title: Pharmacoethnicity in Paclitaxel-Induced Sensory Peripheral Neuropathy.
abstract: OBJECTIVE
  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.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Heather E
authors.initials: HE
authors.lastname: Wheeler
authors.affiliation: 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.
authors.forename: Suyoun
authors.initials: S
authors.lastname: Chung
authors.affiliation: 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.
authors.forename: Siew-Kee
authors.initials: SK
authors.lastname: Low
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Claudia
authors.initials: C
authors.lastname: Wing
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Delaney
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Lidija K
authors.initials: LK
authors.lastname: Gorsic
authors.affiliation: Laboratory for Statistical Analysis, Core for Genomic Medicine, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: Laboratory for Genotyping Development, Core for Genomic Medicine, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, School of Pharmacy and Medicine, University of California, San Francisco, San Francisco, California.
authors.forename: Deanna L
authors.initials: DL
authors.lastname: Kroetz
authors.affiliation: Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. edolan@medicine.bsd.uchicago.edu.
authors.forename: M Eileen
authors.initials: ME
authors.lastname: Dolan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D053487:DEAD-box RNA Helicases / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology; D009363:Neoplasm Proteins / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017239:Paclitaxel / Q000009:adverse effects* / Q000494:pharmacology; D010523:Peripheral Nervous System Diseases / Q000209:etiology*; D010597:Pharmacogenetics / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D051562:Proto-Oncogene Proteins c-bcr / Q000235:genetics
chemical_list: C403625:AIPL1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000972:Antineoplastic Agents, Phytogenic; D002352:Carrier Proteins; D005136:Eye Proteins; D009363:Neoplasm Proteins; D051562:Proto-Oncogene Proteins c-bcr; C473285:DDX54 protein, human; D053487:DEAD-box RNA Helicases; D017239:Paclitaxel