Schneider Bryan P, Lai Dongbing, Shen Fei, Jiang Guanglong, Radovich Milan, Li Lang, Gardner Laura, Miller Kathy D, O'Neill Anne, Sparano Joseph A, Xue Gloria, Foroud Tatiana, Sledge George W
Indiana University School of Medicine, Indianapolis, Indiana, USA.
Dana Farber Cancer Institute, ECOG-ACRIN Biostatistics Center, Boston, Massachusetts, USA.
Oncotarget. 2016 Dec 13;7(50):82244-82253. doi: 10.18632/oncotarget.12545.
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.
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.
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.
Rare variants in SBF2, a CMT gene, predict an increased risk of TIPN in AA patients receiving paclitaxel.
紫杉烷诱导的周围神经病变（TIPN）是癌症患者最重要的生存问题之一。此前研究表明非裔美国人（AA）发生这种毒性反应的风险更高。对种系预测生物标志物进行评估，以帮助预先确定哪些患者可能发生这种毒性反应的风险极高。
在辅助性随机III期乳腺癌试验E5103中，使用213例接受标准剂量和疗程紫杉醇治疗的AA患者的种系DNA进行全外显子组测序。病例定义为发生3-4级（n=64）或2-4级（n=151）TIPN的患者，并与未报告发生TIPN的对照（n=62）进行比较。我们保留次要等位基因频率<3%且经蛋白质预测程序预测为有害的罕见变异进行分析。使用序列核关联检验（SKAT）进行基于基因的病例对照分析，以鉴定携带与TIPN风险增加相关的有害变异失衡的基因。
在3-4级TIPN分析中，5个基因的p值<10-4，在2-4级TIPN分析中，3个基因的p值<10-4。对于3-4级TIPN分析，SET结合因子2（SBF2）与TIPN显著相关（p值=4.35×10-6）。预测SBF2中有5个变异有害。此前SBF2的遗传性突变与常染色体隐性4B2型夏科-马里-图斯（CMT）病相关。
CMT基因SBF2中的罕见变异可预测接受紫杉醇治疗的AA患者发生TIPN的风险增加。
