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 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.


CONCLUSIONS
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.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Chuan
C
Shen
Rameen
R
Beroukhim
Steven E
SE
Schumacher
Jing
J
Zhou
Michelle
M
Chang
Sabina
S
Signoretti
William G
WG
Kaelin
D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D016147:Genes, Tumor Suppressor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D007680:Kidney Neoplasms / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit