Myelodysplastic syndromes Prognostic biomarkers in myelodysplastic syndromes M. Cazzola ABSTRACT Prognostic biomarkers in myelodysplastic syndromes (MDS) include cytogenetic abnormalities and Department of Hematology somatic gene mutations. Recurrent chromosomal abnormalities are found in approximately 50% of Oncology, Fondazione Istituto cases, and are mainly secondary genetic events. By contrast, somatic oncogenic mutations, responsible di Ricovero e Cura a Carattere for disease pathogenesis and progression, are found in up to 90% of MDS patients. Oncogenic muta - Scientifico (IRCCS) Policlinico tions can be classified as: i) founding or initiating driver mutations, which cause a selective advantage San Matteo, and Department in a hematopoietic cell with capacity for self-renewal and lead to formation of a clone of mutated of Molecular Medicine, myelodysplastic cells; ii) subclonal or cooperating driver mutations, which occur in cells of an already University of Pavia, Pavia, Italy established clone and generate subclones carrying both the founding and the newly acquired muta - tion. Driver mutant genes include those of RNA splicing, DNA methylation, histone modification, tran - Correspondence: Mario Cazzola scription regulation, DNA repair, signal transduction, and cohesin complex. Only 6 genes ( TET2, SF3B1, E-mail: [email protected] ASXL1, SRSF2, DNMT3A , and RUNX1 ) are consistently mutated in 10% or more of MDS patients, while Acknowledgments: a long tail of additional genes are mutated less frequently. Reliable genotype/phenotype relationships The studies on the genetic basis of have already been established, primarily the close association between SF3B1 mutation and ring sider - myeloid neoplasms conducted at the oblasts. Clonal and subclonal mutations appear to affect prognosis equally, and outcome correlates Department of Hematology with the number of driver mutations. Ongoing studies aim to develop molecular models for clinical Oncology, Fondazione IRCCS decision-making. Policlinico San Matteo, and the Learning goals Department of Molecular Medicine, University of Pavia, Italy, were sup - At the conclusion of this activity, participants should be able to: ported by grants from the - describe driver somatic mutations in myelodysplastic syndromes, including the main biological Associazione Italiana per la Ricerca pathways involved; sul Cancro (AIRC), Fondazione - explain the difference between founding and subclonal mutations; Cariplo, MIUR (PRIN 2010-2011), - describe at least an established genotype:phenotype relationship in myelodysplastic syndromes; and FIRB (project n. RBAP11CZLK). -describe the diagnostic and prognostic relevance of somatic mutations in myelodysplastic syndromes. Hematology Education: the education program for the annual congress of the European Introduction ized by cytopenia, myelodysplasia, ineffective Hematology Association hematopoiesis, and increased risk of progres - sion to acute myeloid leukemia (AML). 3 The 2014;8:237-242 Diagnostic and prognostic biomarkers in current diagnostic approach to MDS includes myelodysplastic syndromes (MDS) have been peripheral blood and bone marrow morpholo - recently analyzed in this Education Program 1 gy to evaluate abnormalities of peripheral by Hellström-Lindberg. In the present paper, I blood cells and hematopoietic precursors, will focus on genetic biomarkers. We have bone marrow biopsy to assess marrow cellu - recently reviewed the genetic basis of MDS 2 larity and fibrosis, and cytogenetics to identify and its clinical relevance in Blood. The reader non-random chromosomal abnormalities. 4 is, therefore, referred to this open access Based on these parameters, MDS are currently review article for more detailed information categorized according to the 2008 World (http://bloodjournal.hematologylibrary.org/co Health Organization (WHO) classification, ntent/122/25/4021.long), while the present which is reported in Table 1. As shown in paper summarizes the crucial points only. As Figure 1, the current WHO classification of such, the present paper must be considered an MDS has valuable prognostic relevance. acceptable secondary publication intended to disseminate important information to the widest possible audience, in agreement with Pathophysiology of myelodysplastic the criteria of the International Committee of syndromes Medical Journal Editors (ICMJE, http://www. icmje.org/publishing_d.html). Our working model of the pathophysiology of MDS is reported in Figure 2. As demon - strated by Walter et al. 5 through studies of Classification of myelodysplastic whole genome sequencing, the vast majority syndromes of myeloid precursors (i.e. immature red cells, granulocytic/monocytic precursors, and Myelodysplastic syndromes are clonal megakaryocytes) are clonally derived in MDS. hematopoietic stem cell disorders character - The myelodysplastic clone originates from the Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) | 237 | 19 th Congress of the European Hematology Association occurrence in an immature hematopoietic stem cell of a somatic mutation that provides survival and growth advantage: typically this founding mutation involves genes of RNA splicing or DNA methylation. 