Association of the Charcot-Marie-Tooth disease gene ARHGEF10 with paclitaxel induced peripheral neuropathy in NCCTG N08CA (Alliance)

Ganesh K. Boora, Amit A. Kulkarni, Rahul Kanwar, Peter Beyerlein, Rui Qin, Michaela S. Banck, Kathryn J. Ruddy, Josef Pleticha, Cynthia A. Lynch, Robert J. Behrens, Stephan L Zuchner, Charles L. Loprinzi, Andreas S. Beutler

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
JournalJournal of the Neurological Sciences
DOIs
StateAccepted/In press - 2015

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Charcot-Marie-Tooth Disease
Peripheral Nervous System Diseases
Paclitaxel
Drug Therapy
Nucleotides
Polyneuropathies
Genes
Poisons
Area Under Curve
Odds Ratio
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

Cite this

Association of the Charcot-Marie-Tooth disease gene ARHGEF10 with paclitaxel induced peripheral neuropathy in NCCTG N08CA (Alliance). / Boora, Ganesh K.; Kulkarni, Amit A.; Kanwar, Rahul; Beyerlein, Peter; Qin, Rui; Banck, Michaela S.; Ruddy, Kathryn J.; Pleticha, Josef; Lynch, Cynthia A.; Behrens, Robert J.; Zuchner, Stephan L; Loprinzi, Charles L.; Beutler, Andreas S.

In: Journal of the Neurological Sciences, 2015.

Research output: Contribution to journalArticle

Boora, GK, Kulkarni, AA, Kanwar, R, Beyerlein, P, Qin, R, Banck, MS, Ruddy, KJ, Pleticha, J, Lynch, CA, Behrens, RJ, Zuchner, SL, Loprinzi, CL & Beutler, AS 2015, 'Association of the Charcot-Marie-Tooth disease gene ARHGEF10 with paclitaxel induced peripheral neuropathy in NCCTG N08CA (Alliance)', Journal of the Neurological Sciences. https://doi.org/10.1016/j.jns.2015.06.056
Boora, Ganesh K. ; Kulkarni, Amit A. ; Kanwar, Rahul ; Beyerlein, Peter ; Qin, Rui ; Banck, Michaela S. ; Ruddy, Kathryn J. ; Pleticha, Josef ; Lynch, Cynthia A. ; Behrens, Robert J. ; Zuchner, Stephan L ; Loprinzi, Charles L. ; Beutler, Andreas S. / Association of the Charcot-Marie-Tooth disease gene ARHGEF10 with paclitaxel induced peripheral neuropathy in NCCTG N08CA (Alliance). In: Journal of the Neurological Sciences. 2015.
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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.",
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AU - Kulkarni, Amit A.

AU - Kanwar, Rahul

AU - Beyerlein, Peter

AU - Qin, Rui

AU - Banck, Michaela S.

AU - Ruddy, Kathryn J.

AU - Pleticha, Josef

AU - Lynch, Cynthia A.

AU - Behrens, Robert J.

AU - Zuchner, Stephan L

AU - Loprinzi, Charles L.

AU - Beutler, Andreas S.

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