Jones Michael K, Nicklawsky Andrew, Shortt Jonathan, Pattee Jack, Kennerley Victoria, Eule Corbin J, Candelario Nellowe, O'Donnell Peter H, Flaig Thomas W
Internal Medicine Residency, University of Colorado School of Medicine, Aurora, CO, United States.
University of Colorado Cancer Center Biostatistics and Bioinformatics Shared Resource, Aurora, CO, United States.
Support Care Cancer. 2025 Apr 8;33(5):362. doi: 10.1007/s00520-025-09392-y.
Prior studies evaluating the genetic predisposition to chemotherapy induced peripheral neuropathy (CIPN) have been limited by small populations due to difficulty with real-world data extraction. This genome-wide association study (GWAS) evaluates the genetic differences between patients who developed CIPN against those unaffected, using an electronic health record (EHR) definition of CIPN.
This study included all patients who received chemotherapy associated with CIPN and had germline genetic data within the biobank at the Colorado Center for Personalized Medicine. CIPN was defined by a new neuropathic pain medication or an ICD-diagnosis of neuropathy after specified chemotherapy initiation. GWAS were stratified by (1) total population, (2) platinum chemotherapy, (3) taxane chemotherapy, and (4) vinca alkaloid chemotherapy. Genes previously associated with CIPN were analyzed within each GWAS.
Nine hundred fifteen patients received chemotherapy associated with CIPN, with 528 patients (57%) developing CIPN. Median age at chemotherapy initiation was 60.5 years; female sex (n = 517, 56.5%) and White or Caucasian race (n = 822, 89.8%) were most common. Among single nucleotide polymorphisms (SNPs) that reached suggestive levels of genome-wide significance (p < 1 × 10), 60 SNPs occurred within 11 genes that may play a role in the development of or protection against CIPN, including RCOR1, CLDN14, TRIM5, and TMC2. No SNPs previously associated with CIPN achieved genome-wide significance in this population.
This pharmacogenomic study suggests several genomic loci that may modulate the development of CIPN. This EHR-definition may allow for increased sample sizes and improved statistical power in future genetic studies of CIPN.
先前评估化疗诱导的周围神经病变（CIPN）遗传易感性的研究因难以提取真实世界数据而受限于小样本量。本全基因组关联研究（GWAS）使用CIPN的电子健康记录（EHR）定义，评估发生CIPN的患者与未受影响患者之间的遗传差异。
本研究纳入了所有接受与CIPN相关化疗且在科罗拉多个性化医学中心生物样本库中有生殖系遗传数据的患者。CIPN由新的神经性疼痛药物或特定化疗开始后ICD诊断的神经病变定义。GWAS按以下分层：（1）总体人群，（2）铂类化疗，（3）紫杉烷化疗，（4）长春花生物碱化疗。在每个GWAS中分析先前与CIPN相关的基因。
915例患者接受了与CIPN相关的化疗，其中528例（57%）发生CIPN。化疗开始时的中位年龄为60.5岁；女性（n = 517，56.5%）和白种人或高加索人种（n = 822，89.8%）最为常见。在达到全基因组显著性提示水平（p < 1×10）的单核苷酸多态性（SNP）中，60个SNP出现在11个可能在CIPN发生或预防中起作用的基因内，包括RCOR1、CLDN14、TRIM5和TMC2。在该人群中，先前与CIPN相关的SNP均未达到全基因组显著性。
这项药物基因组学研究提示了几个可能调节CIPN发生的基因组位点。这种EHR定义可能会增加未来CIPN基因研究的样本量并提高统计效力。
