Version May 2024
INTRODUCTION — Myelodysplastic syndromes/neoplasms (MDS) are clonal hematopoietic neoplasms that are characterized by chronic cytopenias accompanied by morphologic dysplasia, with a propensity to progress to bone marrow failure or acute myeloid leukemia (AML).
Chromosomal and genetic abnormalities are important for diagnosis, classification, prognosis, and treatment of MDS. Specific cytogenetic (chromosomal) abnormalities are detected in one-half of cases, while nearly all cases of MDS have one or more genetic aberrations (eg, mutations, copy number alterations, aberrant gene expression). Most often, the genetic abnormalities are related to epigenetic regulators, RNA-splicing machinery, transcription factors, and/or cytokine signaling pathways. While most gene aberrations in MDS are acquired abnormalities, a minority of cases are associated with germline pathologic gene variants.
Cytogenetic and genetic features of de novo (primary) MDS are reviewed in this topic.
Related topics include:
●Definitions, methods of detection, and genetic consequences of cytogenetic abnormalities in various hematologic malignancies. (See "General aspects of cytogenetic analysis in hematologic malignancies" and "Chromosomal translocations, deletions, and inversions".)
●Further discussion of prognosis for MDS. (See "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults".)
●Cytogenetic abnormalities in AML. (See "Acute myeloid leukemia: Cytogenetic abnormalities".)
PATHOBIOLOGY — Myelodysplastic syndromes/neoplasms (MDS) are clonal neoplasms that arise from mutations in hematopoietic stem cells. Development of MDS involves a series of genetic changes in hematopoietic stem/progenitor cells, which alters their growth and differentiation and results in accumulation of abnormal, immature myeloid cells in blood and marrow that impairs normal hematopoiesis [1,2]. Driver mutations are detected in >90 percent of cases of MDS. Most mutations are acquired, but some cases are related to germline (inherited) genetic abnormalities. (See 'Acquired mutations' below and 'Pathologic germline variants' below.)
The precise cause of the mutations associated with MDS is unknown for most patients, but in some cases it is associated with exposure to cytotoxic chemotherapy and/or ionizing radiation (ie, therapy-related MDS) or environmental toxins (eg, tobacco, benzene) [3]. Overall, a high fraction of acquired mutations consist of C to T substitutions, which are consistent with spontaneous deamination of cytosine, an event that occurs with clock-like regularity in hematopoietic stem cells and which may explain, at least in part, the association of MDS with aging [4].
Many cases of MDS arise in the setting of clonal hematopoiesis of indeterminate potential (CHIP). With CHIP, similar mutations are present, but the dysplasia and ineffective hematopoiesis that characterize MDS are absent [5,6]. CHIP and related hematopoietic disorders are discussed separately. (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis".)
Inherited genetic abnormalities may also contribute to development of MDS (table 1). Although such associations were previously considered rare, routine targeted sequencing of MDS genomes has increased the identification of cases with an underlying germline predisposition. Pathologic gene variants that may cause familial MDS are discussed below. (See 'Pathologic germline variants' below.)
CLASSIFICATION OF MDS — MDSs are clonal hematopoietic neoplasms manifest as persistent cytopenias (anemia, neutropenia, and/or thrombocytopenia) accompanied by morphologic dysplasia, along with variable rates of progression to acute myeloid leukemia (AML) or bone marrow failure.
There are two contemporary classification systems for MDS; we consider use of either of the following systems acceptable for classification of individual cases:
●International Consensus Classification of Myeloid Neoplasms and Acute Leukemias (ICC) – Briefly, cases of MDS are categorized according to [7]:
•Specific genetic or karyotypic abnormalities – MDS with mutated SF3B1 or del(5q) (deletion of the long arm of chromosome 5)
or
•Dysplasia – MDS, not otherwise specified without dysplasia, with single lineage dysplasia, or with multilineage dysplasia
or
•Excess blasts – MDS with excess blasts (ie, 5 to 9 percent in bone marrow or 2 to 9 percent in peripheral blood) or MDS/AML (ie, 10 to 19 percent in blood or marrow)
●World Health Organization 5th edition (WHO5) – Briefly, cases are classified according to [8]:
•Defining genetic abnormalities – MDS with low blasts and isolated del(5q), SF3B1 mutation, or biallelic TP53 inactivation
or
•Morphologically defined – MDS with hypoplasia (≤25 percent bone marrow cellularity, adjusted for age), MDS with low blasts (<5 percent in marrow and <2 percent in blood), MDS with increased blasts (stratified according to blast percentages up to <20 percent), or MDS with fibrosis
Importantly, labels and diagnostic criteria for categories of MDS differ between ICC and WHO5. Furthermore, the two schemes classify therapy-related MDS, and cases associated with germline genetic abnormalities differently. Further descriptions of these systems are presented separately. (See "Classification of hematopoietic neoplasms", section on 'Myelodysplastic neoplasms/syndromes (MDS)'.)
