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...

as a candidate TSG on chromosome 7. In patients with chromosome deletion at the FZD9 locus, aberrant methylation of the remaining allele was associated with the poorest clinical outcome. These results indicate that aberrant methylation can cooperate with chromosome deletions to silence TSG. However, the ubiquity, extent, and correlation with disease progression suggest that aberrant DNA methylation is the dominant mechanism for TSG silencing and clonal variation in MDS evolution to AML. (Blood.

Two types of acquired loss of heterozygosity are possible in

Single nucleotide polymorphism arrays (SNP-As) have emerged as an important tool in the identification of chromosomal defects undetected by metaphase cytogenetics (MC) in hematologic cancers, offering superior resolution of unbalanced chromosomal defects and acquired copyneutral loss of heterozygosity. Myelodysplastic syndromes (MDSs) and related cancers share recurrent chromosomal defects and molecular lesions that predict outcomes. We hypothesized that combining SNP-A and MC could improve diagnosis/prognosis and further the molecular

A B S T R A C T PurposeInterstitial deletions of chromosome 5q are common in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), pointing toward the pathogenic role of this region in disease phenotype and clonal evolution. The higher level of resolution of single-nucleotide polymorphism array (SNP-A) karyotyping may be used to find cryptic abnormalities and to precisely define the topographic features of the genomic lesions, allowing for more accurate clinical correlations. Patients and MethodsWe analyzed high-density SNP-A karyotyping at diagnosis for a cohort of 1,155 clinically well-annotated patients with malignant myeloid disorders. ResultsWe identified chromosome 5q deletions in 142 (12%) of 1,155 patients and uniparental disomy segments (UPD) in four (0.35%) of 1,155 patients. Patients with deletions involving the centromeric and telomeric extremes of 5q have a more aggressive disease phenotype and additional chromosomal lesions. Lesions not involving the centromeric or telomeric extremes of 5q are not exclusive to 5qϪ syndrome but can be associated with other less aggressive forms of MDS. In addition, larger 5q deletions are associated with either del(17p) or UPD17p. In 31 of 33 patients with del(5q) AML, either a deletion involving the centromeric and/or telomeric regions or heterozygous mutations in NPM1 or MAML1 located in 5q35 were present. ConclusionOur results suggest that the extent of the affected region on 5q determines clinical characteristics that can be further modified by heterozygous mutations present in the telomeric extreme.

SNP-A analysis allows enhanced detection of chromosomal abnormalities and provides important prognostic impact in AML.

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We applied single nucleotide polymorphism arrays (SNP-A) to study karyotypic abnormalities in patients with atypical myeloproliferative syndromes (MPD), including myeloproliferative/myelodysplastic syndrome overlap both positive and negative for the JAK2 V617F mutation and secondary acute myeloid leukemia (AML). In typical MPD cases (N = 8), which served as a control group, those with a homozygous V617F mutation showed clear uniparental disomy (UPD) of 9p using SNP-A. Consistent with possible genomic instability, in 19/30 MDS/MPD-U patients, we found additional lesions not identified by metaphase cytogenetics. In addition to UPD9p, we also have detected UPD affecting other chromosomes, including 1 (2/30), 11 (4/30), 12 (1/30) and 22 (1/30). Transformation to AML was observed in 8/30 patients. In 5 V617F+ patients who progressed to AML, we show that SNP-A can allow for the detection of two modes of transformation: leukemic blasts evolving from either a wild-type jak2 precursor carrying other acquired chromosomal defects, or from a V617F+ mutant progenitor characterized by UPD9p. SNP-A-based detection of cryptic lesions in MDS/MPD-U may help explain the clinical heterogeneity of this disorder.