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 HIF2α is a kidney cancer oncoprotein. In this article, we identify focal, homozygous deletions of the HIF1α locus on 14q in clear cell renal carcinoma cell lines. Wild-type HIF1α suppresses renal carcinoma growth, but the products of these altered loci do not. Conversely, downregulation of HIF1α in HIF1α-proficient lines promotes tumor growth. HIF1α activity is diminished in 14q-deleted kidney cancers, and all somatic HIF1α mutations identified in kidney cancers tested to date are loss of function. Therefore, HIF1α 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 HIF1α is a target of 14q loss in kidney cancer. Cancer Discovery; 1(3); 222–35. © 2011 AACR.

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