Genetic variability of HIF1A and response to treatment with cisplatin in combination with pemetrexed or gemcitabine in patients with malignant mesothelioma

Our plain-English summary of Genetic variability of HIF1A and response to treatment with cisplatin in combination with pemetrexed or gemcitabine in patients with malignant mesothelioma, by M. Setina, E. Setina, Z. Doljak, et al (Radiology and Oncology, 2025).

The study

• Authors: M. Setina, E. Setina, Z. Doljak, K. Goricar, V. Dolzan, V. Kovac
• Journal: Radiology and Oncology
• Published: 2025;59(3):403-411
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: 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 HIF1A gene coding for the regulatory alpha subunit (HIF-1A) and their role in the response to chemotherapy in patients with MM.

Patients And Methods: 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 HIF1A 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.

Results: In heterozygotes with the HIF1A 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 (ROadj = 0.37; 95% CI = 0.14-0.97; Padj = 0.044). HIF1A 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).

Conclusions: Among the investigated HIF1A 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 HIF1A polymorphisms in MM and may offer valuable insights into their impact on other cancers as well.

© 2025 Matic Setina et al., published by Sciendo.

In plain English

This retrospective genetic association study included 234 patients with malignant mesothelioma treated with cisplatin plus pemetrexed or gemcitabine at the Institute of Oncology Ljubljana, Slovenia, between January 2001 and September 2018. Asbestos exposure was confirmed in 173 patients, 74.2% of those whose exposure status was recorded; status was missing for one patient. The authors tested three variants (SNPs) of the HIF1A gene: rs11549465, rs11549467 and rs2057482. Complete or partial response to chemotherapy occurred in 37.8% of patients with the rs11549465 CC genotype and 22.5% with the CT genotype. The CT genotype was linked to a statistically significant poorer response only after adjustment for weight loss and C-reactive protein (adjusted odds ratio 0.37, 95% CI 0.14 to 0.97, p = 0.044). Without adjustment, the difference was not statistically significant. The other two variants were not associated with response, and no variant was associated with progression-free or overall survival. As limitations, the authors noted that rs11549465 genotypes deviated from Hardy-Weinberg equilibrium and that the Slovenian-only population may limit how far the findings apply to other populations. They concluded that, in their opinion, testing for these variants currently has no clinical utility.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: retrospective genetic association study
• Who was studied: 234 patients with malignant mesothelioma (pleural and peritoneal) treated with cisplatin plus pemetrexed or gemcitabine at the Institute of Oncology Ljubljana, Slovenia, from 1 January 2001 to 30 September 2018
• Exposure: Three HIF1A gene variants (rs11549465, rs11549467, rs2057482) in relation to response to cisplatin-based chemotherapy. Asbestos exposure was recorded as a patient characteristic; fiber types were not reported.
• Main results:
  • Asbestos exposure was confirmed in 173 patients (74.2%) and absent in 60 (25.8%); exposure status was missing for 1 patient.
  • Overall, 79 patients (35.0%) had a complete or partial response to chemotherapy.
  • Complete or partial response occurred in 37.8% of rs11549465 CC carriers and 22.5% of CT carriers.
  • rs11549465 CT vs CC: poorer response after adjustment for weight loss and CRP (adjusted OR 0.37; 95% CI 0.14 to 0.97; p = 0.044).
  • Unadjusted, rs11549465 CT vs CC was not statistically significant (OR 0.48; 95% CI 0.21 to 1.08; p = 0.074).
  • rs11549467 and rs2057482 were not significantly associated with chemotherapy response.
  • No significant associations with response among patients treated with gemcitabine/cisplatin alone.
  • No significant associations with response among patients treated with pemetrexed/cisplatin alone.
  • None of the three SNPs was associated with progression-free survival or overall survival.
• The authors' conclusion: The authors concluded that, although the rs11549465 CT genotype was associated with poorer chemotherapy response after adjustment, testing mesothelioma patients for these three HIF1A variants has, in their opinion, no clinical utility for now, and further studies are needed.
• Limitations the authors state:
  • rs11549465 genotype distribution deviated from Hardy-Weinberg equilibrium, although repeat genotyping with a second method gave matching results.
  • The study included only a genetically homogeneous Slovenian population, which may limit application of the findings to other populations.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Cisplatin, Pemetrexed (Alimta), Gemcitabine, Mesothelioma, Chemotherapy, Hypoxia, Progression-Free Survival, Overall Survival.

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