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

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 reduce responsiveness to cisplatin-based chemotherapy. Cellular adaptation to hypoxia occurs through intracellular proteins from the hypoxia-inducible factor (HIF) family, which exist in three isoforms, with only the HIF-1 isoform being expressed in all cells. HIF-1 consists of the regulatory alpha subunit (HIF-1A) and constitutively expressed beta subunit (HIF-1B). Single nucleotide polymorphisms (SNPs) of HIF1A gene may influence its function under hypoxic conditions within the tumor tissue of MM, potentially altering the response of MM to platinum-based chemotherapy. The aim of our study was to investigate the role of HIF-1A in the response to chemotherapy in patients with MM.

Patients and methods. We conducted a retrospective association study that included 234 patients with MM, who were treated at the Institute of Oncology Ljubljana between January 2001 and September 2018 with a combination of cisplatin/pemetrexed or cisplatin/gemcitabine. Selected HIF1A SNPs (rs1154965, rs11549467, and rs2057482) were determined using the competitive allele-specific polymerase chain reaction (KASP). Additionally, we used the Taqman assay for independent confirmation of rs11549465 genotyping results obtained with KASP. 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. All tests were two-tailed.

Results. In heterozygotes with the HIF1A rs11549465 CT genotype, response to chemotherapy was statistically significantly worse compared to homozygotes with the CC genotype, but only with the adjustment for weight loss and CRP (RO_adj = 0.37; 95% CI = 0.14–0.97; P_adj = 0.044). The SNPs rs11549467 and rs2057482 were not associated with response to chemotherapy (P > 0.05). None of the investigated SNPs were associated with progression-free survival (PFS) (P > 0.05) or overall survival (OS) (P > 0.05).

Conclusions. In patients with the HIF1A rs11549465 CT genotype, we found a statistically significantly worse response to chemotherapy compared to the CC genotype with the adjustment for weight loss and CRP. SNPs rs11549467 and rs2057482 were not associated with response to chemotherapy in MM. None of the investigated polymorphisms were associated with PFS or OS in MM chemotherapy treatment. The findings of this study will increase our understanding of the role of HIF1A polymorphisms in MM and may offer valuable insights into their impact on other cancers as well.