicated in adult and pediatric myeloid neoplasia. Chromosome arm 7q contains three MDRs containing genes involved in myelodysplasia and myeloid leukemogenesis:
●7q22, includes cut-like homeobox 1 (CUX1), a haploinsufficient tumor suppressor gene that is mutated recurrently in hematopoietic malignancies and solid tumors [22]. The genetic evidence for CUX1 acting as a tumor suppressor gene is strong, as heterozygous CUX1 inactivating mutations are independently associated with a poor prognosis [23]. Heterozygous deletion of a 2 Mb syntenic interval near Cux1 led to features of MDS in mice [24].
●7q31.31: Using combined cytogenetic, next generation sequencing, and array analysis, investigators defined a minimally deleted region of 18 Mb at 7q31.31 in a cohort of 81 patients with MDS, AML, and other myeloid neoplasia with del(7q) as sole abnormality [25].
●7q34 contains LUC7 like 2, pre-mRNA splicing factor (LUC7L2), which encodes a spliceosomal protein that is mutated in myeloid malignancies [26].
●7q35-q36 contains cullin 1 (CUL1) and EZH2; both genes have been reported to be somatically mutated in myeloid neoplasms [26]. EZH2 encodes the catalytic subunit of the polycomb repressive complex 2 (PRC2), a highly conserved histone H3 lysine 27 (H3K27) methyltransferase that influences stem cell renewal by epigenetic repression of genes involved in cell fate decisions. EZH2 was previously reported to be an oncogene in epithelial tumors, such as breast cancer; however, the mutations identified in MDS/MPN result in loss of function of the histone methyltransferase activity, suggesting that EZH2 acts as a tumor suppressor for myeloid malignancies. This distal MDR segment also contains the haploinsufficient tumor suppressor gene, KMT2C (also known as MLL3) [27].
Frequent mutation of the SAMD9 and SAMD9L genes at 7q21.3 were identified in both adult and pediatric patients with MDS and monosomy 7 or del(7q). SAMD9 mutations are associated with loss of chromosome 7, and cause a novel multisystem disorder, MIRAGE syndrome, characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy [28]. Samd9l-deficient mice model showed that both heterozygous Samd9l+/- mice and Samd9l null mice develop myeloid diseases resembling human diseases associated with -7/del(7q), with enhanced colony formation potential and in vivo reconstitution ability, suggesting that haploinsufficiency of the SAMD9L and or SAMD9 gene(s) contributes to myeloid transformation [29].
Trisomy 8 — Trisomy 8 is seen in <10 percent of patients with MDS and is considered an intermediate risk finding in the International Prognostic Scoring System [7]. Gain of chromosome 8 has been associated with higher expression of anti-apoptotic genes compared with normal cells and may result in a selective advantage over normal hematopoietic precursors. Overexpression of the MYC oncogene at 8q24.2 has also been implicated in the pathogenesis of myeloid disorders with trisomy 8.
Deletions of chromosome 20 — Deletions of the long arm of chromosome 20, del(20q), occur in <5 percent of cases of MDS and are also seen in patients with acute myeloid leukemia and myeloproliferative disorders [1]. A study of 153 patients with MDS with del(20q), including 93 patients with del(20q) as sole abnormality, identified an association of del(20q) in MDS with ASXL1 deletion/mutations and a poor prognosis, including short overall survival and high risk of progression to AML [30].
Use in diagnosis and classification
Diagnosis — The diagnosis of MDS is made based upon an evaluation of the bone marrow and peripheral smear in the appropriate clinical context. Detection of certain chromosomal abnormalities, either by routine cytogenetic analysis or FISH, aids in the classification of MDS and determination of prognostic risk group. (See "Overview of the treatment of myelodysplastic syndromes" and "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults".)
In addition, the presence of one of the following chromosomal abnormalities is presumptive evidence of MDS in patients with otherwise unexplained refractory cytopenia and no morphologic evidence of dysplasia [3] (see "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)", section on 'Cytogenetic and molecular features'):
●-7/del(7q)
●del(5q)/t(5q)
●del(13q)
●del(11q)
●del(12p) or t(12p)
●del(9q)
●idic(X)(q13)
●del(17p)/t(17p) (unbalanced translocations) or i(17q) (ie, loss of 17p)
●t(11;16)(q23.3;p13.3)
●t(3;21)(q26.2;q22.1)
●t(1;3)(p36.3;q21.3)
●t(2;11)(p21;q23.3)
●inv(3)(q21.3q26.2)
●t(6;9)(p23.3;q34.1)
Similarly, the following cytogenetic abnormalities, if found, result in the diagnosis of acute myeloid leukemia, regardless of blast count [4] (see "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Bone marrow infiltration'):
●t(8;21)(q22;q22.1); RUNX1::RUNX1T1 (previously AML1::ETO)
●inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB::MYH11
●t(15;17)(q24.1;q21.2); PML::RARA
5q- syndrome/MDS with an isolated del(5q) — The 5q- syndrome is defined in the World Health Organization (WHO) classification system of MDS (table 2) by identification of an isolated del(5q), or del(5q) plus one other abnormality (with the exception of -7/del(7q)) [4].
