Updates in Cytogenetics and Molecular Markers in MDS

Abstract

Myelodysplastic syndromes (MDS) are clonal hematologic neoplasms that can result in cytopenias and increase the risk of leukemic transformation. The disease is characterized by several recurrent cytogenetic defects, which can affect diagnosis, prognosis, and treatment. Metaphase cytogenetics (MC) is the gold standard in karyotypic analysis in hematology. Progress in molecular analysis, including additional karyotypic tools exemplified by fluorescence in situ hybridization, comparative genomic hybridization, and more importantly, single nucleotide polymorphism array (SNP-A) analysis, has led to increased detection of chromosomal abnormalities in myeloid malignancies and improved prognostic risk stratification. SNP-A, together with MC, has also been instrumental in the discovery of genes that have improved our understanding of the biology of MDS. Newly elucidated molecular abnormalities in MDS include mutations in CBL, TET2, ASXL1, IDH1/IDH2, EZH2, DNMT3A, and UTX. This review provides an update on the changing landscape of molecular and cytogenetic characterization in MDS and its significance in disease biology and clinical practice.

Validation of the new comprehensive cytogenetic scoring system (NCCSS) on 630 consecutive de novo MDS patients from a single institution

“…Despite the efforts of many researchers [6][7][8][9][10][11][12][13]16,20], the prognostic significance of rare single chromosomal defects, double defects and unrelated clones, which flag the extreme heterogeneity of the MDS cytogenetic pattern [2,21,[28][29][30][31]41], has remained ill defined. In fact, most of the aforementioned studies provided conflicting results due to the small number of patients studied.…”

“…The International Prognostic Scoring System (IPSS) [8] was that most commonly used and has been now revised [17][18][19]. Thus, cytogenetic abnormalities remain one of the major determinants of MDS pathogenesis, diagnosis, prognosis and guide any potential treatment decisions [12][13][14][15][16][17][18][19][20][21][22][23][24][25], however more sensitive techniques such as array Comparative Genomic Hybridization, Single Nucleotide Polymorphism arrays (SNP-a) and Next-Generation Sequencing are still used in the research setting only [26][27][28][29][30][31]. The IPSS precisely defines the prognostic value of the most frequent chromosomal defects, whereas it does not define rare or combined abnormalities, which are included within the intermediate category [8].…”

Genome-wide arrays in routine diagnostics of hematological malignancies

“…It is recognized that CNLOH can generate homozygosity for mutated tumor suppressor genes or oncogenes involved in tumor transformation. For this reason, the majority of studies on hematological neoplasms have been performed using SNP arrays [Dougherty et al, 2011;Dunbar et al, 2008;Hagenkord and Chang, 2009;Heinrichs et al, 2009;Tiu et al, 2009Tiu et al, , 2011b. Initially, the sensitivity for detecting genomic abnormalities in mixed cell population using SNP arrays was rather low due to software limitations, but the sensitivity increased dramatically when the B-allele frequency algorithm was added to the analysis software (Fig.…”

“…Emerging data demonstrate that MDS exhibits abundant CNAs and CNLOH, often in the setting of a normal metaphase karyotype and no previously identified clonal marker [Heinrichs et al, 2009;Thiel et al, 2011;Tiu et al, 2011b]. Tiu et al (2011a) proposed a new prognostic risk score, integrating SNP array results in order to improve risk stratification for patients with MDS.…”

“…as chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), multiple myeloma (MM), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML) [Dougherty et al, 2011;Dunbar et al, 2008;Gunnarsson et al, 2011;Hagenkord et al, 2011;Heinrichs et al, 2009;Shao et al, 2010;Simons et al, 2011;Tiu et al, 2009Tiu et al, , 2011aTiu et al, , 2011b. Consequently, array-based molecular karyotyping is slowly but surely finding its way into the clinical laboratories for acquired cytogenetics.…”