HIF1A overexpression is associated with poor prognosis in a cohort of 731 colorectal cancers

Abstract

Tissue hypoxia commonly occurs in tumors. Hypoxia- inducible factor (HIF)-1 and HIF-2, which are essential mediators of cellular response to hypoxia, regulate gene expression for tumor angiogenesis, glucose metabolism, and resistance to oxidative stress. Their key regulatory subunits, HIF1A (HIF-1alpha) and endothelial PAS domain protein 1 (EPAS1; HIF-2alpha), are overexpressed and associated with patient prognosis in a variety of cancers. However, prognostic or molecular features of colon cancer with HIF expression remain uncertain. Among 731 colorectal cancers in two prospective cohort studies, 142 (19%) tumors showed HIF1A overexpression, and 322 (46%) showed EPAS1 overexpression by immunohistochemistry. HIF1A overexpression was significantly associated with higher colorectal cancer-specific mortality in Kaplan-Meier analysis (log-rank test, P < 0.0001), univariate Cox regression (hazard ratio = 1.84; 95% confidence interval, 1.37 to 2.47; P < 0.0001) and multivariate analysis (adjusted hazard ratio = 1.72; 95% confidence interval, 1.26 to 2.36; P = 0.0007) that adjusted for clinical and tumoral features, including microsatellite instability, TP53 (p53), PTGS2 (cyclooxygenase-2), CpG island methylator phenotype, and KRAS, BRAF, PIK3CA, and LINE-1 methylation. In contrast, EPAS1 expression was not significantly associated with patient survival. In addition, HIF1A expression was independently associated with PTGS2 expression (P = 0.0035), CpG island methylator phenotype-high (P = 0.013), and LINE-1 hypomethylation (P = 0.017). EPAS1 expression was inversely associated with high tumor grade (P = 0.0017) and obesity (body mass index > or = 30 kg/m2) (P = 0.039). In conclusion, HIF1A expression is independently associated with poor prognosis in colorectal cancer, suggesting HIF1A as a biomarker with potentially important therapeutic implications.

Figure 1

HIF1A expression and EPAS1 (HIF-2α) expression in colon cancer. A: Strong expression of HIF1A in cytoplasm of colon cancer cells (arrows). B: Moderate expression of HIF1A in cytoplasm of colon cancer cells (arrows). C: Weak expression of HIF1A in cytoplasm of colon cancer cells (arrows). D: No overexpression of HIF1A in colon cancer cells (arrows). E: EPAS1 overexpression in cytoplasm of colon cancer cells (white arrows). F: No expression of EPAS1 in colon cancer cells (black arrows). Stromal cells serve as an internal positive control for EPAS1 expression (arrowhead).

Figure 2

Kaplan-Meier curves for colorectal cancer-specific survival (top panels) and overall survival (bottom panels) according to HIF1A status in colorectal cancer on the training set (left panels, N = 366) (A) and the validation set (right panels, N = 365) (B).

Figure 3

Kaplan-Meier curves for colorectal cancer-specific survival (A and B) and overall survival (C and D) according to HIF1A status (A and C) or EPAS1 (HIF-2α) status (B and D) in colorectal cancer. Tables indicate the number of patients who were alive and at risk of death at each time point after the diagnosis of colorectal cancer.