Abstract 4037: HIF1α signaling contributes to an aggressive hypoxic phenotype in cervical cancer.

Abstract

Abstract Tumor hypoxia is an adverse factor in cervical cancer that would be valuable to implement in the clinical decision-making. In a previous study, we identified a hypoxia gene signature associated with aggressiveness in locally advanced cervical cancer. It consisted of 31 genes, and was predictive of progression free survival in an independent cohort treated with chemoradiotherapy. The signature could be useful in the development of a prognostic test to select patients at risk of failure. The aim of the current study was to obtain a deeper understanding of the pathways reflected in the signature. This could provide an increased insight into the hypoxia-related aggressiveness of cervical cancer and be useful to fully exploit the clinical potential of the signature. The gene signature included a total of 12 genes which are known direct targets of HIF1, and 4 genes involved in the unfolded protein response (UPR), including 3 of the 12 HIF1-targets. To obtain a metric for comparison with other relevant factors, a score was calculated from the expression level of the 31 genes in 154 patients. This hypoxia score correlated significantly with HIF1α protein expression (p<0.001). Furthermore, 8 out of the 12 known HIF1α target genes in the signature showed an individual correlation to the expression of HIF1α (p<0.05), including the 3 UPR genes STC2, ERO1L, and AK2. Cox survival analysis of the hypoxia score was performed on the 154 patients. When stratifying the score on lymph node status, it was predictive of poor outcome only for the patients without metastases to the lymph nodes (89 patients) (p=0.001). When assessing the prognostic value of HIF1α protein expression in the whole patient group, it was not correlated with survival. However, in patients with no lymph node metastases, high levels of HIF1α were found to be a prognostic indicator of poor outcome (p=0.043). Multivariate cox survival analysis was performed on the lymph node negative patients, including the hypoxia score, HIF1α, and clinical parameters. Only the hypoxia score and FIGO stage were found to be independently related to patient survival. In conclusion, it appears that HIF1α is an important mediator of the aggressive phenotype associated with our hypoxia gene signature. However, since the hypoxia score emerged as a significantly better prognostic factor than HIF1α, other signaling pathways may also contribute. Furthermore, this hypoxic phenotype seems to be associated with aggressiveness particularly in patients with no metastases to the lymph nodes. Citation Format: Cathinka Halle, Eva-Katrine Aarnes, Ruth Holm, Gunnar B. Kristensen, Heidi Lyng. HIF1α signaling contributes to an aggressive hypoxic phenotype in cervical cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4037. doi:10.1158/1538-7445.AM2013-4037