Le-Rademacher Jennifer G, Lopez Camden L, Kanwar Rahul, Major-Elechi Brittny, Abyzov Alexej, Banck Michaela S, Therneau Terry M, Sloan Jeff A, Loprinzi Charles L, Beutler Andreas S
Department of Health Sciences Research (Biomedical Statistics and Informatics), Mayo Clinic, Rochester, MN, USA; Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, USA; Mayo Clinic Cancer Center, Rochester, MN, USA.
Department of Health Sciences Research (Biomedical Statistics and Informatics), Mayo Clinic, Rochester, MN, USA.
J Neurol Sci. 2020 Apr 15;411:116687. doi: 10.1016/j.jns.2020.116687. Epub 2020 Jan 14.
Oxaliplatin therapy can be complicated by chemotherapy-induced peripheral neuropathy (CIPN). Other neurotoxic chemotherapies have been linked to single nucleotide variants (SNV) in Charcot-Marie-Tooth disease (CMT) genes. Whether oxaliplatin carries increased risks of CIPN due to SNV in CMT-associated genes is unknown. 353 patients receiving oxaliplatin in NCCTG N08CB were serially evaluated for CIPN using a validated patient-reported outcome (PRO) instrument, the CIPN20 questionnaire (sensory scale). 49 canonical CMT-associated genes were analyzed for rare and common SNV by nextgen sequencing. The 157 patients with the highest and lowest susceptibility to CIPN (cases and controls) harbored 270 non-synonymous SNV in CMT-associated genes (coding regions). 143 of these were rare, occurring only once ("singletons"). CIPN cases had 0.84 singletons per patient compared with 0.98 in controls. An imbalance in favor of cases was noted only in few genes including PRX, which was previously highlighted as a candidate CIPN gene in patients receiving paclitaxel. However, the imbalance was only modest (5 singleton SNV in cases and 2 in controls). Therefore, while singleton SNV were common, they did overall not portend an increased risk of CIPN. Furthermore, testing CMT-associated genes using recurrent non-synonymous SNV did not reveal any significant association with CIPN. Genetic analysis of patients from N08CB provides clinical guidance that oxaliplatin chemotherapy decisions should not be altered by the majority of SNV that may be encountered in CMT-associated genes when common genetic tests are performed, such as exome or genome sequencing. Oxaliplatin's CIPN risk appears unrelated to CMT-associated genes.
奥沙利铂治疗可能会并发化疗引起的周围神经病变（CIPN）。其他具有神经毒性的化疗药物与夏科-马里-图斯病（CMT）相关基因中的单核苷酸变异（SNV）有关。奥沙利铂是否因CMT相关基因中的SNV而增加CIPN风险尚不清楚。在NCCTG N08CB研究中，对353例接受奥沙利铂治疗的患者使用经过验证的患者报告结局（PRO）工具——CIPN20问卷（感觉量表）对CIPN进行了连续评估。通过二代测序分析了49个典型的CMT相关基因中的罕见和常见SNV。对CIPN易感性最高和最低的157例患者（病例组和对照组）在CMT相关基因（编码区）中存在270个非同义SNV。其中143个是罕见的，仅出现一次（“单例”）。CIPN病例组患者平均每人有0.84个单例，而对照组为0.98个。仅在少数基因中发现病例组存在优势不平衡，包括PRX，该基因先前在接受紫杉醇治疗的患者中被视为CIPN候选基因。然而，这种不平衡程度较小（病例组有5个单例SNV，对照组有2个）。因此，虽然单例SNV很常见，但总体上它们并未预示CIPN风险增加。此外，使用复发性非同义SNV检测CMT相关基因并未发现与CIPN有任何显著关联。对N08CB研究中的患者进行基因分析提供了临床指导，即当进行常见基因检测（如外显子组或基因组测序）时，奥沙利铂化疗决策不应因CMT相关基因中可能遇到的大多数SNV而改变。奥沙利铂的CIPN风险似乎与CMT相关基因无关。
