Childhood Leukemia Survivors Risk Genetic Damage from Therapy

Newswise — Children who undergo chemotherapy and survive acute lymphocytic leukemia (ALL) experience a 200-fold increase in the frequency of genetic damage, researchers from the University of Vermont (UVM) College of Medicine reported in the July 1 issue of the journal Cancer Research.

According to Barry A. Finette, M.D., Ph.D., a professor of pediatrics at the UVM College of Medicine and Vermont Cancer Center member, the genetic changes that occur within the children's chromosomes following chemotherapy may elevate their risk for developing new cancers and other diseases later in life.

"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, 10, 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 five to 20 times' greater risk of developing new cancers, 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 times they were diagnosed until after they had completed their treatments. The treatment for ALL consists of a three-phase treatment that lasts about three years. The researchers estimated how frequently chemotherapy altered the DNA sequence by examining the number of T cells - a type of immune cell - in the patients' blood that contained mutations in the HPRT reporter gene. The HPRT reporter gene is a non-essential gene involved with DNA metabolism that is located on the X chromosome. It is often analyzed in the study of mutational events in humans.

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. By the time the patients completed the second 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 frequency of genetic mutations seen in children treated for ALL patients increased over the course of their treatments.

"These therapies 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 genetically toxic effects of the chemotherapies."

ALL is the most common childhood cancer, but most 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."

In addition to Finette, the senior investigator of the study at UVM, other investigators included Sederick Rice, Ph.D., a 2004 UVM doctoral degree recipient who led the study; Pamela Vacek, Ph.D., biostatistician in medical biostatistics and research assistant professor of pathology; Alan Homans, M.D., associate professor of pediatrics; Terri Messier, senior researcher in the Vermont Cancer Center; Jami Rivers, formerly of the Vermont Cancer Center; and Heather Kendall, a graduate student in the department of microbiology and molecular genetics.