Combined comparative genomic hybridization and single-nucleotide polymorphism array detects cryptic chromosomal lesions in both myelodysplastic syndromes and cytopenias of undetermined significance

Abstract

The diagnosis of myelodysplastic syndrome (MDS) can be challenging, and may be facilitated by correlation with cytogenetic testing. Microarray analysis using comparative genomic hybridization and/or single-nucleotide polymorphism array can detect chromosomal abnormalities not seen by standard metaphase cytogenetics. We examined the ability of combined comparative genomic hybridization and single-nucleotide polymorphism analysis (hereafter referred to as 'combined array') to detect changes among 83 patients with unexplained cytopenias undergoing pathologic evaluation for MDS and compared results with 18 normal bone marrow controls. Thirty-seven patients (45%) were diagnosed with MDS, 12 patients (14%) were demonstrated to have 'indeterminate dyspoiesis' (insufficient for classification of MDS), 27 (33%) were essentially normal, and 7 patients (8%) had alternative pathologic diagnoses. Twenty-one MDS patients (57% of diagnoses) had effectively normal metaphase cytogenetics, but combined array showed that 5 of these (13% of MDS patients) harbored major cryptic chromosomal aberrations. Furthermore, nearly half of patients with 'indeterminate dyspoiesis' and 1 with normal morphology had clonal cytopenia(s) of undetermined significance by combined array analysis. Cryptic array findings among MDS patients and those with clonal cytopenias(s) included large-scale copy-neutral loss of heterozygosity (up to 118 Mb) and genomic deletion of loci implicated in MDS pathogenesis (eg, TET2 (4q22) and NUP98 (11p15)). By comparison, in MDS patients with abnormal metaphase cytogenetics, microarray mostly recapitulated findings seen by routine karyotype. Combined array analysis has considerable diagnostic yield in detecting cryptic chromosomal aberrations in MDS and in demonstrating aberrant clonal hematopoiesis in cytopenic patients with indeterminate morphologic dysplasia.

Single-nucleotide polymorphism array (SNP-A) improves the identification of chromosomal abnormalities by metaphase cytogenetics in myelodysplastic syndrome

“…The investigation and definition of smaller lesions that might be involved in disease predisposition should include large cohort of patients that enable the identification of recurrent lesions,22 24 but it is out of the scope of our study. Evans and colleagues20 have recently described an elegant study in which they report all SNP-A lesions defined as deletions and gains >250 kb and UPD >5 Mb in 18 normal bone marrow controls and 83 patients with unexplained cytopenias undergoing pathological evaluation for MDS; the authors have also validated the new lesions using FISH analysis.…”

Identify latent chromosomal aberrations relevant to myelodysplastic syndromes

“…Cryptic array findings among those patients comprised large-scale UPD (up to 118 Mb) and genomic deletion of loci implicated in MDS pathogenesis (eg, TET2 (4q22) and NUP98 (11p15)). The latent chromosomal lesions revealed by SNP-A helped to indicate clonal hematopoiesis and prompted classification as CCUS 41 . Hence microarray analysis significantly improves the detection rate of clinically significant findings.…”

Microarray‐based comparative genomic hybridisation reveals additional recurrent aberrations in adult patients evaluated for myelodysplastic syndrome with normal karyotype

“…Several cases had cnLOH, including the TET2 locus in two cases. Evans et al () showed that 42% of cases with indeterminate morphological findings could be reclassified as clonal cytopenia of undetermined significance. In AA, the presence of mutations in genes that are known to be involved in myeloid malignancies seems to be associated with reduced survival (Bejar, ).…”