The findings will also provide an invaluable resource for exploring the biological events that turn normal white blood cells into leukemic cells, according to James Downing, M.D., chair of the St. Jude department of Pathology. Downing is senior author of a report on this work, which appears in the October issue of Blood.
"Our ability to genetically fingerprint the different subtypes of ALL is extremely important," Downing said. "The only way to know how aggressively to treat a specific patient is to know which subtype of ALL the child has, since each subtype has a different prognosis."
The current work by the St. Jude team builds on work they previously published in 2002. In that study, the team used a single gene chip to identify the known subtypes of ALL. The current study used much higher density gene chips, which provided nearly complete coverage of the human genome. As a result, almost 60 percent of the ALL genes identified in the present study are new.
Pediatric ALL is one of the great success stories of modern cancer therapies, with overall event-free survival rates approaching 80 percent, according to Downing. Part of this success is due to the realization by researchers that there are different subtypes of ALL, each of which must be treated with a different level of intensity. This so-called risk-adapted therapy depends on accurately defining a patient's relative risk of relapse following treatment, and doing so before treatment begins.
"The results of our present study will improve our ability to accurately make those diagnoses," Downing said.
At present, combinations of different laboratory tests are required to diagnosis genetic subtypes of ALL, Downing said. "But the completion of the Human Genome Project has allowed us to tap into the enormous database of human genes to see which ones are related to specific subtypes of ALL. Our present gene chip study showed that each important ALL subtype has a specific genetic fingerprint. That means that we can identify different combinations of genes whose expression is linked to each subtype."
Moreover, the St. Jude study used two gene chips to achieve a 97 percent diagnostic accuracy on samples from 132 patients. That exceeds the level of accuracy routinely achieved using the existing variety of methods, according to Downing.
If the initial accuracy findings are proven in prospective clinical trials, the chip technology might be able to replace the wide variety of laboratory tests now required to identify the specific subtypes of ALL. "That would greatly simplify diagnosis," Downing said.
More importantly, the specific information coming out of these types of gene chip studies might eventually identify a limited number of specific genes that could be used to accurately and reliably determine which ALL subtype a patient has, he said. "That could in the end allow the information gained from these gene chip studies to be incorporated into simpler existing methods to diagnose leukemia and other pediatric and adult cancers," Downing said.
"In that case, our work will have helped point the way to simplifying accurate, reliable diagnosis and care of children with ALL using technology that is already commonly available in many pediatric healthcare facilities," Downing said. "That would offer smaller institutions an economical approach to timely, accurate diagnoses that could improve the outcome of their patients. And in the future, these genetic fingerprints might help us identify new targets in leukemic cells that could lead to the development of more effective therapies."
Other authors of the paper include Mary E. Ross, Xiaodong Zhou, Guangchun Song, Sheila A. Shurtleff, Kevin Girtman, W. Kent Williams, His-Che Liu, Rami Mahfouz, Susana C. Raimondi, Noel Lenny and Anami Patel, all of St. Jude.
This work was supported by the National Cancer Institute and ALSAC.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fund-raising organization. For more information, please visit http://www.stjude.org.
Journal
Blood