The 5q- syndrome is a distinctive type of primary MDS that primarily occurs in older women. The median age at diagnosis is 65 to 70 years, with a female predominance of 7:3 (in contrast to a male predominance in other forms of MDS). Affected patients typically present with a refractory macrocytic anemia and normal or elevated platelet counts and the absence of significant neutropenia [4,12]. Because of the typical absence of thrombocytopenia and significant neutropenia, there is a low incidence of bleeding and infection in these patients. Red blood cell transfusions are frequently required. (See 'Deletions of chromosome 5' above.)
The 5q- syndrome may follow a relatively benign course that extends over several years. The likelihood of progression to AML is very low and 5q- syndrome often responds rapidly to oral lenalidomide [12]. With this treatment, the majority of patients with 5q- syndrome achieve red blood cell transfusion independence and complete cytogenetic remissions. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Chromosome 5q deletion'.)
Cytogenetics as a predictor of prognosis — Particular cytogenetic abnormalities are useful for predicting survival in MDS and progression to acute myeloid leukemia (AML) (table 3) [7]. Information regarding the presence or absence of chromosomal abnormalities is incorporated into the most commonly used prognostic scoring systems for MDS (eg, the original and revised International Prognostic Scoring Systems (table 4) (calculator 1 and calculator 2), the WHO Prognostic Scoring System, and the MD Anderson Cancer Center MDS model (calculator 3)). Prognostic scoring systems for MDS are discussed in more detail separately. (See "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults".)
The ability of cytogenetic analysis to predict the outcome of any individual patient with MDS is difficult because many patients die from persistent and profound pancytopenia, regardless of progression to AML. The ability of these prognostic scoring systems to predict risk of mortality and transformation to AML is time-dependent, with attenuated predictive power for high-risk patients [31].
GENE MUTATIONS — Gene mutations are detected in patients with MDS and acute myeloid leukemia (AML), with or without associated chromosomal abnormalities. Mutations are found in genes that encode proteins which affect epigenetic regulation (eg, DNA methylation, histone modification), RNA-splicing machinery, transcription factors, and cytokine signaling pathways. Many of these mutations are driver mutations in MDS, and have independent prognostic significance (TP53, EZH2, ETV6, RUNX1, and ASXL1) and are associated with progression to AML [10,32]. Thus, many of these gene mutations are even more frequent in AML, particularly in AML with a normal karyotype, and they provide insight into the pathobiology of MDS and its progression to AML [10,32]. (See "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults", section on 'Prognostic factors' and "Prognosis of acute myeloid leukemia", section on 'Gene mutations'.)
In a targeted sequencing study of 111 oncogenic genes, gene mutations were detected in 43 genes in 549 (74 percent) of 738 patients, including 80 percent of patients with MDS and 20 percent of those with CMML or MDS/MPN [33]. The most frequently mutated genes, SF3B1, TET2, SRSF2, and ASXL1, were each mutated in >10 percent of patients, followed by DNMT3A and RUNX1 in 5 to 10 percent each. Similarly, in a study of 944 patients with MDS that used targeted deep-sequencing to identify gene mutations from a total of 104 genes, at least one mutation was identified in 90 percent of patients with a median of three mutated genes per sample [34]. The following genes were mutated in >10 percent of cases: TET2, SF3B1, ASXL1, SRSF2, DNMT3A, and RUNX1. Mutations were most commonly seen in genes involved in mRNA splicing, DNA methylation, chromatin modification, and transcription. The number and pattern of genes mutated differs among the MDS subtypes, with the majority of common mutations identified more frequently in high risk MDS subtypes than in low risk MDS subtypes. Notably, the hierarchies of these multiple gene mutations in MDS change dramatically during treatment with lenalidomide and become more complex with rapid overgrowth of the founder clone, subclones, or even fully independent clones, which is often accompanied by disease progression and treatment failure [35].
