HIF1A overexpression is associated with poor prognosis in a cohort of 731 colorectal cancers.
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.
Baba
Yoshifumi
Y
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Nosho
Katsuhiko
K
Shima
Kaori
K
Irahara
Natsumi
N
Chan
Andrew T
AT
Meyerhardt
Jeffrey A
JA
Chung
Daniel C
DC
Giovannucci
Edward L
EL
Fuchs
Charles S
CS
Ogino
Shuji
S
D000368:Aged; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D018899:CpG Islands; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D010641:Phenotype; D011379:Prognosis; D016016:Proportional Hazards Models
D051795:Hypoxia-Inducible Factor 1, alpha Subunit