Setina Matic, Setina Eva, Doljak Ziga, Goricar Katja, Dolzan Vita, Kovac Viljem
Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Pharmacogenetics Laboratory, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Radiol Oncol. 2025 Sep 5;59(3):403-411. doi: 10.2478/raon-2025-0049. eCollection 2025 Sep 1.
Treatment of malignant mesothelioma (MM) still relies on chemotherapy with cisplatin in combination with pemetrexed or other drugs. Studies indicate that hypoxic conditions within tumour tissue may reduce responsiveness to cisplatin-based chemotherapy. Hypoxia-inducible factors (HIF) play an important role in regulation of cellular adaptation to hypoxia. The aim of our study was to investigate single nucleotide polymorphisms (SNPs) in the gene coding for the regulatory alpha subunit (HIF-1A) and their role in the response to chemotherapy in patients with MM.
Our retrospective genetic association study included 234 patients with MM, who were treated with a combination of cisplatin/pemetrexed or cisplatin/gemcitabine at the Institute of Oncology Ljubljana between January 2001 and September 2018. Selected SNPs (rs1154965, rs11549467, and rs2057482) were genotyped using the competitive allele-specific polymerase chain reaction (KASP). Additionally, we used a TaqMan assay for independent confirmation of rs11549465 genotyping results. The impact of the SNPs on response to chemotherapy was analysed using logistic regression. For survival analysis, we used the Kaplan-Meier method and Cox regression.
In heterozygotes with the rs11549465 CT genotype, response to chemotherapy was significantly worse compared to homozygotes with the CC genotype, but only after adjustment for weight loss and CRP (RO = 0.37; 95% CI = 0.14-0.97; P = 0.044). rs11549467 and rs2057482 were not associated with response to chemotherapy (all P > 0.05). None of the investigated SNPs were associated with progression-free survival or overall survival (all P > 0.05).
Among the investigated SNPs, only rs11549465 has showed association with a worse response to chemotherapy after the adjustment for clinical parameters. The findings of this study have improved our understanding of the role of polymorphisms in MM and may offer valuable insights into their impact on other cancers as well.
恶性间皮瘤（MM）的治疗仍依赖于顺铂联合培美曲塞或其他药物的化疗。研究表明，肿瘤组织内的缺氧状态可能会降低对基于顺铂化疗的反应性。缺氧诱导因子（HIF）在调节细胞对缺氧的适应性中起重要作用。我们研究的目的是调查编码调节性α亚基（HIF-1A）的基因中的单核苷酸多态性（SNP）及其在MM患者化疗反应中的作用。
我们的回顾性基因关联研究纳入了234例MM患者，这些患者于2001年1月至2018年9月在卢布尔雅那肿瘤研究所接受了顺铂/培美曲塞或顺铂/吉西他滨联合治疗。使用竞争性等位基因特异性聚合酶链反应（KASP）对选定的SNP（rs1154965、rs11549467和rs2057482）进行基因分型。此外，我们使用TaqMan分析对rs11549465基因分型结果进行独立验证。使用逻辑回归分析SNP对化疗反应的影响。对于生存分析，我们使用Kaplan-Meier方法和Cox回归。
与CC基因型纯合子相比，rs11549465 CT基因型杂合子对化疗的反应明显更差，但仅在调整体重减轻和CRP后（比值比=0.37；95%置信区间=0.14-0.97；P=0.044）。rs11549467和rs2057482与化疗反应无关（所有P>0.05）。所研究的SNP均与无进展生存期或总生存期无关（所有P>0.05）。
在所研究的SNP中，只有rs11549465在调整临床参数后显示出与化疗反应较差有关。本研究结果增进了我们对MM中多态性作用的理解，也可能为其对其他癌症的影响提供有价值的见解。
