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Molecular Pathology Selected Abstracts, 7/16

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Editors: Donna E. Hansel, MD, PhD, chief, Division of Anatomic Pathology, and professor, Department of Pathology, University of California, San Diego; John A. Thorson, MD, PhD, associate professor of pathology, director of the Clinical Genomics Laboratory, Center for Advanced Laboratory Medicine, UCSD; Sarah S. Murray, PhD, professor, Department of Pathology, and director of genomic technologies, Center for Advanced Laboratory Medicine, UCSD; and James Solomon, MD, PhD, resident, Department of Pathology, UCSD.

Using single nucleotide polymorphism arrays in acute lymphoblastic leukemia

In patients with acute lymphoblastic leukemia/lymphoma, the identification of chromosomal abnormalities at the time of diagnosis is important for risk classification. The current standard of care includes karyotype and FISH analysis to identify recurrent cytogenetic abnormalities. However, many hematologic malignancies will not demonstrate an abnormality using these techniques because karyotyping requires microscopic examination of cells in metaphase and FISH only probes specific genetic sequences. Whole-genome single nucleotide polymorphism (SNP) arrays allow for identification of both copy number alterations and copy neutral loss of heterozygosity at a submicroscopic level across the entire genome, providing a much higher resolution analysis of the chromosomal abnormalities associated with hematologic malignancies. The authors conducted a study in which an SNP array—in which extracted genomic DNA is analyzed with approximately 2.7 million probes—was used in 60 consecutive patients. They determined copy number and genotype of each of the probed areas and compared data to databases of known common copy number variations seen in healthy control subjects. The authors reported gains, losses, and areas of loss of heterozygosity. The SNP array data were integrated with karyotype and FISH analysis to characterize the chromosomal abnormalities. Of the 60 cases, abnormalities in karyotype and FISH were seen in 81 percent and 78 percent of cases, respectively. However, abnormal SNP array results were observed in all 60 acute lymphoblastic leukemia/lymphoma cases, although clinically relevant abnormalities that had prognostic or therapeutic implications were seen only in 34 cases. More importantly, however, combining the SNP array results with the karyotype and FISH analysis increased the detection rate for clinically relevant abnormalities from 56 percent to 75 percent of the leukemia/lymphoma cases. One interesting application is in detecting IKZF1 deletions, which are associated with poor response to induction therapy and overall poor prognosis. Current recommendations are to assess for deletions in IKZF1 and, if positive, perform additional ancillary testing to find targetable tyrosine kinase mutations. In the study, deletion of the IKZF1 gene was seen in 30 percent of cases, with deletions varying in size from 0.03 to 6.2 Mb. While other assays can assess for deletions in IKZF1, many of them are specific for the gene, whereas SNP microarray appears to be equally sensitive while being able to detect other submicroscopic chromosomal alterations and areas of loss of heterozygosity. A caveat is that SNP microarrays are not effective at detecting balanced translocations. Fifteen cases in the current study had balanced translocations seen by karyotype or FISH, or both, 13 of which could not be detected by the SNP microarrays. The authors concluded, however, that when used in conjunction with karyotype and FISH analysis, whole-genome SNP microarrays greatly increase the ability to detect chromosomal alterations that may be clinically relevant.

Wang Y, Miller S, Roulston D, et al. Genome-wide single-nucleotide polymorphism array analysis improves prognostication of acute lymphoblastic leukemia/lymphoma. J Mol Diagn. 2016;18. doi:10.1016/jmoldx.2016.03.004.

Correspondence: Dr. Lina Shao at linashao@med.umich.edu

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