Hypoxia-regulated gene expression and prognosis in loco-regional gastroesophageal cancer

Abstract

Gastroesophageal cancers are heterogeneous diseases with a poor outcome. Prognostic and predictive factors are needed to improve patient survival. Hypoxia is an adverse prognostic factor and is associated with resistance to chemo- and radiotherapy in various cancers. However, knowledge on the impact of hypoxia in gastroesophageal cancer is limited. The aim of this study was to evaluate potential prognostic factors in terms of a subset of hypoxia-responsive genes and clinicopathological parameters in patients with gastroesophageal cancer. Material and methods. Ninety-five patients with loco-regional gastroesophageal cancer treated with curative intent were retrospectively analyzed. Based on formalin-fixed paraffin-embedded diagnostic biopsies gene expressions of 15 hypoxia-induced and pH-independent genes from a previously described hypoxia gene expression classifier was quantified. The prognostic impact was evaluated for overall survival (OS) and disease-specific survival (DSS). Uni- and multivariate Cox proportional hazards model was used to identify hypoxia-responsive gene expression and clinicopathological parameters as prognostic markers. Results. An unsupervised hierarchical clustering of hypoxia regulated genes showed two well-differentiated patient clusters: One cluster of tumors with high gene expression and another with low gene expression, indicating a more hypoxic genotype versus a less hypoxic genotype respectively. As the group of esophageal squamous cell carcinomas (ESCC) alone showed intra-group heterogeneity this group was ranked according to the gene expression of the 15 genes. The most hypoxic third showed a trend towards a poorer outcome in terms of OS [HR = 0.48 (CI 0.21–1.07), p = 0.07] and DSS [HR = 0.48 (CI 0.18–1.24), p = 0.13]. Treatment response was identified as an independent prognostic factor for DSS in the group of ESCC [HR = 0.21 (CI 0.05–0.95), p = 0.04]. Conclusion. Gene expression analysis of 15 hypoxia-responsive genes was identified as a promising prognostic marker in patients with ESCC. Further studies confirming these results in larger patient cohorts are needed.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

The study is supported by The Danish Cancer Society, CIRRO – The Lundbeck Foundation Center for Interventional Research in Radiation Oncology and The Danish Council for Strategic Research, The A.P. Møller Foundation for the Advancement of Medical Science, Karen A. Tolstrups Fund and The Family Spogaards Fund.