We favor use of either the ICC or WHO5, rather than earlier nosologic schemes, because they emphasize the chromosomal and genetic aspects of MDS that contribute importantly to diagnosis, classification, prognosis, and treatment [7,8].
Clinical presentation, evaluation, diagnosis, and prognosis of MDS are discussed separately. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Diagnosis' and "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults".)
CHROMOSOMAL ABNORMALITIES — Approximately one-half of cases of de novo MDS (primary MDS; ie, not therapy-related or caused by germline conditions) have at least one chromosomal abnormality at the time of diagnosis. For some patients, karyotypic abnormalities first emerge during observation or treatment.
Detection — Chromosome analysis should be performed in all patients with MDS or with a clinical presentation that suggests the diagnosis. The application of chromosomal findings to the diagnosis and classification of MDS is discussed separately. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)
Karyotyping (chromosomal banding) and fluorescence in situ hybridization are used to detect chromosomal abnormalities in patients with MDS. Other techniques, such as single nucleotide polymorphism microarrays or comparative genomic hybridization techniques, can detect some additional genomic and chromosomal abnormalities with greater resolution and possibly better sensitivity, but they are not widely available. Techniques for identifying genomic and chromosomal abnormalities are described separately. (See "General aspects of cytogenetic analysis in hematologic malignancies".)
Recurring abnormalities — Many of the chromosomal abnormalities associated with MDS reflect characteristic, recurrent karyotypic events (table 2). Some of these abnormalities are uniquely associated with MDS and are important for diagnosis and classification of MDS, but many of the common chromosome abnormalities are also seen in acute myeloid leukemia (AML) or myeloproliferative neoplasms [7,8]. The diagnosis of MDS is excluded by detection of certain chromosomal abnormalities. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Diagnosis'.)
Among 2902 patients presenting with MDS, an abnormal karyotype was seen in 45 percent of cases [9]. Similarly, cytogenetic abnormalities were detected by G-banding in 41 percent of nearly 3000 cases of MDS [10]. The proportion of patients with MDS-associated chromosomal abnormalities is somewhat lower than in patients with de novo AML (ie, 70 to 80 percent), but the likelihood of karyotypic abnormalities is increased in patients with advanced MDS. Complex karyotypes are found in 10 to 15 percent of patients with primary MDS, but additional chromosomal aberrations may emerge later in the course of MDS, or an abnormal clone may emerge in a patient with a previously normal karyotype; such changes may portend progression to AML [11].
Types of chromosomal abnormalities — Most chromosomal abnormalities in MDS involve a numerical change (ie, monosomy or trisomy) or a structural abnormality of a single chromosome (eg, interstitial deletion, inversion). Complex karyotypes (ie, multiple chromosomal abnormalities) are common, particularly in cases of higher-risk MDS. A general description of chromosomal abnormalities is presented separately. (See "Chromosomal translocations, deletions, and inversions".)
Characteristic chromosomal abnormalities in MDS include:
●Numerical and unbalanced structural abnormalities – The del(5q), -7/del(7q), +8, and del(20q) are commonly found in MDS. Loss of the Y chromosome is often seen in older males, but it is not thought to play a role in the pathogenesis of MDS.
Except for del(5q), specific chromosomal abnormalities have not correlated with specific clinical or morphological subsets of MDS. (See 'del(5q)' below.)
The del(5q), -7/del(7q), +8, and del(20q) are also seen in AML (especially AML that emerged from MDS), therapy-related myeloid neoplasms (t-MN; ie, AML following treatment with alkylating agents and/or radiation therapy), and in some cases of advanced stage chronic myeloid leukemia (CML).
