Common Genetic Variations May Contribute to Treatment-related Cognitive Problems in Children with Leukemia
December 09, 2014
variations may contribute to treatment-related cognitive problems in children
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
(ALL), according to a study 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.
data, presented in San Francisco at the 56th annual meeting of the
American Society of Hematology (abstract #856), suggest that it may be possible
to genomically screen ALL patients for their risk of long-term
treatment-related effects on memory, attention and learning and to study
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 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."
is the most common childhood cancer, with survival rates of around 90 percent. ALL patients receive chemotherapy to the
central nervous system, and some receive cranial radiation, in order to
eliminate cancer cells that can lurk in the brain and raise their risk of
relapse. ALL survivors often experience problems with persisting
attention, memory and learning, which have been documented by neurocognitive
studies conducted in the years after completion of curative treatment.
more we look, the more we find that many survivors experience changes in how
they think," said study lead author Peter Cole, MD, a pediatric
hematologist/oncologist at The Children’s Hospital at Montefiore and associate
professor of pediatrics at Albert Einstein College of Medicine of Yeshiva
University. The variability in these
changes, he added, raises an interesting question: "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?"
determine whether inherited genetic variations might have roles to play, the
research team gathered stored blood samples and cognitive function test data
(e.g., 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, 95-01 (1996-2000) or 00-01
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.
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," Cole said.
controlling for factors such as age at diagnosis, sex, socioeconomic status and
whether the child received 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.
researchers note that the retrospective nature of the study means they cannot
prove that the gene variants themselves increased patients' risk of poor
neurocognitive outcomes. They are now conducting prospective studies to try to
establish that link. Any potential protective interventions would also need to
undergo preclinical and clinical testing to rule out the risk of interactions
that could negatively impact a patient's likelihood of being cured.
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," said Lewis Silverman, MD, clinical director
of the Hematologic Malignancy Center at Dana-Farber/Boston Children's,
principal investigator of the DFCI ALL Consortium clinical trials group, and a
co-author on the study. "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 neurocognitive late
effects without adversely impacting the chance for cure."