MARCH 29, 2007 | A genetic analysis model developed by researchers at the University of Arkansas for Medical Sciences (UAMS) has outperformed all current clinical tests for identifying patients with aggressive multiple myeloma, a cancer of the bone marrow.
In a large-scale study of more than 500 myeloma patients, the team in the Myeloma Institute for Research and Therapy (MIRT) identified 17 genes whose altered expression could distinguish patients with a high-risk or low-risk form of the disease. Using the genetic analysis model, the research team led by John D. Shaughnessy Jr., Ph.D., reported significantly higher survival rates in patients identified as having the low-risk form of the disease.
An article on the study was deemed of “exceptional scientific importance” in the field of hematology when it was published in the March issue of Blood, the journal of the American Society of Hematology. The article, “A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1,” is available online at www.bloodjournal.org.
“In addition to finding a better test for risk assessment, identifying the 17 genes provide valuable targets for unraveling the mechanisms of drug resistance and for developing new and more powerful treatments,” said Shaughnessy, director of the Lambert Laboratory in the MIRT and a professor in the UAMS College of Medicine.
While initially responsive to treatment, a subset of multiple myelomas exhibits resistance at the outset of therapy and most will develop resistance over time, the researchers noted. Therefore, long-term survival in patients with multiple myeloma can vary considerably and it is difficult to predict outcome based on current laboratory tests.
In an effort to develop better prognostic tests and to understand why drug therapy did or did not work, Shaughnessy and colleagues examined the genetic characteristics of myeloma tumors. Using a powerful new technology known as microarray profiling they looked to see if differences in the activity of genes in tumor cells from 523 patients could be used to identify those with the high-risk form of the disease.
It was in this analysis that the researchers identified the 17 specific genes that distinguished patients at low versus high risk. The 13 percent of patients deemed to have high-risk myeloma had a median survival of only 24 months, whereas 65 percent of the remainder were alive at six years, according to the study.
Investigating samples taken at diagnosis and relapse, the researchers also found that a group of patients that switched from low risk at diagnosis to high risk at relapse. Shaughnessy said the findings suggest the acquisition over time of genetic features that cause the shift and explain the poor outcome of patients in the high-risk category.
Shaughnessy is the lead author of the article in Blood. Other UAMS authors included:
- Fenghuang Zhan, M.D., Ph.D., assistant professor, UAMS College of Medicine
- Yongsheng Huang, computer scientist research associate, MIRT
- Simona Colla, Ph.D., post doctoral fellow, MIRT
- Ichiro Hanamura, M.D., Ph.D., post doctoral fellow, MIRT
- James P. Stewart, Ph.D., post doctoral fellow, MIRT
- Bob Kordsmeier, research assistant, MIRT
- Christopher Randolph, research assistant, MIRT
- David R. Williams, research assistant, MIRT
- Yan Xiao, research assistant, MIRT
- Hongwei Xu, research assistant, MIRT
- Joshua Epstein, D.Sc., professor of medicine, UAMS College of Medicine
- Elias Anaissie, M.D., professor of medicine, UAMS College of Medicine
- Somashekar G. Krishna, M.D., assistant professor, UAMS College of Medicine
- Michele Cottler-Fox, director of cell therapy and transfusion medicine for the MIRT and a professor of pathology, UAMS College of Medicine
- Klaus Hollmig, M.D., assistant professor of medicine, UAMS College of Medicine
- Abid Mohiuddin, M.D., assistant professor of medicine, UAMS College of Medicine
- Mauricio Pineda-Roman, M.D., assistant professor of medicine, UAMS College of Medicine
- Guido Tricot, M.D., Ph.D., professor of medicine and pathology, UAMS College of Medicine
- Frits van Rhee, M.D., Ph.D., associate professor of medicine, UAMS College of Medicine
- Jeffrey Sawyer, Ph.D., director of cytogenetics for the MIRT and a professor of pathology, UAMS College of Medicine
- Yazan Alsayed, M.D., assistant professor of medicine, UAMS College of Medicine
- Ronald Walker, M.D., assistant professor of radiology, UAMS College of Medicine
- Maurizio Zangari, M.D., associate professor of medicine, UAMS College of Medicine
- Bart Barlogie, M.D., Ph.D., director of the MIRT and a professor of medicine and pathology in the UAMS College of Medicine
Shaughnessy and the MIRT continue to be at the forefront of myeloma research.
In September 2006, Shaughnessy and his colleagues reported in Blood that genetic analysis of myeloma had identified seven subtypes of the disease that had a bearing on a patient’s prognosis. Of the seven genetic disease subtypes identified, four were associated with better patient outcomes.
The researchers also reported identification of a critical genetic lesion that contributes to disease progression and drug resistance in myeloma.
Also, an article to be published in the May 2007 issue of The FASEB Journal, the journal of the Federation of American Societies of Experimental Biology, reports identification of the molecular trigger for birth defects caused by the drug thalidomide, which has been used as a treatment for myeloma. The abstract is available online for free at http://www.fasebj.org/cgi/content/abstract/fj.06-7603comv1.
Myeloma, also called multiple myeloma, is the second largest of the blood cancers, affecting an estimated 750,000 people worldwide.