Some children who are treated for acute lymphoblastic leukemia (ALL) develop brain impairments, and the risk of this happening may be linked to certain genes.
ALL is the most common cancer in childhood and about 90 percent of patients survive. But the treatment, which usually includes chemotherapy and can include cranial radiation, may trigger long-term problems with memory, learning or other cognitive functions.
Memory impairment is a particularly debilitating symptom, because of the central role memory plays in daily life and academic or occupational success.
Now, Deborah Waber, Ph.D, and colleagues at Boston Children’s Hospital, Massachusetts, U.S., have found four specific gene variants that appear to raise the risk. These variants are related to brain inflammation and cells’ response to damage from oxidative stress, such as cellular damage caused by chemotherapy.
They made the discovery using stored blood samples and cognitive function test results on 350 ALL survivors from the U.S. and Canada. The cognitive tests included IQ, memory, attention span, and hyperactivity behaviors.
The four highlighted genes, NOS3, SLCO2A1, HFE, and COMT, were among a group of 28 genes investigated due to their roles in drug metabolism or cellular damage responses.
Specific variants of these four were “significantly associated with neurocognitive effects,” the team reports. All are involved in pathways regulating inflammation in the brain or protect cells from oxidative stress.
Waber said, “Our goal is to be able to identify who is at risk for cognitive late effects and provide neuroprotective interventions. 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.”
Findings from the study were presented at the 56th annual meeting of the American Society of Hematology, held in December 2014. The team hopes it will become possible to genomically screen ALL patients for their risk of long-term memory, attention, and learning effects.
Lead author, Peter Cole, M.D., said, “The more we look, the more we find that many survivors experience changes in how they think. If we give all ALL patients the same treatment, why is it that some of them experience memory or cognitive deficits, but not all of them?
“We limited ourselves to variants that are present in at least 10 percent of the population, deciding that we were interested in explaining what could be happening in most patients.”
Despite the significant findings, Cole adds that further work must be done to confirm the role of the four genes. A prospective study, in which patients’ genes are tested in advance of treatment, would provide more reliable evidence.
In addition, any protective interventions must undergo preclinical and clinical testing to ensure the success of treatment is not compromised.
Co-author Lewis Silverman, M.D., said, “A major ongoing priority in childhood ALL clinical research is to reduce the toxicity of treatment, and certainly we want to reduce neurocognitive late effects if possible.
“Hopefully this work will lead to a way to identify those patients at highest risk of neurocognitive late effects in whom we can focus our research efforts, adjusting our treatment approach or testing novel protective strategies with the goal of reducing the effects without adversely impacting the chance for cure.”
Waber added that her work on the brain impact of ALL treatment spans ten collaborating institutions in North America. Her early studies highlighted a significant cognitive impact among children treated successfully for ALL, and showed “a dramatic sex difference, with females being far more vulnerable to toxicity.”
Pediatric oncologists have long sought less toxic therapies. “Dose reduction or elimination of cranial radiation has resulted in a significant improvement in cognitive outcomes, particularly for females,” Waber said.
Current work is focused on the particular brain areas that show the greatest damage. Waber said, “The hippocampus is central to episodic memory encoding and is exquisitely vulnerable to chemotherapy and radiotherapy.”
Deficits in memory encoding and learning, working memory, attention, information processing speed, and visuospatial skills “localize neuroanatomically in the hippocampus in the medial temporal lobes and the frontal lobes.”
Radiation and chemotherapy damage hippocampal neural stem cells and precursor cells, hindering their renewal and holding back myelination, the vital process in which brain cells grow an insulating sheath that speeds up brain signals, not fully complete until about age 30. These changes have been seen in postmortems of individuals treated for primary brain tumors and leukemia.
“Taken together,” Waber concluded, “these findings provide a functional and structural basis for some of the cognitive symptoms experienced by survivors of childhood leukemia.”
Trial reported at the 56th annual meeting American Society of Hematology annual meeting, held from 6-9 December 2014, at the Moscone Center, San Francisco, CA.