Recurring gene mutations that are associated with isolated -7 or del(7q) may have prognostic significance in MDS. In a cohort of 81 patients with MDS, AML, or other myeloid neoplasms with del(7q) as the sole abnormality, mutations of ASXL1, TET2, DNMT3A, RUNX1, and/or SRSF2 were present in 90 percent of 80 patients; the association of RUNX1 and ASXL1 mutations with AML with del(7q) was especially notable [25]. Somatic mutations, most commonly ASXL1, U2AF1, DNMT3A, RUNX1, EZH1, and TET2, were detected in 79 percent of 117 MDS patients with monosomy 7 or del(7q) as the sole abnormality [36]. In multivariate analysis, blast count, TP53 mutations, and the number of mutations were independent predictors of overall survival; the cytogenetic subgroups did not retain prognostic relevance.
●TET2 – DNA methylation is a prognostic marker and predictor of response to therapy among patients with MDS and appears to be a mechanism of disease progression to acute myeloid leukemia (AML) [10,32-35]. TET (ten-eleven translocation) genes encode proteins involved in the epigenetic control of DNA expression through demethylation. Somatic mutations in TET2 occur in approximately 15 percent of myeloid cancers, and up to 30 percent of MDS [34]. Loss of function mutations of TET2 results in increased methylation and silencing of genes that are normally expressed. When present in MDS, TET2 mutations have been associated with a more favorable prognosis.
●DNMT3A – The DNMT3A gene, located at 2p23, is one of three genes that encode DNA methyltransferase enzymes catalyzing the addition of a methyl group to the cytosine residue of CpG dinucleotides, which are prevalent in gene promoters, thereby regulating gene expression. Mutations of DNMT3A have been detected in 8 to 13 percent of primary MDS patients [10,32-35], and in 22 percent of de novo AML, particularly in AML with a normal karyotype. Mutations of DNMT3A are associated with worse overall survival in MDS, and more rapid progression to AML.
●IDH – Mutations in the isocitrate dehydrogenase oncogenes (ie, IDH1 and IDH2) have been reported in some cases of MDS, result in DNA hypermethylation and alteration of gene expression, and are thought to portend a poor prognosis [10,32-35].
●ASXL1 – The additional sex-comb like-1’ (ASXL1) gene encodes a protein involved in the epigenetic regulation of gene expression and is mutated in approximately 10 to 20 percent of MDS cases [10,32-35]. ASXL1 mutations are associated with a decreased overall survival and shorter time to progression to AML.
●SF3B1 – The SF3B1 gene encodes for part of a nuclear ribonucleoprotein that complexes with other nuclear ribonucleoproteins to create the spliceosome that is responsible for splicing messenger RNA. Recurrent somatic point mutations in this gene were identified in 72 of 352 patients (20 percent) with MDS in one study, and represent the most commonly mutated gene in MDS [10,32-35,37]. Within this group, mutations of SF3B1 were common among patients with MDS with prominent ring sideroblasts (65 percent), but less common in patients with refractory anemia (10 percent), refractory cytopenia and multilineage dysplasia (6 percent), and refractory anemia with excess blasts (5 percent). Subsequent studies have confirmed the presence of SF3B1 gene mutations in a subgroup of patients with MDS and also identified mutations in other genes affecting mRNA splicing (eg, U2AF1, U2AF35, ZRSR2, and SRSF2) in patients with MDS [34,37-43].
Notably, SF3B1 mutations provides presumptive evidence of MDS in patients with persistent unexplained cytopenia [37]. Based on the unique pathologic phenotype and favorable outcomes, MDS with SF3B1 mutations may come to be recognized as a distinct, low-risk subtype of MDS.
●SRSF2 – The SRSF2 gene at 17q25 encodes a serine/arginine-rich splicing factor 2 that is critical for assembly of the spliceosome, selection of the correct splice-sites, and constitutive and alternative RNA splicing during the processing of precursor mRNA to mature mRNA. Mutations of SRSF2 are detected in 12 to 15 percent of MDS patients [43], with a higher frequency in elderly males, and are associated with a poor prognosis.
●RUNX1 – Mutations of the transcriptional core-binding factor gene RUNX1 are seen in 7 to 15 percent of cases of de novo MDS, are more common in cases of therapy-related MDS, and portend a poorer prognosis [34]. In addition, RUNX1 is a translocation partner for RUNX1T1 (ETO) in cases of AML with the t(8;21). (See "Cytogenetic abnormalities in acute myeloid leukemia", section on 't(8;21); RUNX1-RUNX1T1'.)
