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Clin Cancer Res. 2015 Oct 1;21(19):4337-46. doi: 10.1158/1078-0432.CCR-15-0133. Epub 2015 May 26.

Pharmacoethnicity in Paclitaxel-Induced Sensory Peripheral Neuropathy.

Author information

1
Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
2
Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. Division of Cancer Development System, National Cancer Center Research Institute, Tokyo, Japan.
3
Laboratory for Statistical Analysis, Core for Genomic Medicine, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
4
Laboratory for Statistical Analysis, Core for Genomic Medicine, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
5
Laboratory for Genotyping Development, Core for Genomic Medicine, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
6
Department of Bioengineering and Therapeutic Sciences, School of Pharmacy and Medicine, University of California, San Francisco, San Francisco, California.
7
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
8
Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
9
Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. edolan@medicine.bsd.uchicago.edu.

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.

PMID:
26015512
PMCID:
PMC4592389
DOI:
10.1158/1078-0432.CCR-15-0133
[Indexed for MEDLINE]
Free PMC Article

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