Gene mutation protects against cancer-related cognitive impairment
A single nucleotide polymorphism (SNP) in the BDNF (brain-derived neurotrophic factor) gene that converts valine to methionine at codon 66 (Val66Met) appears to protect against global subjective cancer-related cognitive impairment (CRCI), according to a recent Singapore study.
“As cancer- and treatment-related toxicities such as CRCI have been shown to have a devastating impact on cancer survivors, prediction models to estimate the risk of these toxicities should be established and tested for clinical use, so that survivors at risk can be targeted at an earlier stage for interventional measures to improve their daily functioning and quality of life,” said researchers, adding that genetic markers such as the BDNF Val66Met could contribute to this end.
In 193 breast cancer patients (mean age 51.9±8.9 years) included in the study, majority (52.3 percent) were positive for the Val66Met polymorphism. In comparison, 26.9 percent and 20.7 percent had the Val/Val and Met/Met genotypes, respectively. [Mol Neurobiol 2018;doi:10.1007/s12035-018-1410-4]
In terms of cognitive impairment, 31.1 percent (n=60) of the patients reported subjective CRCI. Decline in the domains of mental acuity (28.5 percent), concentration (28.0 percent), multitasking (25.9 percent), verbal ability (20.2 percent), functional interference (19.2 percent) and memory (17.9 percent) were the most common.
“After adjusting for potential confounders including anxiety and fatigue, Met allele carriers showed a consistent trend of decreasing odds of subjective CRCI across all domains,” said researchers.
However, statistical significance was achieved only in the domains of memory (odds ratio [OR], 0.24; 95 percent CI, 0.09–0.61; p=0.003), multitasking (OR, 0.30; 0.14–0.67; p=0.003) and mental acuity (OR, 0.46; 0.21–0.99; p=0.047).
The SNP had no such effect for the total subjective cognitive impairment score, and for the domains of verbal ability, concentration and functional interference. There was likewise no impact on any of the measures of objective cognitive impairment.
Researchers then performed a meta-analysis combining the present cohort with a previous, temporally separate group of breast cancer patients (n=145; mean age 50.7±8.8 years) and found similar trends. [Neurooncology 2016;18:244-251]
Particularly, those carrying the Val66Met genotype were significantly less likely to develop CRCI in the domains of memory (OR, 0.34; 0.17–0.70; p=0.003), multitasking (OR, 0.33; 0.18–0.59; p<0.001) and verbal ability (OR, 0.46; 0.24–0.88; p=0.02).
“[W]e postulate that the protective effect of BDNF Val66Met polymorphism on cognitive impairment is conditional on the presence of active malignancy or ongoing cancer treatment, both of which have been hypothesized as possible causes of CRCI,” researchers argued, pointing out that thus far, the only studies on this SNP have been in healthy individuals and have reported no significant associations. [Neurobiol Aging 2013;34:2457-2464]
That there is a lack of consonance between the subjective and objective measures of CRCI is unfortunate, but common, they continued. This may be because of other chemotherapy-related psychological sequelae, such as anxiety and depression, that can complicate the interactions.
“One may therefore speculate that BDNF Val66Met polymorphism may be protective against these accompanying symptoms rather than CRCI, explaining the lack of agreement between the association of BDNF polymorphism with objective and subjective CRCI observed in our study.”
Future studies should therefore seek to clarify the relationships among these factors, as well as elucidate the biological mechanisms that link the BDNF polymorphism to CRCI, said researchers.
“Augmented with more findings from gene and protein expression studies, this work will contribute to current knowledge on the biochemical pathways that are involved with the development of CRCI. This allows us to identify potential drug targets, which can be further screened for candidates of pharmacological interventions to attenuate the negative impact of CRCI among cancer patients,” they added.