Abstract
PurposeTaxane-induced peripheral neuropathy (TIPN) is one of the most important survivorship issues for cancer patients. African Americans (AA) have previously been shown to have an increased risk for this toxicity. Germline predictive biomarkers were evaluated to help identify a priori which patients might be at extraordinarily high risk for this toxicity.Experimental designWhole exome sequencing was performed using germline DNA from 213 AA patients who received a standard dose and schedule of paclitaxel in the adjuvant, randomized phase III breast cancer trial, E5103. Cases were defined as those with either grade 3-4 (n=64) or grade 2-4 (n=151) TIPN and were compared to controls (n=62) that were not reported to have experienced TIPN. We retained for analysis rare variants with a minor allele frequency <3% and which were predicted to be deleterious by protein prediction programs. A gene-based, case-control analysis using SKAT was performed to identify genes that harbored an imbalance of deleterious variants associated with increased risk of TIPN.ResultsFive genes had a p-value < 10−4 for grade 3-4 TIPN analysis and three genes had a p-value < 10−4 for the grade 2-4 TIPN analysis. For the grade 3-4 TIPN analysis, SET binding factor 2 (SBF2) was significantly associated with TIPN (p-value=4.35 x10−6). Five variants were predicted to be deleterious in SBF2. Inherited mutations in SBF2 have previously been associated with autosomal recessive, Type 4B2 Charcot-Marie-Tooth (CMT) disease.ConclusionRare variants in SBF2, a CMT gene, predict an increased risk of TIPN in AA patients receiving paclitaxel.
Highlights
The taxanes are commonly employed chemotherapeutic agents for a variety of malignancies. [1] While improving disease-specific outcomes, they can impart substantial morbidity
Five variants were predicted to be deleterious in SET binding factor 2 (SBF2)
Inherited mutations in SBF2 have previously been associated with autosomal recessive, Type 4B2 Charcot-Marie-Tooth (CMT) disease
Summary
The taxanes are commonly employed chemotherapeutic agents for a variety of malignancies. [1] While improving disease-specific outcomes, they can impart substantial morbidity. The taxanes are commonly employed chemotherapeutic agents for a variety of malignancies. [1] While improving disease-specific outcomes, they can impart substantial morbidity. There are no agents that have been proven to prevent this toxicity and very few have demonstrated benefit in improving symptoms after the toxicity has occurred.[3] Several demographic variables have been shown to increase the risk of TIPN, including: older www.impactjournals.com/oncotarget age, obesity, and the dose and schedule of the taxane.[4] Previously, we found that patients who were genetically defined as African American (AA) had a markedly increased risk for both moderate (grade 2-4) and severe (grade 3-4) TIPN.[5] Despite these findings, much ambiguity remains as to which patients might be at the highest risk for TIPN. Understanding which AA patients might be at exceptional risk would be beneficial for proper counseling and therapeutic decision-making when considering the risk to benefit ratio for a specific clinical scenario
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