A Novel Look at MDS Patients: Utilization and Effectiveness of a SNP Microarray for the Detection of Both Copy Number and Copy Neutral Changes

Abstract 4846

Myelodysplastic syndrome (MDS), includes a variety of hematological dysplasias that can be divided into high grade or low grade disease. Individuals with high grade MDS have an increased chance of having their disease progress to Acute Myelogenous Leukemia. Both standard chromosomal analysis and fluorescence in-situ hybridization (FISH) are utilized to detect abnormal clones aiding in the diagnosis and prognosis of the patient. FISH probes can be used to detect a deletion of 5q, 7q and 20p as well as trisomy 8 in frequently used routinely panels. Both standard cytogenetic analysis and FISH analysis can detect abnormalities in approximately 35–40% of MDS patients. The promise of microarray analysis of MDS clones is the 100x resolution power compared to routine chromosome analysis in identifying clonal genetic alterations and the comprehensive genomic coverage compared to the limited targets in routine FISH analysis.

In order to validate microarray analysis and verify its usefulness for studying CLL, we have examined 27 patients, including both normal (19) and abnormal (8) patients using the Affymetrix SNP 6.0 microarray.

The studies have indicated a number of interesting and important findings including: (1) Of the 19 normal cases, 7 clinically significant abnormalities were detected by the array analysis (37%), indicative of the usefulness of SNP array analysis rather than FISH; (2) The remaining 8 cases had at least one abnormality which was detected by either cytogenetics or FISH. Six of these cases (75%) showed additional abnormalities by the array analysis; (3) There were a number of potentially important oncogene deletions identified by the array analysis, including: miRNA 15–16, RUNX1, NFAT5, TET2, IGK, BCL2, MYC, PTCH1 and ETV6; (4) The utilization of a genotyping array proved to be extremely valuable since there were five cases (18.5%) with UPD. [UPD1, UPD4, UPD12, UPD17 and UPD 22]. The majority of these were segmental except chromosome 22 and were detected in the patients that already demonstrated abnormalities; (5) The array could detect every abnormality detected by FISH that was present in at least 14.5% of the cells.

These studies clearly show the importance of utilizing genotyping array analysis to study patients with MDS through both 100x improved resolution over cytogenetics as well as offering the capability to identify “silent” clonal evolution based copy neutral changes. In particular, the high percent of abnormalities detected in patients considered normal by FISH and chromosome analysis is extremely important for establishing a true genetic basis for the MDS. The large percent of copy neutral changes detected by the genotyping array is intriguing and likely to be proven important for the prognosis of the patient. Additionally, the array has been very useful in better clarifying abnormalities seen by cytogenetic analysis that cannot be fully delineated. The high success rates are likely to include blood sample analysis, so that marrow aspirate may not be mandatory. Based on our referral pattern- using SNP microarray allows for better diagnostic information in 46% of cases.