Targeted Sequencing Reveals Low-Frequency Variants in EPHA Genes as Markers of Paclitaxel-Induced Peripheral Neuropathy.
Clin Cancer Res
; 23(5): 1227-1235, 2017 Mar 01.
Article
in En
| MEDLINE
| ID: mdl-27582484
ABSTRACT
Purpose:
Neuropathy is the dose-limiting toxicity of paclitaxel and a major cause for decreased quality of life. Genetic factors have been shown to contribute to paclitaxel neuropathy susceptibility; however, the major causes for interindividual differences remain unexplained. In this study, we identified genetic markers associated with paclitaxel-induced neuropathy through massive sequencing of candidate genes.ExperimentalDesign:
We sequenced the coding region of 4 EPHA genes, 5 genes involved in paclitaxel pharmacokinetics, and 30 Charcot-Marie-Tooth genes, in 228 cancer patients with no/low neuropathy or high-grade neuropathy during paclitaxel treatment. An independent validation series included 202 paclitaxel-treated patients. Variation-/gene-based analyses were used to compare variant frequencies among neuropathy groups, and Cox regression models were used to analyze neuropathy along treatment.Results:
Gene-based analysis identified EPHA6 as the gene most significantly associated with paclitaxel-induced neuropathy. Low-frequency nonsynonymous variants in EPHA6 were present exclusively in patients with high neuropathy, and all affected the ligand-binding domain of the protein. Accumulated dose analysis in the discovery series showed a significantly higher neuropathy risk for EPHA5/6/8 low-frequency nonsynonymous variant carriers [HR, 14.60; 95% confidence interval (CI), 2.33-91.62; P = 0.0042], and an independent cohort confirmed an increased neuropathy risk (HR, 2.07; 95% CI, 1.14-3.77; P = 0.017). Combining the series gave an estimated 2.5-fold higher risk of neuropathy (95% CI, 1.46-4.31; P = 9.1 × 10-4).Conclusions:
This first study sequencing EPHA genes revealed that low-frequency variants in EPHA6, EPHA5, and EPHA8 contribute to the susceptibility to paclitaxel-induced neuropathy. Furthermore, EPHA's neuronal injury repair function suggests that these genes might constitute important neuropathy markers for many neurotoxic drugs. Clin Cancer Res; 23(5); 1227-35. ©2016 AACR.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Paclitaxel
/
Peripheral Nervous System Diseases
/
Receptor, EphA5
/
Receptor, EphA6
/
Receptor, EphA8
Type of study:
Prognostic_studies
Aspects:
Patient_preference
Limits:
Adult
/
Aged
/
Female
/
Humans
/
Middle aged
Language:
En
Journal:
Clin Cancer Res
Journal subject:
NEOPLASIAS
Year:
2017
Document type:
Article
Affiliation country:
Spain