Dr. Gordana Raca and her lab at the Cancer Cytogenetics Laboratory at the University of Chicago have used microarrays to detect chromosomal abnormalities in patients with hematological cancers. These abnormalities were not detected using cytogenetic testing, and in some cases, yielded actionable therapeutic targets that could have resulted in changes in therapy that might have improved outcomes for those patients.
Translational research has established that microarrays are a robust, reproducible, and reliable technology that could potentially be used in a clinical setting. Microarrays have already been used as an aid to developmental delay and/or intellectual disability diagnoses in post-natal settings. Chromosomal microarrays can detect small deletions, duplications, and loss of heterozygosity that are not detected using conventional FISH karyotyping. Chromosomal microarrays can also be used when cells do not divide in culture, which prevents cytogenetic analysis. But are these advancements clinically useful in cancer testing?
Dr. Raca reports that in published studies, 30–40% of hematological cancer cases with normal cytogenetic results revealed abnormalities when tested on chromosomal microarrays. In her pilot studies in patients with multiple types of hematological cancers, these microarrays have also uncovered prognostic markers, or even targetable mutations, that were not detected with cytogenetic testing.
In one case study that came to Dr. Raca's lab, a patient first presented with what appeared to be solid tumors with no involvement of bone marrow so cytogenetic testing was not indicated. Without cytogenetic testing, it can take a long time to recognize a hematologic cancer from a solid tumor. It can be very difficult to determine the patient's risk level and to decide on a therapeutic strategy. Chromosomal microarray testing revealed that this patient had a very rare and unusual form of acute myeloid leukemia that first appears as tumor masses that are often presumed to be solid tumors. Dr. Raca's team conducted a small study with these types of cancers, in which microarray analysis identified multiple genes with duplications and deletions, indicating an adverse outcome.
In another case study, an 11-year-old girl was diagnosed with B-cell acute lymphocytic leukemia (B-ALL) that was unresponsive to chemotherapy. Normal FISH karyotyping did not reveal any characteristic abnormalities. Bone marrow biopsy after initial chemotherapy treatment showed no decrease in tumor burden. However, chromosomal microarray testing showed a deletion that leads to upregulation of a tyrosine kinase. Based on the microarray data, a tyrosine kinase inhibitor was added to the patient's consolidation trial treatment. Her tumor burden diminished. Once she was in complete remission, she could proceed with stem cell transplant.
As a result of these studies, Dr. Raca believes that chromosomal microarray testing could be used as an adjunct to conventional testing when cytogenetic analysis is normal and molecular markers are negative, or when cytogenetic analysis is inconclusive or unavailable. Further studies of the utility of chromosomal microarrays in management of hematological malignancies are underway.