Charcot-Marie-Tooth gene, SBF2, associated with taxane-induced peripheral neuropathy in African Americans
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Bryan P. Schneider1,*, Dongbing Lai1,*, Fei Shen1,*, Guanglong Jiang1, Milan Radovich1, Lang Li1, Laura Gardner1, Kathy D. Miller1, Anne O’Neill2, Joseph A. Sparano3, Gloria Xue1, Tatiana Foroud1,** and George W. Sledge Jr4,**
1 Indiana University School of Medicine, Indianapolis, Indiana, USA
2 Dana Farber Cancer Institute, ECOG-ACRIN Biostatistics Center, Boston, Massachusetts, USA
3 Albert Einstein University, Montefiore Medical Center, Bronx, New York, USA
4 Stanford University School of Medicine, Stanford, California, USA
* These authors have contributed equally to this work
** These authors have contributed equally to this work
Bryan P. Schneider, email:
Keywords: whole exome sequencing, African American, paclitaxel, peripheral neuropathy, SBF2
Received: August 29, 2016 Accepted: September 18, 2016 Published: October 09, 2016
Purpose: Taxane-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 design: Whole 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.
Results: Five 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.
Conclusion: Rare variants in SBF2, a CMT gene, predict an increased risk of TIPN in AA patients receiving paclitaxel.
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