Huang Hanxue, Liu Junyan, Xiao Qi, Mao Chenxue, She Lei, Yu Lulu, Yu Bing, Lei Mengrong, Gao Ying, He Baimei, Pan Pinhua, Li Xi, Yin Jiye, Liu Zhaoqian
Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China.
Institute of Clinical Pharmacology, Engineering Research Center for Applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha 410078, China.
Acta Biochim Biophys Sin (Shanghai). 2025 Apr 28;57(8):1281-1291. doi: 10.3724/abbs.2025013.
Platinum-based chemotherapy remains the mainstay for non-small cell lung cancer (NSCLC), but it frequently causes dose-limiting myelosuppression, with significant individual variability in susceptibility. However, the genetic basis of myelosuppression side effects remains elusive, greatly hindering personalized therapeutic approaches. In this study, we perform a comprehensive genome-wide association analysis on 491 NSCLC patients receiving platinum-based chemotherapy, examining 4,690,998 single-nucleotide polymorphisms (SNPs) to identify relevant genetic variants. LDBlockShow, FUMA, and MAGMA are utilized to explore linkage disequilibrium, expression quantitative trait loci (eQTLs), chromatin interaction, and conduct gene-based and gene set-based analysis of candidate SNPs. The GWAS results reveal that rs6856089 and its linked SNPs are significantly associated with platinum-based chemotherapy-induced myelosuppression. Specifically, patients with the A allele of rs6856089 have a significantly lower risk of myelosuppression [odds ratio (OR) = 0.1300, = 7.59 × 10 ]. Furthermore, gene-based analysis reveals that ( = 2.47 × 10 ), which encodes endomucin, a marker for hematopoietic stem cells, might mediate myelosuppression. This study provides a scientific basis for the individual differences in platinum-based chemotherapy-induced myelosuppression.
铂类化疗仍然是非小细胞肺癌（NSCLC）的主要治疗方法，但它经常导致剂量限制性骨髓抑制，个体易感性存在显著差异。然而，骨髓抑制副作用的遗传基础仍然不清楚，这极大地阻碍了个性化治疗方法的发展。在本研究中，我们对491例接受铂类化疗的NSCLC患者进行了全面的全基因组关联分析，检测了4,690,998个单核苷酸多态性（SNP）以确定相关的遗传变异。利用LDBlockShow、FUMA和MAGMA来探索连锁不平衡、表达数量性状位点（eQTL）、染色质相互作用，并对候选SNP进行基于基因和基于基因集的分析。全基因组关联研究（GWAS）结果显示，rs6856089及其连锁的SNP与铂类化疗引起的骨髓抑制显著相关。具体而言，携带rs6856089 A等位基因的患者发生骨髓抑制的风险显著较低[比值比（OR）=0.1300，=7.59×10]。此外，基于基因的分析表明，编码造血干细胞标志物内黏蛋白的（=2.47×10）可能介导骨髓抑制。本研究为铂类化疗引起的骨髓抑制的个体差异提供了科学依据。