●Balanced translocations – Balanced translocations involving two distinct chromosomes are uncommon with MDS, with the following exceptions:
•t(3;21)(q26.2;q22.1)
•inv(3)(q21.3q26.2)/t(3;3)(q21.3;q26.2)
•t(11;16)(q23.3;p13.3)
The above findings are also seen in AML with myelodysplastic features, t-MNs, and in rare cases of CML during accelerated or blast phase.
Importantly, the following balanced translocations, which are associated with distinct subsets of AML, exclude the diagnosis of MDS [7,8]:
•t(8;21)
•inv(16)/t(16;16)
•t(15;17).
del(5q) — Deletion of the long arm of chromosome 5 (5q) is the most common chromosomal abnormality in MDS, occurring in approximately 15 percent of cases overall [9,12-14].
This lower-risk category of MDS is defined by deletion of 5q alone, or by del(5q) accompanied by only one other cytogenetic aberration, except for -7 or del(7q). This syndrome is called "MDS with del(5q)" in the International Consensus Classification of Myeloid Neoplasms and Acute Leukemias (ICC) [7] and "MDS with low blasts and isolated 5q deletion" by the WHO5 [8]. (See "Classification of hematopoietic neoplasms", section on 'Myelodysplastic neoplasms/syndromes (MDS)'.)
●Clinical features – Distinctive clinical features of MDS with del(5q) include female predominance, severe macrocytic anemia, normal or elevated platelet counts with hypolobulated micromegakaryocytes, a low rate of progression to AML, and responsiveness to the immunomodulatory drug, lenalidomide [15]. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Chromosome 5q deletion'.)
●Prognosis – Cases of MDS where del(5q) is the sole chromosomal abnormality have a relatively favorable prognosis and good chance of responding to treatment with lenalidomide (table 3) [2,13]. (See "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults".)
●Deleted regions – Although deletions of 5q are large and interstitial (ie, two chromosomal breaks, with loss of the intervening segment), cytogenetic and molecular analysis has led to the identification of two smaller commonly deleted regions (CDRs) [13,14,16]:
•5q32-33.1 – All patients with MDS with del(5q) have this region deleted. Isolated deletion of this locus is usually associated with a favorable prognosis.
•5q31.2 – Deletion of this locus is more commonly seen with higher-risk MDS or therapy-related MDS and is frequently associated with a complex karyotype, TP53 loss or mutation, and more aggressive disease.
Most patients have large deletions that span both CDRs. The del(5q) is often accompanied by other chromosomal abnormalities, but association of del(5q) with loss of chromosome 7 or del(7q) excludes the diagnosis of MDS with del(5q). In each case of del(5q), the deletions occur on a single chromosome, resulting in a hemizygous (haploinsufficient) state, with retention of one normal allele of all genes within the deleted segment. Except for rare cases, no homozygous mutations of genes on 5q have been detected by gene sequencing.
●Involved genes – Both protein-coding genes and microRNAs (miRNAs) that lie within 5q have been implicated in the macrocytic anemia, neutropenia, and defective immunity associated with the MDS with del(5q) [2,14,17]. Haploinsufficiency of genes on 5q appears to provide a growth advantage to affected cells, compared with wild-type cells. Among other genes, RPS14, CSNK1A1, and miRNA-145 have been implicated in the pathogenesis of this disorder, although some of them may contribute only indirectly to the phenotype (eg, by activation of WNT/Beta catenin signaling or by cooperating with a TP53 mutation).
•Protein-encoding genes – The following genes are thought to contribute to the pathophysiology of MDS with del(5q):
-RPS14 – The RPS14 protein, which is required for maturation of 40S ribosomal subunits, has been implicated in abnormalities of erythropoiesis and altered immunity in MDS with del(5q) [13,14]. Knock-down of RPS14 blocked erythroid differentiation, whereas forced overexpression of RPS14 in cells from MDS patients with del(5q) rescued erythropoiesis. Haploinsufficiency of RPS14 induces expression of other ribonucleoproteins, which can decrease MDM2 (a negative regulator of p53) and thereby activate p53 and enhance apoptosis. Loss of RPS14 may also act by increasing expression of S100 calcium-binding proteins (S100A8 and S100A9), which are involved in innate immune signaling [18].
Interestingly, the ribosomal processing defect caused by haploinsufficiency of RPS14 in MDS with del(5q) 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'.)
