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. 2020 Apr 15;411:116687.
doi: 10.1016/j.jns.2020.116687. Epub 2020 Jan 14.

Neurological Safety of Oxaliplatin in Patients With Uncommon Variants in Charcot-Marie-tooth Disease Genes

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Free PMC article

Neurological Safety of Oxaliplatin in Patients With Uncommon Variants in Charcot-Marie-tooth Disease Genes

Jennifer G Le-Rademacher et al. J Neurol Sci. .
Free PMC article

Abstract

Oxaliplatin therapy can be complicated by chemotherapy-induced peripheral neuropathy (CIPN). Other neurotoxic chemotherapies have been linked to single nucleotide variants (SNV) in Charcot-Marie-Tooth disease (CMT) genes. Whether oxaliplatin carries increased risks of CIPN due to SNV in CMT-associated genes is unknown. 353 patients receiving oxaliplatin in NCCTG N08CB were serially evaluated for CIPN using a validated patient-reported outcome (PRO) instrument, the CIPN20 questionnaire (sensory scale). 49 canonical CMT-associated genes were analyzed for rare and common SNV by nextgen sequencing. The 157 patients with the highest and lowest susceptibility to CIPN (cases and controls) harbored 270 non-synonymous SNV in CMT-associated genes (coding regions). 143 of these were rare, occurring only once ("singletons"). CIPN cases had 0.84 singletons per patient compared with 0.98 in controls. An imbalance in favor of cases was noted only in few genes including PRX, which was previously highlighted as a candidate CIPN gene in patients receiving paclitaxel. However, the imbalance was only modest (5 singleton SNV in cases and 2 in controls). Therefore, while singleton SNV were common, they did overall not portend an increased risk of CIPN. Furthermore, testing CMT-associated genes using recurrent non-synonymous SNV did not reveal any significant association with CIPN. Genetic analysis of patients from N08CB provides clinical guidance that oxaliplatin chemotherapy decisions should not be altered by the majority of SNV that may be encountered in CMT-associated genes when common genetic tests are performed, such as exome or genome sequencing. Oxaliplatin's CIPN risk appears unrelated to CMT-associated genes.

Keywords: Charcot-Marie-tooth disease; Chemotherapy; Hereditary; Neuropathy; Oxaliplatin; Risk factors.

Conflict of interest statement

Declaration of Competing Interest The authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.. Selection of OIPN cases and controls.
OIPN case- and control groups of equal sizes were selected by extreme phenotype sampling. A) A CONSORT diagram shows the selection of patients without OIPN (controls) and with OIPN (cases) identified by the rate of progression of OIPN symptoms with increasing cumulative oxaliplatin dose. Equal number of cases and controls were selected from the tail ends of the distribution of OIPN rates. Specifically, the OIPN rates were ordered by the upper bound of their rate confidence interval and the bottom 25% were taken as controls. Similarly, the cases were obtained by ordering the OIPN slopes by the lower bound of their CI and taking the top 25%. The red, blue, and grey colored points in the panel correspond to cases, controls and unselected patients. B) Two examples showing extreme CIPN20 phenotypes. The left graph shows the data from the sensory subscale of the CIPN20 questionnaire for a patient who did not develop OIPN throughout his/her 12 cycles of chemotherapy. The right graph shows the example of a patient who quickly developed the symptoms of OIPN and had to be taken off the drug after 6 cycles.
Figure 2.
Figure 2.. Uncommon (rare) “singleton” SNV found in cases (red) or controls (blue) across 49 canonical CMT-associated genes.
Genes are ordered according to the excess of mutations found in cases (top) to excess in controls (bottom).

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