Association of c-Kit mutations with higher likelihood of recurrence of t(8;21) AML

Abstract

A new study by researchers at the Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James) shows that mutations in a cancer-related gene may help predict whether a more common subtype of acute myeloid leukemia (AML) is more likely to return in patients.The researchers found that patients with mutations in a gene called KIT - which is already linked to this form of AML - were associated with significantly higher recurrence rates.Dr. Peter Paschka, who is completing a research fellowship under the guidance of Dr. Clara D. Bloomfield at OSUCCC - James and the study's lead author, presented the findings during a plenary session at the annual meeting of the American Society of Clinical Oncology held this month in Atlanta. The meeting attracted more than 30,000 oncologists from the United States and abroad. Only 6 of the more than 4,400-plus abstracts are selected for this honor because of their potential practice-changing findings."These findings could represent a significant advance in the therapy of AML. They could lead to the development of more effective targeted therapies and improved cure rates for certain AML patients," Paschka said. "We can apply our findings to patients to predict which ones may have a greater likelihood of a relapse. Those with a higher risk can then be treated with new targeted therapies, or more aggressively, perhaps with a stem cell transplant."In AML - the most common type of adult leukemia - cancerous immature blood cells replace normal blood cells in the bone marrow and other tissues. All patients in the study had core-binding factor (CBF) AML, a subtype of the disease that is generally associated with a more favorable clinical outcome. This subtype makes up about 15 percent of AML cases.Patients with CBF AML have one of two specific chromosome abnormalities: a translocation between the chromosomes 8 and 21, referred to as t(8:21), or an inversion of chromosome 16, referred to as inv(16). Although chemotherapy has greatly improved the outcome of these patients, more than half relapse within five years. This has led researchers to look for markers that might identify at diagnosis those patients who are likely to experience a recurrence, Paschka said.In this study, blood and bone marrow samples collected at diagnosis from 110 patients with CBF AML who were already enrolled in CALGB were analyzed for specific mutations. More than 25 percent of the patients in the study had KIT mutations.Of the study patients with t(8;21) AML, the 5-year recurrence rates were 70 percent for those with the KIT mutations and 36 percent for those without them. For patients with inv(16) AML, recurrence rates were 56 percent for those with KIT mutations and 29 percent for those without.Mutations in KIT have been linked to other types of cancer as well, including gastrointestinal stromal tumors, germ cell tumors and mastocytosis. These mutations in the KIT gene result in abnormally activated KIT protein, which in turn promotes growth and proliferation of malignant cells."By using targeted therapies, we can switch off these signals for growth," Paschka says. "This principle is applicable in these other cancers as well, and for some already used in clinical practice."The study was funded by the National Cancer Institute and the Leukemia Clinical Research Foundation.Other Ohio State researchers involved in the study are Guido Marcucci, Amy S. Ruppert, Krzysztof Mrozek, Hankui Chen, Rick A. Kittles, Tamara Vukosavljevic, Danilo Perrotti and Clara D. Bloomfield.The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute is one of the nation's leading centers for research on the prevention, detection, diagnosis and treatment of cancer. The OSUCCC - James encompasses seven interdisciplinary research programs and includes more than 250 investigators who generate over $100 million annually in external funding. It is a founding member of the National Comprehensive Cancer Network, and OSU's James Cancer Hospital is consistently ranked by U.S. News & World Report as one of America's best hospitals for cancer care.For more information contact: Eileen Scahill; Tel.: 614.293.3737; Email: Eileen.Scahill@osumc.edu