-CSNK1A1 – CSNK1A1 encodes casein kinase 1A, a serine-threonine kinase. CSNK1A1 is a component of the APC destruction complex, which regulates WNT signaling via degradation of beta catenin (CTNNB1). Mutations in CSNK1A1 were detected in 7 of 39 patients with MDS and del(5q) [19]. Haploinsufficiency of CSNK1A1 enhances proliferation of del(5q) cells by decreasing inhibition of beta catenin more than it decreases inhibition of apoptosis (through de-repressed pP53) [20]. Haploinsufficiency of Csnk1a1 in animal models led to clonal expansion and a proliferative advantage in a beta catenin-dependent manner [21,22].
This functional mechanism has been associated with how lenalidomide is effective against del(5q) cells. The direct protein target of lenalidomide is cereblon (CRBN), a component of the Cul4-based E3 ubiquitin ligase. Lenalidomide modulates CRBN function, leading to ubiquitination/degradation of specific protein substrates and it may also decrease levels of CK1A, Ikaros (IKZF1) and Aiolos (IKZF3) via ubiquitination [23]. TP53 mutations have been linked to lenalidomide resistance and progression to AML in del(5q) MDS patients [24]. Hemizygous mutations in CSNK1A1 have been reported [25,26].
-Other genes – Other hematopoiesis-related genes and tumor suppressor genes that are located in the CDR regions include CTNNA1, PPP2CA, EGR1, TIFAB, SPARC, and CDC25C, but their specific contributions to the del(5q) phenotype in MDS are not well-defined [27].
•MicroRNAs – Haploinsufficiency of miR-145 and miR-146a, which are micro-RNAs (miRNAs) located near the RPS14 gene and are abundant in hematopoietic stem/progenitor cells (HSPCs), may 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 MDS with del(5q) [13].
Studies in a mouse model suggest that a p53-dependent mechanism underlies MDS with del(5q), perhaps due to activation of the innate immune system and induction of S100A8-S100A9 expression, leading to a p53-dependent erythroid differentiation defect [28,29]. In one report, the low expression of RPS14 in 23 patients with MDS with del(5q) was not due to promoter hypermethylation, suggesting that the use of hypomethylating agents (eg, azacitidine, decitabine) is unlikely to benefit this MDS subset [13].
Monosomy 7 and del(7q) — Approximately 10 percent of patients with de novo MDS and up to one-half of patients with therapy-related MDS demonstrate -7 or del(7q), either alone or as part of a complex karyotype [9]. Approximately 90 percent of such cases have loss of the entire chromosome 7 (-7), while 10 percent have a del(7q) (ie, deletion of the long arm of the chromosome). Deletion of chromosome 7 in MDS is associated with adverse prognosis. (See "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults".)
Genes that have been implicated in the pathogenesis of MDS with chromosome 7 deletion include [30]:
●SAMD9/SAMD9L – Human SAMD9 and SAMD9L encode related endosomal proteins that facilitate homotypic fusion of endosomes that are critical for endosomal trafficking, including metabolism of cytokine receptors [31].
SAMD9 mutations also cause MIRAGE syndrome, a multisystem disorder characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy [32]. (See "Inborn errors of immunity (primary immunodeficiencies): Classification".)
●EZH2 – EZH2 is a methyltransferase that is a component of the polycomb repressive complex 2 (PRC2), which catalyzes trimethylation of lysine 27 of histone H3 (H3K27) and generally serves as a gene silencer that influences stem cell renewal by repression of genes involved in cell fate decisions [33].
●MLL3 – MLL3 has histone methyltransferase activity for lysine 4 of histone 3 (H3K4), a histone mark that is associated with active transcription [34].
●Others – Other genes implicated in MDS with -7 include CUX1 (a cut-like homeobox gene that is a haploinsufficient tumor suppressor gene) [35,36], LUC7L2 (a LUC7-like pre-mRNA splicing factor), and CUL1 (which encodes a spliceosomal protein) [25].
Certain recurring gene mutations are associated with isolated -7 or del(7q) and some 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 [37]. In another study, 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 [38]. 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. (See 'Acquired mutations' below.)
