Charcot-Marie-Tooth gene, SBF2, associated with taxaneinduced peripheral neuropathy in African Americans

Bryan P. Schneider, Dongbing Lai, Fei Shen, Guanglong Jiang, Milan Radovich, Lang Li, Laura Gardner, Kathy D. Miller, Anne O'Neill, Joseph A. Sparano, Gloria Xue, Tatiana Foroud, George W. Sledge

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)82244-82253
Number of pages10
JournalOncotarget
Volume7
Issue number50
DOIs
StatePublished - Jan 1 2016

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Keywords

  • African American
  • Paclitaxel
  • Peripheral neuropathy
  • SBF2
  • Whole exome sequencing

ASJC Scopus subject areas

  • Oncology

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