Liability of the voltage‐gated potassium channel KCNN3 repeat polymorphism to acute oxaliplatin‐induced peripheral neurotoxicity

Abstract

Thus far, there are conflicting results on the causal role of K+ channels in the pathogenesis of acute oxaliplatin‐induced peripheral neurotoxicity (OXAIPN). As such, we tested the hypothesis that the voltage‐gated K+ channel KCNN3 repeat polymorphism confers liability to acute OXAIPN. DNA from 151 oxaliplatin‐treated patients for colorectal cancer was extracted and genotyped. The incidence of acute OXIPN was measured by the OXA‐neuropathy questionnaire, while the severity of acute OXAIPN was scored basing on the number of symptoms reported by the patients at each clinical assessment. The increased number of acute symptoms was considered as being suggestive of an increased severity of acute OXAIPN. A total of 130/151 (86.1%) patients developed any grade of acute OXAIPN. Grade I acute neurotoxicity was revealed in 43 (28.5%) patients; grade II in 34 (22.5%); and grade III in 53 (53.1%) patients. Genotyping revealed alleles carrying 11 to 20 CAG repeats. The majority of patients were heterozygous (131; 89.4%). The most common numbers of CAG repeats were 15 (n = 46), 16 (n = 53), and 17 (n = 95). Patients carrying alleles with either 15 to 17 CAG repeats (P = .601) did not experience a higher incidence of grade III (treatment‐emergent) acute OXAIPN. Likewise, no increased incidence of acute treatment‐emergent OXAIPN was noted in heterozygous patients carrying either two short alleles (<19 CAG repeats) or one short and one long (≥19 CAG repeats) allele (P = .701). Our results do not support a causal relationship between the KCNN3CAG repeat polymorphism and acute OXΑIPN.

Oxaliplatin, neurotoxicity, and the search for the lost channel

“…We read with interest the paper by Argyriou et al, 1 in which authors attempted to reproduce the results of a previous study conducted at our Institution, 2 regarding a possible association between acute oxaliplatin-related neurotoxicity and a short CAG-repeats polymorphism of KCNN3 channel.…”

“…Moreover, authors set a cut-off point of 19 CAG repeats to distinguish long alleles and short alleles, but only 6% of patients had a long allele. 1 What is the meaning of a statistical analysis in which most patients (94%) were grouped together and compared to the remaining 6%? May be it could make sense (but we have lot of doubts on statistical power) if you suspect a higher incidence of neurotoxicity in those patients (6%) carrying a longer allele.…”

Voltage‐gated sodium channel dysfunction and the search for other satellite channels in relation to acute oxaliplatin‐induced peripheral neurotoxicity

“…There is no gold standard clinical assessment for CIPN or specifically for acute OXAIPN. In our study, 1 This approach may also be problematic due to the extremely high incidence of patients who demonstrate neurophysiological abnormalities following oxaliplatin treatment, leading to ceiling effects.…”

“…The main message of the Modoni and Basso letter is that their previously published study, which showed a positive association between KCNN3 CAG repeat polymorphisms and increased risk of acute OXAIPN 2 is not comparable to our study, which failed to reproduce these results. 1 Identification of robust genetic risk factors that influence susceptibility to OXAIPN is critical in order to identify patients at risk prior to chemotherapy administration and enable tailored treatment approaches to minimize toxicity. To date, there have been difficulties in identifying genetic variants consistently associated with neurotoxicity risk across different patient cohorts.…”

“…4 While we acknowledge methodological differences that may account for some of the discrepancies in results between studies, we definitely cannot concur with the suggestion by Modoni and Basso that findings are not able to be compared between our studies. 1,2 A key area of difference between the studies is in the selection of outcome measures. There is no gold standard clinical assessment for CIPN or specifically for acute OXAIPN.…”