Trisomy 8 — Trisomy 8 is seen in <10 percent of patients with MDS and is considered an intermediate-risk finding [39]. Gain of chromosome 8 has been associated with higher expression of anti-apoptotic genes compared with normal cells and may provide a selective advantage over unaffected hematopoietic precursors. Overexpression of MYC at 8q24.2 has also been implicated in the pathogenesis of myeloid disorders with trisomy 8.
del(20q) — Deletions of the long arm of chromosome 20 occur in <5 percent of cases of MDS and are also seen in patients with AML and myeloproliferative disorders [9]. 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 [40].
Other karyotypic abnormalities — Among other chromosomal abnormalities that have been reported in MDS are [41]:
●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)
GENE MUTATIONS — Gene mutations are detected in nearly all patients with MDS, whether they are associated with chromosomal abnormalities or not. Although most reflect acquired mutations, pathogenic or likely-pathogenic germline variants may also be found in patients with MDS of all ages. (See 'Pathologic germline variants' below.)
Combining genomic profiling with hematologic and cytogenetic parameters has improved risk stratification of patients with MDS. (See "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults", section on 'Mutation-based models'.)
Acquired mutations — Mutations are primarily found in genes that encode proteins that affect epigenetic regulation (eg, DNA methylation, histone modification), RNA-splicing machinery, transcription factors, and cytokine signaling pathways. Many are driver mutations that have independent prognostic significance (TP53, EZH2, ETV6, RUNX1, and ASXL1) and are associated with progression to acute myeloid leukemia (AML) [2,42]. As an example, mutations were identified in 94 percent of nearly 3000 patients with MDS; genes mutated in >10 percent of cases included TET2, ASXL1, SF3B1, DNMT3A, SRSF2, RUNX1, and TP53 [10]. Other large studies have reported similar findings [43,44]. (See "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults", section on 'Prognostic factors' and "Acute myeloid leukemia: Risk factors and prognosis".)
Genes that have been implicated in the pathogenesis of specific cytogenetic abnormalities associated with MDS are discussed above. (See 'Types of chromosomal abnormalities' above.)
Genes that are most often mutated in MDS include [2,42,43,45]:
●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 AML. TET 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 [43]. Loss-of-function mutations of TET2 result 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.
●ASXL1 – ASXL1 encodes a protein involved in epigenetic regulation of gene expression and is mutated in 10 to 20 percent of MDS cases [2,42,43,45]. ASXL1 mutations are associated with a decreased overall survival and shorter time to progression to AML.
●SF3B1 – The SF3B1 gene encodes a nuclear ribonucleoprotein component of the spliceosome, which is responsible for splicing messenger RNA. Recurrent somatic point mutations in SF3B1 are found in at least one-fifth of cases of MDS [43]. MDS with SF3B1 mutations identifies a distinct subset of MDS that includes >90 percent of cases with ≥5 percent ring sideroblasts [7,8,46]. (See 'Classification of MDS' above.)
●DNMT3A – DNMT3A, located at 2p23, encodes a DNA methyltransferase that catalyzes 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 [2,42,43,45] and associated with worse overall survival in MDS and more rapid progression to AML.
●SRSF2 – SRSF2 at 17q25 encodes serine/arginine-rich splicing factor 2, which 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 [47], with a higher frequency in older adult 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 [43]. RUNX1 is a translocation partner for RUNX1T1 (ETO) in cases of AML with the t(8;21). (See "Acute myeloid leukemia: Cytogenetic abnormalities", section on 't(8;21); RUNX1::RUNX1T1'.)
●TP53 – The TP53 tumor suppressor gene, located on 17p, encodes the p53 protein (also referred to as TP53), which mediates cell cycle arrest in response to a variety of cellular stressors. In MDS, about 5 to 15 percent of cases have TP53 mutations at the time of diagnosis, frequently in association with a del(5q) [24,43]. Abnormalities of 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 an independent marker of poor prognosis [9].
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 [48]. TP53 mutations were enriched in MDS with del(5q), and MDS with ≥5 cytogenetic abnormalities, all of which are associated with shorter overall survival. Integrative genomic analyses suggested that TP53 mutation allelic status and variant allele frequency (VAF) may provide further precision in predicting clinical outcomes [49]. 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 [50-52].
Note that MDS with bi-allelic TP53 mutations constitute distinct categories in the International Consensus Classification of Myeloid Neoplasms and Acute Leukemias (ICC) and WHO5 nosologies, described below. (See 'MDS with mutated TP53' below.)
●Other mutated genes
•IDH – Mutations in the isocitrate dehydrogenase oncogenes, 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 [42,43].