●TP53 – The TP53 tumor suppressor gene is located on 17p; the TP53 protein mediates cell cycle arrest in response to a variety of cellular stressors. In MDS, about 5 to 15 percent of cases have known TP53 mutations at the time of diagnosis, frequently in association with a del(5q) [10,34,44]. Abnormalities in TP53 are more common in patients with MDS associated with prior exposure to alkylating agents or radiation (ie, therapy-related MDS). Loss of wild-type TP53 is associated with resistance to treatment and is a marker of poor prognosis independent of the IPSS risk score [1,10].
TP53 mutations are associated with adverse outcomes in patients with MDS with complex karyotype (CK). In one study, TP53 mutations were identified in 55 percent of 359 patients with MDS-CK [45]. TP53 mutations were enriched in MDS with del(5q), monosomal karyotype, MDS with ≥5 cytogenetic abnormalities, all of which are associated with shorter overall survival. Integrative genomic analyses have also revealed that TP53 mutation allelic status and variant allele frequency (VAF) may provide further precision in predicting clinical outcomes [46]. Analysis of 261 patients with MDS and TP53 mutations reported that TP53 deletion was associated with lower rates of response to treatment. Median TP53 VAF was 0.39 (range, 0.01 to 0.94); higher VAF was associated with adverse prognosis and lower VAF was inversely correlated with response to hypomethylating agents. TP53 mutations in myeloid neoplasms, including de novo and therapy-related MDS and AML, are associated with adverse prognosis, particularly in cases with complex karyotypes, multi-hit or biallelic TP53 mutations, and high VAF status [47,48].
●RAS – The RAS (HRAS, KRAS, NRAS) proto-oncogenes play an important role in signal transduction. Mutations of RAS have been identified in 10 to 35 percent of cases of MDS and in a subset of patients with AML [8,10,32,34]. The majority of the mutations in MDS are in the NRAS gene; KRAS mutations occur less frequently. In both AML and MDS, RAS mutations have been reported more frequently in cases with a monocytic morphology (eg, chronic myelomonocytic leukemia). The significance of RAS mutations in MDS remains unclear; however RAS mutations are associated with MDS characterized by -7/del(7q).
●FLT3 – While mutations of FLT3 are uncommon in MDS, they have been associated with a worse prognosis [32]. (See "Prognosis of acute myeloid leukemia", section on 'FLT3 gene'.)
●U2AF1 – U2AF1, encoding one of the RNA splicing core components, is mutated in about 5 to 10 percent of patients with MDS, which is associated with worse survival outcome and increased risk of progression to AML [38-41,49].
●ZRSR2 – ZRSR2, an RNA spliceosome gene, encodes an SR-rich protein that is critical for the recognition of the 3' splice acceptor site involved in pre-mRNA splicing. ZRSR2 is mutated in about 5 percent of patients with MDS. Because ZRSR2 is located at Xp22.2, its mutations are manifest mainly in male patients and result in loss of function. ZRSR2 mutations may be associated with an unfavorable prognosis in MDS [38-40,49].
●EZH2 – EZH2 encodes a histone methyltransferase involved in the polycomb repressor complex. Mutations in EZH2 have been reported in 5 to 10 percent of MDS particularly with deletion or loss of chromosome 7, and they are associated with poor prognosis [10].
●BCOR – BCOR is a transcription factor that is a component of the polycomb repressor complex. Mutations in BCOR/BCORL1 occur in about 5 percent of MDS and may be associated with an unfavorable outcome [10].
●STAG2 – STAG2 is one of the cohesin complex proteins that regulate the separation of sister chromatids during cell division. Mutations of STAG2 are the most frequent among the cohesin complex genes in myeloid neoplasms, occurring in 5 to 7 percent of MDS, and is associated with a poor prognosis [10].
CLONAL HEMATOPOIESIS — Clonal hematopoiesis of indeterminate potential (CHIP) refers to clonal hematopoiesis with associated somatic mutations. The incidence of CHIP increases with age, and CHIP is associated with an increased risk for development of hematological cancers. Mutations of certain genes (eg, DNMT3A, ASXL1, TET2, TP53) are found in both CHIP and MDS/AML [9]. In addition to gene mutations, CHIP may result from large alterations of chromosomes involved in recurring abnormalities in MDS/AML, eg, del(5q), del(7q), representing an independent risk factor for leukemia development [50]. (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis", section on 'Clonal hematopoiesis of indeterminate potential (CHIP)'.)
