Shilbayeh Sireen Abdul Rahim, Khedr Naglaa F, Alshabeeb Mohammad A, Alsaleh Abdulmonem Ali, Alanizi Abdalrhman Hamdan, Abd El-Baset Omnia A, Werida Rehab H
Department of Pharmacy Practice, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
Biochemistry Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt.
Front Pharmacol. 2025 Jun 4;16:1604473. doi: 10.3389/fphar.2025.1604473. eCollection 2025.
Hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality, is commonly treated with doxorubicin (DOX). However, its effectiveness varies significantly among patients.
The present study aimed to identify potential genetic variants affecting the response of HCC patients to DOX.
78 patients with HCC who received DOX via transarterial chemoembolization (TACE) technology were selected. DNA was extracted from blood for genome-wide genotyping using the Applied Biosystems™ Axiom™ Precision Medicine Diversity Research™ Array. Genetic data were analysed using Axiom™ Analysis Suite software v5.2.
Six hits in five genes [AK3 (rs378117), TRPM3 (rs1329774 and rs4745058), CDH4 (rs2427043), LINC00504 (rs76228864), and GRIN2D (rs76754767)] were associated with a risk of tumour progression, whereas variants in HPGD (rs45593131) and RC3H2 (rs2792999) were suggested as protective factors. rs8038528 in the PCSK6 gene was categorized as a low-response variant associated with an unsatisfactory reduction in α-fetoprotein (AFP) levels after DOX chemotherapy (P = 6.82 × 10). In contrast, three SNPs (rs1998853, rs12440990, and rs4774596) located within two genes (NPAS3 and DMXL2) were identified as predictors of good response rates to the treatment, as AFP levels were reduced by ≥ 20%. Death incidents showed associations with five SNPs that reached p ≤ 5.0 × 10; four of these are located within the DENND1B, LOC107986086, TMEM169, and RNF152 genes.
These findings support the incorporation of pharmacogenomic testing into clinical practice for HCC therapy, paving the way for customized treatment methods that may improve therapeutic efficacy and patient outcomes. Future research is needed to replicate these genetic connections.
肝细胞癌（HCC）是癌症相关死亡的主要原因，常用阿霉素（DOX）进行治疗。然而，其疗效在患者之间差异显著。
本研究旨在确定影响HCC患者对DOX反应的潜在基因变异。
选取78例通过经动脉化疗栓塞（TACE）技术接受DOX治疗的HCC患者。从血液中提取DNA，使用Applied Biosystems™ Axiom™ 精准医学多样性研究™ 芯片进行全基因组基因分型。使用Axiom™ 分析套件软件v5.2分析基因数据。
五个基因[AK3（rs378117）、TRPM3（rs1329774和rs4745058）、CDH4（rs2427043）、LINC00504（rs76228864）和GRIN2D（rs76754767）]中的六个位点与肿瘤进展风险相关，而HPGD（rs45593131）和RC3H2（rs2792999）中的变异被认为是保护因素。PCSK6基因中的rs8038528被归类为低反应变异，与DOX化疗后甲胎蛋白（AFP）水平降低不显著相关（P = 6.82×10）。相反，位于两个基因（NPAS3和DMXL2）内的三个单核苷酸多态性（rs1998853、rs12440990和rs4774596）被确定为治疗反应良好率的预测指标，因为AFP水平降低了≥20%。死亡事件与五个p≤5.0×10的单核苷酸多态性相关；其中四个位于DENND1B、LOC107986086、TMEM169和RNF152基因内。
这些发现支持将药物基因组学检测纳入HCC治疗的临床实践，为可能提高治疗效果和患者预后的个性化治疗方法铺平道路。未来需要进行研究以重复这些基因关联。
