Abstract
HIF1α has been termed a tumor-suppressor in clear cell renal cell carcinoma (ccRCC), primarily based on functional proliferation studies in cell lines (in vitro and in vivo) with genetic manipulation, and the adverse prognosis of 14q-deleted ccRCC patients. In other malignancies, however, HIF1α has an established tumor-promoting role. Therefore, this study sought to further examine the role of HIF1α in ccRCC using bioinformatic analyses of 530 ccRCC patients from The Cancer Genome Atlas (TCGA) and The Cancer Proteome Atlas (TCPA) registries. Although lower copy numbers of HIF1A (encoding HIF1α, located at 14q23.2) was associated with worse survival, there was no survival difference based on either HIF1A mRNA or HIF1α protein expression. Interestingly, L2HGDH (L-2-Hydroxyglutarate Dehydrogenase), a recently characterized epigenetic modulating ccRCC tumor-suppressor with a marked impact on survival, was found to be located only ~ 11.5Mbp from HIF1A on 14q (at 14q21.3). L2HGDH was therefore co-deleted in ~ 95% of 14q deletions involving HIF1A locus. Remarkably, HIF1A CNV had a markedly stronger correlation with L2HGDH expression (Rho = 0.55) than its own gene expression (Rho = 0.27), indicating high preserved-allele compensation of HIF1A. Genetic loss of HIF1A was therefore associated with a much greater reduction of L2HGDH gene expression than its own gene expression, providing a possible explanation for survival differences based on HIF1A CNV and mRNA expression. Furthermore, in 14q-deleted ccRCC patients with complete (uncensored) survival data, in the relatively rare cases where genetic loss of HIF1A occurred without genetic loss of L2HGDH (n = 5), the survival was significantly greater than where there was simultaneous genetic loss of both (n = 87) (mean survival 1670.8 ± 183.5 days vs 885.1 ± 78.4 days; p = 0.007). In addition, there was no correlation between HIF1A mRNA and HIF1α protein expression in ccRCC (R = 0.02), reflecting the primarily post-translational regulation of HIF1α. Lastly, even between L2HGDH and HIF1A loci, 14q was found to have several other yet-to-be-characterized potential ccRCC tumor-suppressors. Taken together, the data indicate that HIF1α is not a target of 14q deletion in ccRCC and that it is not a tumor-suppressor in this malignancy.
Highlights
HIF1α has been termed a tumor-suppressor in clear cell renal cell carcinoma, primarily based on functional proliferation studies in cell lines with genetic manipulation, and the adverse prognosis of 14q-deleted ccRCC patients
Results lower HIF1A CNV was associated with inferior survival in ccRCC, there was no difference in survival based on HIF1A expression, both at mRNA and protein levels
Consistent with previous reports of 14q loss, lower HIF1A CNV was associated with worse overall survival than higher HIF1A CNV in ccRCC
Summary
HIF1α has been termed a tumor-suppressor in clear cell renal cell carcinoma (ccRCC), primarily based on functional proliferation studies in cell lines (in vitro and in vivo) with genetic manipulation, and the adverse prognosis of 14q-deleted ccRCC patients. CcRCC accounts for ~ 80% of all kidney cancer, and VHL inactivation, either through genetic sequence alteration or promoter methylation occurs in ~ 86% of all ccRCC as an early initiating feature during p athogenesis[19,20] This results in the constitutive activation of the HIF pathway, which consists of HIF2α. HIF1A has been termed a ‘target of 14q deletion’ in ccRCC and a kidney cancer suppressor gene, based on these functional proliferation studies in ccRCC cell lines, the adverse prognosis of 14q-deleted ccRCC patients (large 14q deletions are seen in ~ 40% of ccRCC) and loss of function mutations of HIF1A (HIF1A mutation occurs in ~ 1% of ccRCC tumors (TCGA)[35]. Recently, HIF2α inhibitor-resistant ccRCC patient-derived xenograft tumors were observed to have significantly greater HIF1A mRNA expression than HIF2α inhibitor-sensitive ccRCC tumors, raising the possibility that HIF1α may be oncogenic in ccRCC tumors with no response despite HIF2α inhibition[43]
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