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

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)4337-4346
Number of pages10
JournalClinical Cancer Research
Volume21
Issue number19
DOIs
Publication statusPublished - 01-10-2015

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Peripheral Nervous System Diseases
Paclitaxel
Genome-Wide Association Study
Genes
Neurites
Cell Line
Overlapping Genes
HapMap Project
Neurons
Induced Pluripotent Stem Cells
Pharmacogenetics
Ovarian Neoplasms
Single Nucleotide Polymorphism
Breast
Lung

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Komatsu, M., Wheeler, H. E., Chung, S., Low, S. K., Wing, C., Delaney, S. M., ... 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
Komatsu, Masaaki ; Wheeler, Heather E. ; Chung, Suyoun ; Low, Siew Kee ; Wing, Claudia ; Delaney, Shannon M. ; Gorsic, Lidija K. ; Takahashi, Atsushi ; Kubo, Michiaki ; Kroetz, Deanna L. ; Zhang, Wei ; Nakamura, Yusuke ; Dolan, M. Eileen. / Pharmacoethnicity in paclitaxel-induced sensory peripheral neuropathy. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 19. pp. 4337-4346.
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abstract = "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.",
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Komatsu, M, Wheeler, HE, Chung, S, Low, SK, Wing, C, Delaney, SM, Gorsic, LK, Takahashi, A, Kubo, M, Kroetz, DL, Zhang, W, Nakamura, Y & Dolan, ME 2015, 'Pharmacoethnicity in paclitaxel-induced sensory peripheral neuropathy', Clinical Cancer Research, vol. 21, no. 19, pp. 4337-4346. https://doi.org/10.1158/1078-0432.CCR-15-0133

Pharmacoethnicity in paclitaxel-induced sensory peripheral neuropathy. / Komatsu, Masaaki; Wheeler, Heather E.; Chung, Suyoun; Low, Siew Kee; Wing, Claudia; Delaney, Shannon M.; Gorsic, Lidija K.; Takahashi, Atsushi; Kubo, Michiaki; Kroetz, Deanna L.; Zhang, Wei; Nakamura, Yusuke; Dolan, M. Eileen.

In: Clinical Cancer Research, Vol. 21, No. 19, 01.10.2015, p. 4337-4346.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Pharmacoethnicity in paclitaxel-induced sensory peripheral neuropathy

AU - Komatsu, Masaaki

AU - Wheeler, Heather E.

AU - Chung, Suyoun

AU - Low, Siew Kee

AU - Wing, Claudia

AU - Delaney, Shannon M.

AU - Gorsic, Lidija K.

AU - Takahashi, Atsushi

AU - Kubo, Michiaki

AU - Kroetz, Deanna L.

AU - Zhang, Wei

AU - Nakamura, Yusuke

AU - Dolan, M. Eileen

PY - 2015/10/1

Y1 - 2015/10/1

N2 - 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.

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Komatsu M, Wheeler HE, Chung S, Low SK, Wing C, Delaney SM et al. Pharmacoethnicity in paclitaxel-induced sensory peripheral neuropathy. Clinical Cancer Research. 2015 Oct 1;21(19):4337-4346. https://doi.org/10.1158/1078-0432.CCR-15-0133