Chromosomal lesions and uniparental disomy detected by SNP arrays in MDS, MDS/MPD, and MDS-derived AML

Abstract

IntroductionThe myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem-cell disorders characterized by cytopenias and frequent leukemic progression. MDS constitutes a prototype of age-related malignancy, with a prevalence in the United States that may be more than 100 000. 1 Its incidence in the United States, estimated to be more than 10 000 yearly, is likely to further increase due to the greater life expectancy of the general population (http://www.census.gov/).Chromosomal aberrations can be detected by metaphase cytogenetics (MC) in approximately 50% of MDS patients and are responsible for some of the observed clinical diversity. Based on the experience that certain chromosomal lesions have a major impact on survival in MDS, 2-5 cytogenetic results were included in The International Prognostic Scoring System (IPSS), the most commonly applied prognostic algorithm for MDS. Moreover, recent studies demonstrate that MDS patients with certain cytogenetic abnormalities may be candidates for targeted therapies. For example, lenalidomide results in a high remission rate in MDS patients with 5q-abnormalities. 6,7 High-resolution single nucleotide polymorphisms arrays (SNP-A) can be applied in karyotypic analysis. SNP-A-based karyotyping does not depend upon the availability of live, dividing cells, and consequently can yield results when routine MC is not informative. Moreover, due to the higher resolution of SNP-A as compared with MC, smaller, previously cryptic deletions and duplications can be detected. A major advantage of this technology over MC is its ability to identify loss of heterozygosity (LOH) that occurs without concurrent changes in the gene copy number (CN). Such defects are consistent with acquired uniparental disomy (UPD) and can be attributed to errors in mitotic recombination occurring in somatic cells. Acquired segmental UPD is being increasingly recognized in a variety of neoplasms. 8,9 UPD has been described in chronic lymphocytic leukemia 10 and polycythemia vera as a mechanism leading to homozygosity for the Jak2 mutation. 11 Recently, an extensive study of acute lymphoblastic leukemia using SNP-A revealed chromosomal deletions and amplifications, many of them involving genes encoding principal regulators of B-lymphocyte development. 12 SNP-A also has been used for detecting genomic lesions in smaller case series of myeloma, 13 leukemias, 14-16 and lymphoma. 17 Initially using 50K arrays, we have demonstrated the potential diagnostic value of this technology, in a smaller cohort of myelodysplastic syndrome (MDS) patients. 18 This preliminary study demonstrated frequent detection of UPD in MDS. Subsequent larger studies limited to low-risk MDS showed similar results. 19 MDS is a particularly suitable target for demonstrating the use of SNP-A, as acquired cytogenetic abnormalities are relatively frequent and mostly unbalanced. 20 Using this disease as a model, we tested the hypothesis that high-density SNP-A can complement routine MC and enhance its diagnostic re...

Comprehensive array CGH of normal karyotype myelodysplastic syndromes reveals hidden recurrent and individual genomic copy number alterations with prognostic relevance

“…Deletions with similar breakpoints were described in two patients with refractory anemia 6 and in two patients with chronic myelomonocytic leukemia. 32 Taken together, this del(7q22) with similar deletion end points seems to be a frequent recurrent hidden aberration. Although the deletion in 8ptel can be seen in the Agilent workbench program, the log ratio is very low.…”

“…This gene is also the most frequent target for chromosomal translocations in leukemia and the fusion protein inhibits the function of the native allele. 36 So far only a few RUNX1 deletions have been described in MDS (for example, Heinrichs et al 10 and Gondek et al 32 ). Inactivation of the normal RUNX1 function is not sufficient to cause leukemia and other cooperating alterations were postulated.…”

Distinctive microRNA expression profiles in CD34+ bone marrow cells from patients with myelodysplastic syndrome

“…We hypothesized that the cluster upregulation might be caused by altered imprinting in DMR, possibly because of uniparental disomy (UPD) and/or deregulated epigenetic mechanisms in 14q32. We read through recent publications whether any defect was detected in this region; however, the absence of copy number variations or UPD found in 14q32 25,26 suggests a change in the methylation or acetylation status or aberrant characteristics of some transcriptional regulators. Limited information is available on the function of 14q32 miRNAs; however, several publications suggested their implication in cell development and oncogenesis.…”

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

“…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].…”