Molecular definition of chromosome arm 5q deletion end points and detection of hidden aberrations in patients with myelodysplastic syndromes and isolated del(5q) using oligonucleotide array CGH

Abstract

Isolated deletions of the long arm of chromosome 5, del(5q), are observed in 10% of myelodysplastic syndromes (MDS) and are associated with a more favorable prognosis, although the clinical course varies considerably. If one or more additional chromosomal aberrations are present, this correlates with a significantly shorter overall survival. To assess the frequency of hidden abnormalities in cases with an isolated cytogenetic del(5q), we have performed a genome wide high resolution 44 K 60mer oligonucleotide array comparative genomic hybridization (aCGH) study using DNA from bone marrow cells of 12 MDS and one AML patient. In one case a single additional hidden 5.6 Mb deletion of 13q14 and in another case multiple larger aberrations involving many chromosomes were found. Fluorescence in situ hybridization demonstrated that aberrations present in 35% of the bone marrow cells can be detected by aCGH. Furthermore with oligonucleotide aCGH the deletion end points in 5q were mapped precisely, revealing a cluster of proximal breakpoints in band q14.3 (n = 8) and a distal cluster between bands q33.2 and q34 (n = 11). This study shows the high resolution of oligonucleotide CGH arrays for precisely mapping genomic alterations and for refinement of deletion end points. In addition, the high sensitivity of this method enables the study of whole bone marrow cells from MDS patients, a disease with a low blast count.

Survival, prognostic factors and rates of leukemic transformation in 381 untreated patients with MDS and del(5q): A multicenter study

“…Similar results with regard to the prognostic relevance of additional karyotype alterations were published by the German --Austrian MDS Group. 17 Using comparative genome hybridization, Evers et al 18 and Thiel et al 19 were also able to show the prognostic value of additional abnormalities. Moreover, it has been shown recently that the status of p53 expression at baseline is an important driver for disease progression in del(5q).…”

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

“…The same was observed by us previously for the del(5q), which was found in 35-91% of interphase cells. 7 It is remarkable that two patients had alterations affecting genes that are associated with elliptocytosis. Patient P20 had a deletion of 147 kb in 15q15 including the EPB42 (Supplementary Figure S3).…”

“…6 Using oligonucleotide aCGH on MDS/AML with a 5q-syndrome or del(5) as the sole cytogenetic abnormality, we have described the presence of additional hidden aberrations in 2/12 patients. 7 With single-nucleotide polymorphism (SNP) arrays, copy number alterations as well as loss of heterozygosity through uniparental disomy (UPD) can be detected. Two reports described the use of SNP arrays to study low-risk MDS for hidden genomic imbalances.…”

5q– myelodysplastic syndromes: chromosome 5q genes direct a tumor-suppression network sensing actin dynamics

“…Conventional cytogenetic and array-based comparative genomic hybridization analyses point to CDRs in aggressive MDS and AML centered on 5q31, as well as a CDR associated with the 5q-subset of MDS localized to 5q32 (Van den Berghe et al, 1985;Le Beau et al, 1993;Boultwood and Fidler, 1995;Horrigan et al, 2000;Boultwood et al, 2002;Crescenzi et al, 2004;Giagounidis et al, 2004;Evers et al, 2007;Herry et al, 2007). The emergence of array-based, high-resolution, DNA copy number analysis has allowed the chromosome 5q region to be examined in more detail (Evers et al, 2007). In addition, array-based approaches allow the determination of gene expression changes that accompany the progression to acute leukemia.…”

“…. MDS cells with chromosome 5q deletions were examined by high-resolution array comparative genomic hybridization (n ¼ 10) as described in Evers et al (2007). The region of most frequent deletion maps between 5q23.3 and 5q33.3.…”