Credit: NIGMS
NASHVILLE—New research suggests we may need to use more sensitive methods to analyze patients with cytogenetically normal acute myeloid leukemia or myelodysplastic syndrome (CN-AML/MDS).
Using “highly sensitive” microarray technology, researchers found a distinct pattern of genetic abnormalities in 22 patients diagnosed with CN-AML/MDS.
The team identified 3 overlapping regions of homozygosity in 3 genes, 2 of which are known to be involved in carcinogenesis.
This suggests that using karyotyping or FISH, or simply looking for known mutations, is not sufficient for evaluating patients with CN-AML/MDS, according to Ravindra Kolhe, MD, PhD, of the Medical College of Georgia at Georgia Regents University.
“The technology we currently use can’t identify specifically what’s wrong,” Dr Kolhe said. “We have to use more sensitive tests to give patients the proper answer.”
Dr Kolhe presented this finding, and the research to support it, at the American College of Medical Genetics and Genomics Annual Clinical Genetics Meeting.
He and his colleagues analyzed 22 patients. Seventeen had AML, and 5 had MDS, including 1 with refractory anemia with excess blasts-2. All patients had normal karyotype and FISH and had greater than 20% blasts in the bone marrow.
The researchers analyzed samples from these patients using a high-resolution, single-nucleotide polymorphism (SNP) microarray called CytoScanHD.
According to the company that markets this technology (Affymetrix, Inc.), the assay includes 750,000 SNPs with over 99% accuracy to detect accurate breakpoint estimation, loss of heterozygosity determination, regions identical-by-descent, maternal contamination, and low-level mosaicism.
For Dr Kolhe and his colleagues, the assay revealed small, previously undetectable changes in patients thought to be cytogenetically normal.
Specifically, the researchers identified 3 overlapping regions of homozygosity in all 22 cases—chromosome 1p34.3, chromosome 1p32.3, and chromosome 16q22.1 in the SFPQ, EPS15, and CTCF genes, respectively.
SFPQ and CTCF are already known to be involved in carcinogenesis, and Dr Kolhe and his colleagues are now investigating the role of EPS15 in leukemogenesis.
The researchers also identified additional abnormalities and are investigating these as well. They are sequencing the genes to identify homozygous or compound heterozygous mutations, performing expression studies to confirm that these mutations are leukemic, and conducting experiments in knockout mice to demonstrate that these genes produce the same leukemia phenotype.
The materials and reagents for this study were provided by Affymetrix. The test design, experimentation, data collection, analysis, and interpretation were done independently by the researchers.