Clonal selection (the selection for pre-existing mutant clones at the expense of normal, healthy hematopoietic stem cells [HSC]) may contribute to the pathogenesis of some forms of MDS or AML. HSC selection may be driven by oligoclonality associated with normal aging coupled with various chemical and/or environmental exposures [51]. Clonal competition may arise during regenerative hematopoiesis driven by aging, inflammation, immune destruction, viral infections, defects in the bone marrow niche, and/or dysfunctional hematopoiesis. As an example, aplastic anemia is associated with a high incidence of CHIP (47 to 73 percent) and MDS [52]. Indeed, various hematopoietic stressors promote the expansion of distinct long-lived clones, carrying specific mutations, of varying leukemogenic potential [53].
MDS WITH FAMILIAL PREDISPOSITION — Some cases of MDS occur in association with inherited germline mutations, and may also manifest distinct clinical findings. (See "Familial disorders of acute leukemia and myelodysplastic syndromes".)
The World Health Organization classification recognizes three groups of familial myeloid neoplasms associated with germline mutations [3,54,55]:
●No pre-existing disorder or organ dysfunction (eg, AML with CEBPA mutation, MDS with DDX41 mutation)
●Pre-existing platelet disorders (eg, mutations of RUNX1, ANKRD26, or ETV6)
●Other organ dysfunction syndromes, such as GATA2 mutation, bone marrow failure (eg, Fanconi anemia), dyskeratosis congenita, neurofibromatosis, or Down syndrome
Recognition of such syndromes is important for clinical management and long-term follow-up of affected individuals and family members. (See "Familial disorders of acute leukemia and myelodysplastic syndromes".)
GENOMIC MICROARRAY STUDIES — Single nucleotide polymorphism (SNP) microarray or array comparative genomic hybridization techniques provide much higher resolution than conventional cytogenetic analysis in detecting genomic and chromosomal abnormalities leading to copy number alterations in hematological neoplasms.
SNP arrays can detect genomic imbalances such as loss or gain of gene copy numbers, and copy-neutral loss of heterozygosity (copy-neutral LOH), so-called acquired uniparental disomy (UPD), due to incomplete chromosome segregation or to mitotic recombination. Various cryptic copy number changes and copy-neutral LOH have been found in up to 80 percent of MDS patients, and in about 30 percent of MDS patients with a normal karyotype.
A cryptic defect at 4q24, leading to alterations of the TET2 gene, was initially identified in a series of patients with MDS and other myeloid diseases using SNP microarrays and DNA sequencing. TET2 mutations are now detected by DNA sequencing.
SUMMARY
●Chromosomal abnormalities – Clonal chromosomal abnormalities are found in approximately half of patients with primary myelodysplastic syndromes (MDS). Although rates vary depending upon the technique used and the population studied, the most common chromosomal abnormalities in MDS are del(5q), -7 or del(7q), trisomy 8, del(20q), and loss of the Y chromosome (table 1 and table 2). (See 'Recurring abnormalities' above.)
●Diagnosis – The diagnosis of MDS is usually made by evaluating the bone marrow and a blood smear in the appropriate clinical context. Certain cytogenetic abnormalities are sufficient for the diagnosis of MDS in patients with otherwise unexplained refractory cytopenia and no morphologic evidence of dysplasia. Similarly, there are cytogenetic abnormalities that result in the diagnosis of acute myeloid leukemia rather than MDS, regardless of blast count. (See 'Diagnosis' above.)
●5q- – The 5q- syndrome is a distinctive category of MDS that is defined in the World Health Organization (WHO) classification (table 2) by isolated del(5q) or del(5q) plus one other abnormality (with the exception of -7/del(7q)). The 5q- syndrome has a relatively good prognosis and good probability of responding to treatment with lenalidomide. In comparison, del(5q) or structural rearrangements of 5q with >1 additional chromosomal change is associated with advanced MDS and a worse prognosis. (See '5q- syndrome/MDS with an isolated del(5q)' above.)
●Prognosis – Particular cytogenetic abnormalities have prognostic significance for survival and progression to AML (table 3). Specific chromosomal abnormalities are incorporated into prognostic scoring systems for MDS (eg, the original International Prognostic Scoring Systems [IPSS] (table 3) and revised IPSS [IPSS-R] (table 4), the WHO Prognostic Scoring System, the MD Anderson Cancer Center MDS model (calculator 3)). (See 'Cytogenetics as a predictor of prognosis' above and "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults".)
●Gene mutations – Specific, recurrent gene mutations may confer prognostic significance and provide insight into the pathobiology of MDS, but they are not currently integrated into prognostic scoring systems. (See 'Gene mutations' above.)
●Gene expression – Even patients without obvious abnormalities detected by cytogenetic analysis, FISH, or gene mutation analyses likely have abnormalities in gene expression profiles or have acquired copy number alterations that may help to identify genes important for the pathogenesis of MDS. (See 'Genomic microarray studies' above.)
