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HIF1A Overexpression Is Associated with Poor Prognosis in a Cohort of 731 Colorectal Cancers

https://doi.org/10.2353/ajpath.2010.090972Get rights and content
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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-1α) and endothelial PAS domain protein 1 (EPAS1; HIF-2α), 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 ≥ 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.

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Supported by U.S. National Institute of Health grants P01 CA87969 (to S. Hankinson), P01 CA55075 (to W. Willett), P50 CA127003 (to C.S.F.), K07 CA107412 (to A.T.C.), and K07 CA122826 (to S.O.) and in part by grants from the Bennett Family Fund and from the Entertainment Industry Foundation National Colorectal Cancer Research Alliance. K.N. was supported by a fellowship grant from the Japan Society for Promotion of Science. In addition, A.T.C. was supported by a grant from the Damon Runyon Cancer Research Foundation.

Y.B., K.N., and K.S. contributed equally.