背景:化疗诱导的周围神经病变(CIPN)是化疗后常见的继发毒性。遗传因素在诱发患者这种不良反应方面可能很重要。
方法:我们研究了950名原发性肺癌患者,谁接受铂或铂类药物联合化疗,谁有可用于研究的DNA。我们分析了279CIPN患者和456例非CIPN患者的流行病学危险因素,以及141CIPN患者和259例非CIPN患者的遗传危险因素。研究的危险因素包括人口统计学,诊断,和治疗数据,以及谷胱甘肽中43个候选基因的174个标签SNP(单核苷酸多态性),细胞周期,DNA修复,细胞信号,和凋亡途径。
结果:患有糖尿病的患者更可能患有CIPN(p=0.0002)。与CIPN相关的其他流行病学危险因素包括周期数(p=0.0004)和同步化疗类型(p<0.001)。与CIPN最相关的SNP是谷胱甘肽过氧化物酶7(GPX7)基因(p值0.0015和0.0028,未调整和调整)和ATP结合盒亚家族C成员4(ABCC4)基因(p值0.037和0.006,未调整和调整)。我们还发现了甲基-o-鸟嘌呤-甲基转移酶(MGMT)和谷胱甘肽-S-转移酶(GST)亚型中的其他暗示性关联。
结论:本队列中与CIPN相关的流行病学和遗传危险因素,包括化疗药物的类型,化疗的强度,和已知与化疗耐药相关的基因。这些发现表明,区分化疗药物的细胞毒性和神经毒性机制具有挑战性,但代表了朝着个性化治疗和改善患者生活质量迈出的重要一步。
BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity secondary to chemotherapy. Genetic factors may be important in predisposing patients to this adverse effect.
METHODS: We studied 950 primary lung cancer patients, who received platinum or platinum-combination drug chemotherapy and who had DNA available for
study. We analyzed epidemiological risk factors in 279 CIPN patients and 456 non-CIPN patients and genetic risk factors in 141 CIPN patients and 259 non-CIPN patients. The risk factors studied included demographic, diagnostic, and treatment data, as well as 174 tag SNPs (single nucleotide polymorphisms) across 43 candidate genes in the glutathione, cell cycle, DNA repair, cell signaling, and apoptosis pathways.
RESULTS: Patients who had diabetes mellitus were more likely to have CIPN (p=0.0002). Other epidemiologic risk factors associated with CIPN included number of cycles (p=0.0004) and type of concurrent chemotherapy (p<0.001). SNPs most associated with CIPN were in glutathione peroxidase 7 (GPX7) gene (p values 0.0015 and 0.0028, unadjusted and adjusted) and in ATP-binding cassette sub-family C member 4 (ABCC4) gene (p values 0.037 and 0.006, unadjusted and adjusted). We also found other suggestive associations in methyl-o-guanine-methyl-transferase (MGMT) and glutathione-S-transferase (GST) isoforms.
CONCLUSIONS: Epidemiological and genetic risk factors associated with CIPN in this cohort, included the type of chemotherapy drug, intensity of chemotherapy treatment, and genes known to be associated with chemotherapy resistance. These findings suggest that differentiating between cytotoxic and neurotoxic mechanisms of chemotherapy drugs is challenging but represents an important step toward individualized therapy and improving quality of life for patients.