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.

Targeted Sequencing Reveals Low-Frequency Variants in EPHA Genes as Markers of Paclitaxel-Induced Peripheral Neuropathy

“…We did not find low frequency variants in PRX and common variants in ARHGEF10 associated with paclitaxel-induced neuropathy, although the 2 nd and 3 rd top protective genes were these two, similarly to Beutler et al For the ARHGEF10 common variant rs9657362 we also found a trend towards protection (20,45). We also observed a trend towards increased neuropathy risk for other CMT genes (SEPT9 and SH3TC2).…”

National Cancer Institute-supported chemotherapy-induced peripheral neuropathy trials: outcomes and lessons

“…Next-gen genomic DNA sequencing associated Charcot-Marie-Tooth disease (hereditary neuropathy) related genes to CIPN in the N08C1 study [50]. Importantly, key results could be retested in N08CA, in which the same PRO-based CIPN phenotyping had been performed, validating the lead finding [51]. A literature review on taxane-associated neuropathy single nucleotide polymorphisms (SNPs) was conducted, and then a validation study was conducted in samples from the N08C1 paclitaxel neuropathy natural history trial; a manuscript describing these findings is currently under review (Beutler, personal communication, October 2015).…”

Future cancer research priorities in the USA: a Lancet Oncology Commission

“…Basic science studies of genetic predisposition to toxic effects and pharmacogenetics are needed. Achievements to date include an understanding of the genomic basis for aromatase-associated arthralgias 189,190 and associated chemotherapy-induced peripheral neuropathy. 191 Additional funding is needed for translational studies that bridge laboratory data to treatment in the clinic and home and for clinical trials to investigate drug mechanisms and evaluate potential therapies in patients.…”