Jul 1 2004
Children who undergo chemotherapy and survive acute lymphocytic leukemia (ALL) endure a 200-fold increase in the frequency of somatic mutations in their DNA, researchers from the University of Vermont Medical School reported in the July 1 issue of the journal Cancer Research.
The alterations in the children's gene sequence remain embedded within their chromosomes and may pose elevated risk for development of second malignancies and other diseases later in life, cautioned Barry A. Finette, M.D., Ph.D., associate professor of pediatrics at the University of Vermont.
"The treatments that are used to help children defeat this disease are keeping a very large percentage of them alive," Finette said. "Pediatricians are continually monitoring these children as they live beyond five, ten, and more recently, 15 years after their ALL is in remission. We now need to be proactive about studying any long term genetic ramifications that these children may face due to the treatment therapy they endured during their bout with cancer."
Finette noted that children who are cured of ALL after chemotherapy have a 5-20 times greater risk of developing secondary malignant neoplasm's as well as other complications. Subsequent illnesses may be associated with increased changes in the patient's genes resulting from their treatments during ALL therapy.
Finette and his team of scientists examined the frequencies of alterations found within a marker gene in the blood cells of ALL patients at four intervals, between the time they were diagnosed until after they had completed their treatments. By examining the number of T cells in the patients' blood that contained mutations in the HPRT reporter gene, the researchers estimated how frequently chemotherapy altered the DNA sequence within that specific marker gene.
The research showed that at the time of diagnosis, the blood of patients contained an average of 1.4 cells with HPRT mutations out of every million T cells, Finette said. The treatment for ALL consists of a three-phase regimen, including induction, consolidation and maintenance. By the time the patients completed their consolidation phase of treatment, an average of 52 T cells per million cells contained HPRT mutations. By the final stage of treatment, an average of 93 of every million T cells had mutations in HPRT. After treatment was stopped, an average of 271 of every million T cells contained HPRT mutations, more than a 200-fold increase.
The study included 45 children with ALL who averaged 5.5 years of age at time of diagnosis. The number of HPRT mutations found in the patients at the time of diagnosis did not differ from healthy children of the same age, the researchers reported. The increase in genetic mutations seen in the ALL patients accumulated over the course of their treatments.
"The mutations that arise during treatment for ALL remained elevated after completion of therapy," Finette noted. But in the absence of the mutagenic chemotherapy, the rate of further genetic damage subsided. The post-treatment rate of HRPT mutations in the ALL survivors paralleled the number of new gene alterations observed in healthy children of similar age.
The chemical therapeutics administered to the patients, however, are powerful, and while they are designed to keep cancer cells from proliferating and to induce cancer cell death, normal cells can also be affected.
"The therapies used to assist these children overcome ALL have the potential to cause genetic damage to many different cell populations in their rapidly growing bodies," Finette said. "Because they have larger numbers of replicating cell populations during their growth and development stages than adults have, they are more susceptible than adults to effects of the chemotherapies genotoxicity."
ALL is the most common pediatric malignancy, but many ALL patients respond well to chemotherapeutic interventions. Since the 1960s, the five-year survival rate for children with ALL has increased to almost 80 percent. Patient remission and long-term survival is credited to the development of national standardized chemotherapeutic treatment protocols. More than 70 percent of ALL children less than 20 years of age, and 85 percent of children less than 15 years old participate in the standardized ALL chemotherapy treatment regimes.
"Because of the effectiveness of the treatment employed today, we are able to give many more children a chance for a long life without cancer," Finette said. "Our studies are aimed at enabling us to better understand further challenges that we may face in keeping these patients healthy as they get 10, 15 or more years out from overcoming ALL."