Utility of SNP Microarray in the Diagnosis of MDS

Abstract 4806

A series of 206 bone marrow aspirates/blood submitted for diagnostic testing for possible MDS/MPN was studied by high resolution SNP microarray to determine the efficacy of this technology for detecting clonal copy number alterations and copy neutral loss of heterozygosity. The latter, acquired uniparental disomy (aUPD), is associated with oncogene mutations that through mitotic recombination have converted to the homozygous state, offering additional selective advantage to daughter cells. Of the 206 patient samples classified as possible MDS, 76 were abnormal by the array. Thirty one of these were either copy neutral or demonstrated copy number alterations below the resolution of cytogenetics. Twenty-three cases demonstrated aUPD and in 14 of these it was the only abnormality detected. Two of these 14 had multiple aUPD (9q/14q and 1p/4q/14q). When the aUPD clones were accompanied by copy number alterations, they could be seen as either the early primary alteration or as a later evolutionary event. The most common segmental UPD regions in MDS were 4q(9), 7q(4),11q(4) and 14q(4) while 9p(4) was the most common a(UPD in the patients with MPN which was likely to be associated with a homozygous JAK2 mutation (confirmed in two cases). The small MPN group (12 cases) demonstrated eight clones with aUPD, only three of which had copy number alterations. All the aUPDs found in this study involved terminal chromosome arm exchange and almost all involved a percentage of the DNA tested, consistent with an acquired change. Whole chromosome aUPD was not seen in these patients. There were three instances of possible interstitial LOH which were not included in this report until normal patient DNA can be obtained to confirm this uncommon observation. Two of these three showed mosaic LOH consistent with an acquired change. The most common deletions below the resolution of cytogenetics involved the RUNX1 and TET2 genes. In summary, the SNP microarray increased the abnormal clone detection from 45 by cytogenetics to 76 in cases of MDS and from 4 to 8 in the small MPN cohort, underscoring the utility of the testing while laying the groundwork for the discovery of new driver genes in the aUPD regions in the pathogenesis of MDS.