2 During the natural course of the disease, the acquisition of additional driver mutations leads to formation of subclones of hematopoietic cells with further impaired differentiation and/or maturation capacity: the proportion of blast cells progressively increases over time, and overt AML eventu - ally develops. Recurrent chromosomal abnormalities in myelodys - plastic syndromes Recurrent chromosomal abnormalities are detected in approximately half of patients with MDS, 6 and the most common aberrations include del(5q), trisomy 8, del(20q), and monosomy 7 or del(7q). 6,7 While most of these abnor - malities are secondary genetic events, the isolated del(5q) of the 5q- syndrome represents a founding event, involv - ing haploinsufficiency for RPS14 and miR-145. 8-10 The recent study of 7012 patients aimed to develop the revised International Prognostic Scoring System (IPSS-R) for MDS has clearly demonstrated the prognostic rele - vance of chromosomal abnormalities with respect to sur - 11 vival and risk of evolution into AML. This cytogenetic Figure 1. Kaplan-Meier analysis of overall survival and risk classification has also been found to predict the out - leukemia-free survival of 1110 patients diagnosed with come of allogeneic hematopoietic stem cell transplanta - MDS at the Department of Hematology Oncology, 12 Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, tion (HSCT) in MDS patients. In particular, patients with between 1990 and 2012. MDS patients are stratified monosomal karyotype, defined as the karyotype of according to the 2008 WHO classification categories. patients who had two (or more) autosomal monosomies or Multilineage dysplasia and excess of blasts have a consid - erable impact on outcomes. Reproduced from Cazzola et one monosomy in combination with other structural al. 2 abnormalities, have a very poor outcome. 12 Table 1. 2008 WHO classification of myelodysplastic syndromes (from Swerdlow et al. 3). MDS subtype Blood findings Bone marrow findings Refractory cytopenia Unicytopenia or bicytopenia, Unilineage dysplasia ( ≥10% of the cells in one myeloid lineage) <5% blasts, with unilineage dysplasia (RCUD) no or rare blasts (<1%) <15% ringed sideroblasts within erythroid precursors Refractory anemia with ringed Anemia, no blasts Erythroid dysplasia only, < 5% blasts, ≥15% ringed sideroblasts within erythroid precursors sideroblasts (RARS) Refractory cytopenia with Cytopenia(s), no or rare blasts Dysplasia in ≥10% of cells in 2 or more myeloid multilineage dysplasia (RCMD) (<1%), no Auer rods, cell lineages (erythroid precursors and/or neutrophil precursors and/or megakaryocytes), <1x10 9/L monocytes <5% blasts, no Auer rods (the percentage of ringed sideroblasts is irrelevant) Refractory anemia with Cytopenia(s), <5% blasts, no Unilineage or multilineage dysplasia, 5-9% blasts, no Auer roads excess blasts-1 (RAEB-1) Auer roads, <1x10 9/L monocytes Refractory anemia Cytopenia(s), 5-19% blasts, Unilineage or multilineage dysplasia, 10-19% blasts, occasional Auer rods with excess blasts-2 (RAEB-2) occasional Auer rods, <1x10 9/L monocytes Myelodysplastic syndrome associated Anemia, normal to increased Normal to increased megakaryocytes with hypolobated nuclei, <5% blasts, no Auer with isolated del(5q) platelet count, no or rare blasts rods, isolated del(5q) (<1%) Myelodysplastic syndrome, Cytopenia (various combinations), Unequivocal dysplasia in less than 10% of cells in one or more myeloid cell lines when unclassifiable (MDS-U) no or rare blasts (<1%) accompanied by a cytogenetic abnormality considered as presumptive evidence for a diagnosis of MDS, <5% blasts | 238 | Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) Milan, Italy, June 12-15, 2014 Somatic gene mutations in myelodysplastic Diagnostic, prognostic and predictive significance syndromes of driver mutations, and development of molecular models for clinical decision-making Our understanding of the molecular basis of MDS has improved dramatically in the last four years as a result of 13-22 The identification of founding and subclonal driver a few fundamental studies. A list of the most common mutations has the potential to considerably improve diag - recurrently