title: Association of the Charcot-Marie-Tooth disease gene ARHGEF10 with paclitaxel induced peripheral neuropathy in NCCTG N08CA (Alliance).
abstract: The predisposition of patients to develop polyneuropathy in response to toxic exposure may have a genetic basis. The previous study Alliance N08C1 found an association of the Charcot-Marie-Tooth disease (CMT) gene ARHGEF10 with paclitaxel chemotherapy induced peripheral neuropathy (CIPN) related to the three non-synonymous, recurrent single nucleotide variants (SNV), whereby rs9657362 had the strongest effect, and rs2294039 and rs17683288 contributed only weakly. In the present report, Alliance N08CA was chosen to attempt to replicate the above finding. N08CA was chosen because it is the methodologically most similar study (to N08C1) performed in the CIPN field to date. N08CA enrolled patients receiving the neurotoxic chemotherapy agent paclitaxel. Polyneuropathy was assessed by serial repeat administration of the previously validated patient reported outcome instrument CIPN20. A study-wide, Rasch type model was used to perform extreme phenotyping in n=138 eligible patients from which "cases" and "controls" were selected for genetic analysis of SNV performed by TaqMan PCR. A significant association of ARHGEF10 with CIPN was found under the pre-specified primary endpoint, with a significance level of p=0.024. As in the original study, the strongest association of a single SNV was seen for rs9657362 (odds ratio=3.56, p=0.018). To further compare results across the new and the previous study, a statistical "classifier" was tested, which achieved a ROC area under the curve of 0.60 for N08CA and 0.66 for N08C1, demonstrating good agreement. Retesting of the primary endpoint of N08C1 in the replication study N08CA validated the association of ARHGEF10 with CIPN.
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ganesh K
authors.initials: GK
authors.lastname: Boora
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Amit A
authors.initials: AA
authors.lastname: Kulkarni
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Kanwar
authors.affiliation: Department of Diagnostic Bioinformatics, Technische Hochschule Wildau, Wildau, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Beyerlein
authors.affiliation: Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Qin
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Michaela S
authors.initials: MS
authors.lastname: Banck
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Ruddy
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Josef
authors.initials: J
authors.lastname: Pleticha
authors.affiliation: Guthrie Corning Cancer Center, Sayre, PA, USA.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Lynch
authors.affiliation: Iowa Wide Oncology Research Coalition, Des Moines, IA, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Behrens
authors.affiliation: Department of Human Genetics and Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Loprinzi
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN, USA. Electronic address: beutler.andreas@mayo.edu.
authors.forename: Andreas S
authors.initials: AS
authors.lastname: Beutler
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects; D016022:Case-Control Studies; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009154:Mutation; D017239:Paclitaxel / Q000009:adverse effects*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000235:genetics*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics*
chemical_list: C577232:ARHGEF10 protein, human; D000972:Antineoplastic Agents, Phytogenic; D064067:Rho Guanine Nucleotide Exchange Factors; D017239:Paclitaxel