•RAS – The RAS oncogenes, HRAS, KRAS, and NRAS, are important in signal transduction and have been identified in 10 to 35 percent of cases of MDS [1,2,42,43]. Most RAS mutations in MDS are in NRAS, while KRAS mutations are less common. 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, but RAS mutations are associated with MDS characterized by -7/del(7q).
•FLT3 – While mutations of FLT3, which encodes the FLT3 cytokine receptor, are uncommon in MDS, they have been associated with a worse prognosis [42]. (See "Acute myeloid leukemia: Risk factors and prognosis".)
•U2AF1 – U2AF1, encoding a component of the RNA splicing core complex, is mutated in about 5 to 10 percent of patients with MDS; mutations are associated with worse survival outcome and increased risk of progression to AML [53-57].
•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 effects are manifest mainly in male patients and result in loss-of-function. ZRSR2 mutations may be associated with an unfavorable prognosis in MDS [53-55,57].
•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 [2].
•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 [2].
MDS with mutated TP53 — ICC and WHO5 introduced a new subtype of MDS, defined by the presence of multi-hit TP53 mutations (ie, both alleles are mutated or deleted), which defines a highly aggressive disease with short survival [50,52]. This subtype is labeled "MDS with biallelic TP53 inactivation" by WHO5 [8]. In the ICC it is labeled "MDS with mutated TP53" and, rather than including it under MDS, it is included along with other TP53-mutated neoplasms in a new category (Myeloid neoplasms with mutated TP53) [7]. (See "Classification of hematopoietic neoplasms", section on 'Myeloid neoplasms with mutated TP53'.)
Multi-hit TP53 can be confirmed by the presence of two or more distinct TP53 mutations (VAF frequency ≥10 percent), or a single TP53 mutation associated with either (1) a cytogenetic aberration involving the TP53 locus at chromosome 17p, (2) a VAF of >50 percent, or (3) copy-neutral loss of heterozygosity (CN-LOH) at the 17p TP53 locus. In the absence of LOH information, the presence of a single TP53 mutation in the context of any complex karyotype is considered equivalent to a multi-hit TP53. Complex karyotypes, del(5q), -7/del(7q), and 17p abnormalities are common in this subtype.
Pathologic germline variants — Some cases of MDS are associated with pathogenic germline gene variants. Although such associations were previously considered rare, routine targeted sequencing of MDS genomes has increased identification of cases with an underlying germline predisposition. Recognition of pathogenic germline gene variants is important for clinical management of affected individuals and family members.
Examples of inherited genetic abnormalities that may contribute to development of MDS (table 1) include:
●Trisomy 21/Down syndrome
●Fanconi anemia
●Bloom syndrome
●Dyskeratosis congenita and other telomere biology disorders
●Shwachman-Diamond syndrome
●Ataxia telangiectasia
●Paroxysmal nocturnal hemoglobinuria
●Congenital neutropenia
Familial MDS has been reported in association with germline mutations in RUNX1, ANKRD26, CEBPA, DDX41, ETV6, TERC, TERT, SRP72, and GATA2 [58] (table 4). There are three categories of familial myeloid neoplasms associated with germline mutations:
●No associated phenotype – MDS with DDX41 mutation and AML with CEBPA mutation are syndromes of MDS in association with a germline disorder, but they manifest no other pre-existing disorder or organ dysfunction [59].
●Platelet disorders – Germline variants involving RUNX1, ANKRD26, or ETV6 are associated with MDS with pre-existing platelet disorders.
●Other syndromes – MDS in association with other organ dysfunction syndromes include GATA2 mutation; Fanconi anemia, dyskeratosis congenita, and other bone marrow failure syndromes; neurofibromatosis; and Down syndrome.
Familial MDS is discussed in more detail separately. (See "Familial disorders of acute leukemia and myelodysplastic syndromes".)
HIGHER-RISK MDS — Subtypes of MDS that are characterized by increased blasts in bone marrow or blood are associated with adverse prognosis. The International Consensus Classification of Myeloid Neoplasms and Acute Leukemias (ICC) and World Health Organization 5th edition (WHO5) define, label, and categorize these subtypes differently [7,8]:
●MDS with excess blasts (MDS-EB) – MDS-EB is characterized by ≥5 percent myeloid blasts in bone marrow, ≥2 percent blasts in peripheral blood (or 1 percent documented on two occasions), or the presence of Auer rods (irrespective of blast cell count), according to the ICC [7]. This subtype is named "MDS with increased blasts" and is included in the broader category of MDS, morphologically defined by the WHO5 [8].
