Pam Harrison

October 19, 2011

October 19, 2011 (Montreal, Quebec) — Investigators at the University of Pittsburgh have developed a comparative genome hybridization (CGH) microarray that offers significantly superior resolution and a greater ability to detect chromosome abnormalities than classic chromosome tests for the diagnosis of hematologic malignancies.

Svetlana Yatsenko, MD, associate director of the cytogenetics laboratory, University of Pittsburgh, Pennsylvania, and colleagues developed the custom genome-wide microarray for this purpose. She presented the research here at the 12th International Congress of Human Genetics and the 61st American Society of Human Genetics Annual Meeting.

Oligonucleotide Probes

"Chromosome analysis is a classic and well-established test for the diagnosis of hematologic malignancies, but the resolution of the test is very limited because certain abnormalities in the cancer genome exist beyond the resolution of karyotype analysis," Dr. Yatsenko told Medscape Medical News.

Fluorescence in situ hybridization (FISH) analysis requires knowing where probes need to be applied and what researchers want to test for, "so you have to have a deep understanding of the disease in order to test a particular region for abnormalities," she explained.

In contrast, the customized CGH microarray analysis does not require any knowledge of the disease. It is applied to the whole genome, where it is able to detect abnormalities with a high degree of resolution, well beyond the capabilities of existing techniques. As Dr. Yatsenko noted, this additional genetic information could have significant implications for the subsequent treatment of patients, because knowing exactly what abnormality is involved in the pathogenesis of the malignancy might allow physicians to treat patients differently, improving their chances of disease-free and overall survival.

The CGH microarray contains 180,000 oligonucleotide probes that can detect chromosome abnormalities — including gains and losses — with an average resolution of 150 kb and an enhanced 5 to 10 kb resolution for 900 genes involved in hematologic carcinogenesis. (In contrast, it is virtually impossible to pick up regions of less than 10 to 15 Mb with classic chromosomal analysis).

The microarray was validated for clinical use by analyzing 20 bone marrow specimens of pediatric and adult leukemias and lymphomas. Specimens had a total of 49 aberrations previously characterized with classic cytogenetic analysis or FISH.

Using the CGH microarray, "we identified 67 acquired copy-number changes of diagnostic or prognostic significance," Dr. Yatsenko reported, as well as 18 of unclear clinical significance and 23 benign copy-number variants. The microarray analysis also revealed pathogenic aberrations not seen with karyotype, FISH, or both in more than half the specimens tested.

Coinvestigator Susanne M. Gollin, PhD, FFACMG, professor of human genetics, otolaryngology, and pathology at the University of Pittsburgh, told Medscape Medical News that the significantly higher resolution made possible by the CGH microarray is an important step forward.

"There are chromosomal gains and losses at the breakpoints of many translocations, as well as other rearrangements in these lesions, that were not detectable by other methods, so this is very exciting," she said. She went on to explain that knowing that there might be deletions or duplications of DNA at these breakpoints could help physicians tailor specific treatment for specific tumors.

"Function may be altered, which has implications not only in disease progression, but also in resistance to treatment," Dr. Gollin said.

Peter vanTuinen, MD, director of the clinical cytogenetic laboratory and associate professor of pathology, Medical College of Wisconsin, Milwaukee, was very interested to hear about the new technology, because he is personally looking for applications of microarray technology for his own lab's exploration of leukemias.

"I was gratified to see that a lot of the rearrangements were detectable by microarray," he told Medscape Medical News. "For those interested in the diagnosis and prognosis of leukemias and other hematologic malignancies, this is an important new microarray."

12th International Congress of Human Genetics (ICHG) and the 61st American Society of Human Genetics (ASHG) Annual Meeting: Abstract 36. Presented October 12, 2011.


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