Treatment-related cognitive issues in children with leukemia may have a genetic link

Common variations in four genes related to brain inflammation or cells' response to damage from oxidation may contribute to the problems with memory, learning, and other cognitive functions seen in children treated for acute lymphoblastic leukemia (ALL), according to a new study.

The study results suggest that genomic screening for long-term risk of treatment-related effects on memory, attention, and learning in patients treated for ALL, as well as potential interventions, may be possible. The data, led by researchers from Boston Children's Hospital, The Children's Hospital at Montefiore, and Dana-Farber/Boston Children's Cancer and Blood Disorders Center in Massachusetts, was presented at the 56th annual meeting of the American Society of Hematology in San Francisco, California.

"Our goal is to be able to identify who is at risk for cognitive late effects and provide neuroprotective interventions," said study senior author Deborah Waber, PhD, senior associate in psychiatry and director of the Learning Disabilities Program in Boston Children's Department of Neurology, who has spent 30 years studying the relationship between cognitive decline and ALL therapy, including cranial radiation and/or chemotherapy to the central nervous system.

"This retrospective analysis tells us that going forward we may wish to examine children's genotypes at baseline and conduct prospective research to learn why these specific gene variants may increase risk of toxicity."

ALL is the most common childhood cancer, with survival rates of approximately 90%. Patients with ALL receive chemotherapy to the central nervous system, and some undergo cranial radiation, to eliminate cancer cells that can lurk in the brain and increase their risk of relapse. ALL survivors often experience persisting problems with attention, memory, and learning, which have been documented by neurocognitive studies conducted in the years after completion of curative treatment.

"The more we look, the more we find that many survivors experience changes in how they think," said study lead author Peter Cole, MD. The variability in these changes, he added, raises an interesting question: If all patients with ALL undergo the same treatment, why do some of them experience memory or cognitive deficits, but not all of them?

To determine whether inherited genetic variations might have roles to play, the research team gathered stored blood samples and cognitive function test data (eg, IQ, memory, attention span, hyperactivity behaviors) on 350 ALL survivors treated at eight centers in the United States and Canada. All of the survivors had been treated on one of two consecutive Dana-Farber Cancer Institute ALL Consortium therapy protocols.

The researchers then examined each survivor's genome for common variants in 28 genes involved in drug metabolism or cellular damage responses, and then compared the results against the cognitive data.

"We limited ourselves to variants that are present in at least 10% of the population, deciding that we were interested in explaining what could be happening in most patients," Cole said.

After controlling for factors such as age at diagnosis, sex, socioeconomic status, and whether the child underwent radiation to the brain, the research team found that variants in four genes—NOS3, SLCO2A1, HFE and COMT—were significantly associated with neurocognitive effects. All four are members of pathways that regulate inflammation in the brain or protect cells from oxidative stress, a form of cellular damage caused by chemotherapy.

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