Genetic and Functional Studies Implicate HIF1α as a 14q Kidney Cancer Suppressor Gene

Kidney cancers often delete chromosome 3p, spanning the VHL tumor suppressor gene, and chromosome 14q, which presumably harbors >= 1 tumor suppressor genes. pVHL inhibits the hypoxia-inducible transcription factor (HIF), and HIF2 alpha is a kidney cancer oncoprotein. In this article, we identify focal, homozygous deletions of the HIF1 alpha locus on 14q in clear cell renal carcinoma cell lines. Wild-type HIF1 alpha suppresses renal carcinoma growth, but the products of these altered loci do not. Conversely, downregulation of HIF1 alpha in HIF1 alpha-proficient lines promotes tumor growth. HIF1a activity is diminished in 14q-deleted kidney cancers, and all somatic HIF1 alpha mutations identified in kidney cancers tested to date are loss of function. Therefore, HIF1 alpha has the credentials of a kidney cancer suppressor gene. SIGNIFICANCE: Deletion of 14q is a frequent event in clear cell renal carcinoma and portends a poor prognosis. In this study, we provide genetic and functional evidence that HIF1 alpha is a target of 14q loss in kidney cancer. Cancer Discovery; 1(3);222-35. (C) 2011 AACR.