●MDS/AML – The ICC applies the label, MDS/acute myeloid leukemia (AML), to cytopenic myeloid neoplasms with 10-19 percent blasts in blood or marrow; this new terminology was applied to acknowledge the biologic continuum between MDS and AML [7]. These cases are labeled "MDS with increased blasts" in WHO5 [8] (and were previously called MDS-EB-2 in WHO4R [60]). TP53 mutations, complex karyotypes, del(5q), -7/del(7q) and 17p abnormalities are common in this subtype. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Diagnosis' and "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults".)
USE OF CYTOGENETICS/MUTATIONS FOR PROGNOSIS — Particular cytogenetic abnormalities and molecular findings are useful for predicting survival in MDS and progression to acute myeloid leukemia (AML) (table 3) [39]. Chromosomal abnormalities are incorporated into each of the following prognostic scoring systems for MDS; IPSS-M also incorporates molecular findings:
●International Prognostic Scoring System (IPSS)–Molecular (IPSS-M) [10]
●IPSS–revised (IPSS-R)
●IPSS–original (IPSS)
These prognostic models and prognostic calculators are presented separately. (See "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults".)
SUMMARY
●Description – Myelodysplastic syndromes/neoplasms (MDS) are a heterogeneous group of clonal hematopoietic disorders characterized by cytopenias, dysplasia, and variable rates of progression to acute myeloid leukemia (AML) and bone marrow failure.
●Classification – We favor use of either of the following contemporary classification systems for MDS; both incorporate cytogenetic and molecular findings, but details of the specific category labels and diagnostic criteria differ (see 'Classification of MDS' above):
•International Consensus Classification (ICC)
•World Health Organization 5th edition (WHO5)
●Chromosomal abnormalities – One-half of cases of de novo MDS have at least one chromosomal abnormality at diagnosis; other cases may acquire cytogenetic abnormalities during observation or treatment. (See 'Chromosomal abnormalities' above.)
•Detection – Chromosomal abnormalities are generally detected by karyotyping (chromosomal banding) and/or fluorescence in situ hybridization. (See 'Detection' above.)
•Types of abnormalities – Most chromosomal abnormalities in MDS involve a numerical change (ie, monosomy or trisomy) or structural abnormality of a single chromosome (eg, interstitial deletion, inversion); complex karyotypes (ie, multiple chromosomal abnormalities) are common. Balanced translocations are less common in MDS, but usually involve t(3;21), inv(3)/t(3;3), or t(11;16). Certain balanced translocations that are associated with AML exclude the diagnosis of MDS: t(8;21), inv(16), t(16;16), t(15;17). (See 'Types of chromosomal abnormalities' above.)
•Chromosomal abnormalities in MDS – The most common chromosomal findings in MDS are:
-del(5q) – Deletion of the long arm of chromosome 5, del(5q), is a favorable prognostic category with distinctive clinical features; genes implicated in the pathogenesis are described above. (See 'del(5q)' above.)
However, del(5q) in the setting of MDS with excess blasts or MDS/AML, which is typically associated with a complex karyotype, is associated with a poor prognosis.
--7 or del(7q) – Monosomy 7 or del(7q) is an unfavorable prognostic finding and may be an isolated finding or in association with a complex karyotype; genes implicated in the pathogenesis are described above. (See 'Monosomy 7 and del(7q)' above.)
-Others – Less common chromosomal abnormalities in MDS include trisomy 8, del(20q), and others.
●Mutations – Acquired mutations are detected in nearly all cases of MDS and most often involve genes encoding epigenetic regulators, RNA-splicing machinery, transcription factors, and cytokine signaling pathways. (See 'Acquired mutations' above.)
Less often, MDS is associated with germline variants of certain genes, such as DDX41, CEBPA, GATA2, RUNX1, and inherited bone marrow failure syndromes. (See 'Pathologic germline variants' above.)
●Prognosis – Cytogenetic findings, with or without mutation analysis, are incorporated into contemporary MDS prognostic models. (See 'Use of cytogenetics/mutations for prognosis' above.)
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