Researchers from the University of Nebraska Medical Center and National Human Genome Research Institute (NHGRI) have combined to perform the first mutation analysis using microarray technology on the ATM gene in lymphoma. The study was reported in the April 29 issue of the Proceedings of the National Academy of Sciences.
Joseph Hacia, Ph.D., now at the University of Southern California, designed the chip while working at the NHRGI, which is part of the National Institutes of Health in Bethesda, Md., along with workers at Affymetrix, a DNA technology company in Santa Clara, Calif.
The microarray technology was used to analyze a gene mutation frequently found previously in patients with the inherited condition of ataxia telangiectasia. The mutation – called ataxia telangiectasia mutated (ATM) – showed up in several different types of lymphoma, but was most prevalent in mantle cell lymphoma (MCL). The mutation showed up in 43 percent (12 of 28) of MCL cases studied, but in 10 percent or less of other types of lymphoma cases studied.
“This is an important step to better understanding the role of this mutation in lymphoma,” said Timothy Greiner, M.D., associate professor of pathology/microbiology at UNMC and one of the co-authors of the study. “Ultimately, this research may lead to an understanding of why this mutation occurs at such a high rate in mantle cell lymphoma.”
The microarray technology allowed the researchers to use small chips with approximately 250,000 DNA probes on each chip to look for changes in the DNA at every single position on the gene – or about 9,600 different positions in the tumors.
“This would be a huge task if done manually,” Dr. Greiner said, “but the microarray technology makes it easier to identify the mutations.”
He said most of the ATM mutations were found only in the tumor cells and not in the patient’s normal DNA. This would be different from what is seen with breast cancer patients who have a pre-disposed gene (BRCA-1) that mutates cells into cancer.
“We don’t know the clinical significance of the ATM mutation,” Dr. Greiner said. “In the next year we hope to figure out what the functional biology is of the mutation. We hope to compare the gene expression of ATM mutant cases of lymphoma with lymphoma tumors that have normal ATM. This should provide us some important data that we can use to translate into more effective care for our patients.”
Other researchers at UNMC involoved in the study were: Dennis Weisenburger, M.D., professor of pathology/microbiology; Wing C. (John) Chan, M.D., professor of pathology/microbiology; James Armitage, M.D., dean of the UNMC College of Medicine; Julie Vose, M.D., professor of internal medicine and chief of the oncology/hematology section; and Lynette Smith, a statistical coordinator in the preventive & societal medicine department.