Mutational analysis of hypoxia-related genes HIF1α and CUL2 in common human cancers

Hypoxia is a general feature of solid cancer tissues. Hypoxia upregulates hypoxia-inducible factor 1 alpha (HIF1 alpha) that transactivates downstream genes and contributes to cancer pathogenesis. HIF1 alpha is upregulated not only by hypoxia but also by genetic alterations in HIF1 alpha-related genes, including VHL. Cullin 2 (CUL2) interacts with the trimeric VHL-elongin B-elongin C complex and plays an essential role in the ubiquitinated degradation of HIF1 alpha. The aim of this study was to explore whether HIF1 alpha and CUL2 genes are somatically mutated, and contribute to HIF1 alpha activation in common human cancers. For this, we have analyzed the coding region of oxygen-dependent degradation domain of HIF1 alpha in 47 colon, 47 gastric, 47 breast, 47 lung, and 47 hepatocellular carcinomas, and 47 acute leukemias by a single-strand conformation polymorphism assay. In addition, we analyzed mononucleotide repeat sequences (A8) in CUL2 in 55 colorectal and 45 gastric carcinomas with microsatellite instability (MSI). We found one HIF1 alpha mutation (p.Ala593Pro) in the hepatocellular carcinomas (1/47; 2.1%), but none in other cancers. We found two CUL2 frameshift mutations in colon cancers (p.Asn292MetfsX20), which were exclusively detected in high MSI cancers (4.9%; 2/41). Our data indicate that somatic mutation of HIF1 alpha is rare in common cancers, and somatic mutation of CUL2 occurs in a fraction of colorectal cancers (colorectal cancers with high MSI). The data suggest that neither HIF1 alpha nor CUL2 mutation may play a central role in HIF1 alpha activation in gastric, colorectal, breast, lung and hepatocellular carcinomas, and acute leukemias.