title: Charcot-Marie-Tooth gene, SBF2, associated with taxane-induced peripheral neuropathy in African Americans.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  Rare variants in SBF2, a CMT gene, predict an increased risk of TIPN in AA patients receiving paclitaxel.
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Bryan P
authors.initials: BP
authors.lastname: Schneider
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Dongbing
authors.initials: D
authors.lastname: Lai
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Shen
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Guanglong
authors.initials: G
authors.lastname: Jiang
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Milan
authors.initials: M
authors.lastname: Radovich
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Lang
authors.initials: L
authors.lastname: Li
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Gardner
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Kathy D
authors.initials: KD
authors.lastname: Miller
authors.affiliation: Dana Farber Cancer Institute, ECOG-ACRIN Biostatistics Center, Boston, Massachusetts, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: O'Neill
authors.affiliation: Albert Einstein University, Montefiore Medical Center, Bronx, New York, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Sparano
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Gloria
authors.initials: G
authors.lastname: Xue
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
authors.affiliation: Stanford University School of Medicine, Stanford, California, USA.
authors.forename: George W
authors.initials: GW
authors.lastname: Sledge
mesh_terms: D001741:Black or African American / Q000235:genetics*; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000208:ethnology; D017024:Chemotherapy, Adjuvant; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D017239:Paclitaxel / Q000009:adverse effects*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics*; D012307:Risk Factors; D000073359:Exome Sequencing
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C475072:SBF2 protein, human; D017239:Paclitaxel
keywords: African American; SBF2; paclitaxel; peripheral neuropathy; whole exome sequencing