Pharmacoethnicity in paclitaxel-induced sensory peripheral neuropathy

Masaaki Komatsu, Heather E. Wheeler, Suyoun Chung, Siew Kee Low, Claudia Wing, Shannon M. Delaney, Lidija K. Gorsic, Atsushi Takahashi, Michiaki Kubo, Deanna L. Kroetz, Wei Zhang, Yusuke Nakamura, M. Eileen Dolan

研究成果: Article

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Purpose: Paclitaxel is used worldwide in the treatment of breast, lung, ovarian, and other cancers. Sensory peripheral neuropathy is an associated adverse effect that cannot be predicted, prevented, or mitigated. To better understand the contribution of germline genetic variation to paclitaxel-induced peripheral neuropathy, we undertook an integrative approach that combines genome-wide association study (GWAS) data generated from HapMap lymphoblastoid cell lines (LCL) and Asian patients. Methods: GWAS was performed with paclitaxel-induced cytotoxicity generated in 363 LCLs and with paclitaxel-induced neuropathy from 145 Asian patients. A gene-based approach was used to identify overlapping genes and compare with a European clinical cohort of paclitaxel-induced neuropathy. Neurons derived from human-induced pluripotent stem cells were used for functional validation of candidate genes. Results: SNPs near AIPL1 were significantly associated with paclitaxel-induced cytotoxicity in Asian LCLs (P < 10-6). Decreased expression of AIPL1 resulted in decreased sensitivity of neurons to paclitaxel by inducing neurite morphologic changes as measured by increased relative total outgrowth, number of processes and mean process length. Using a gene-based analysis, there were 32 genes that overlapped between Asian LCL cytotoxicity and Asian patient neuropathy (P < 0.05), including BCR. Upon BCR knockdown, there was an increase in neuronal sensitivity to paclitaxel as measured by neurite morphologic characteristics. Conclusions: We identified genetic variants associated with Asian paclitaxel-induced cytotoxicity and functionally validated the AIPL1 and BCR in a neuronal cell model. Furthermore, the integrative pharmacogenomics approach of LCL/patient GWAS may help prioritize target genes associated with chemotherapeutic-induced peripheral neuropathy.

元の言語English
ページ(範囲)4337-4346
ページ数10
ジャーナルClinical Cancer Research
21
発行部数19
DOI
出版物ステータスPublished - 01-10-2015

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

フィンガープリント Pharmacoethnicity in paclitaxel-induced sensory peripheral neuropathy' の研究トピックを掘り下げます。これらはともに一意のフィンガープリントを構成します。

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    Komatsu, M., Wheeler, H. E., Chung, S., Low, S. K., Wing, C., Delaney, S. M., Gorsic, L. K., Takahashi, A., Kubo, M., Kroetz, D. L., Zhang, W., Nakamura, Y., & Dolan, M. E. (2015). Pharmacoethnicity in paclitaxel-induced sensory peripheral neuropathy. Clinical Cancer Research, 21(19), 4337-4346. https://doi.org/10.1158/1078-0432.CCR-15-0133