Haploinsufficiency in tumor predisposition syndromes: Altered genomic transcription in morphologically normal cells heterozygous for VHL or TSC mutation

Suraj Peri, Elena Caretti, Rossella Tricarico, Karthik Devarajan, Mitchell Cheung, Eleonora Sementino, Craig W. Menges, Emmanuelle Nicolas, Lisa A. Vanderveer, Sharon Howard, Peggy Conrad, James A. Crowell, Kerry S. Campbell, Eric A. Ross, Andrew K. Godwin, Anthony T. Yeung, Margie L. Clapper, Robert G. Uzzo, Elizabeth P. Henske, Christopher J. RickettsCathy D. Vocke, W. Marston Linehan, Joseph R. Testa, Alfonso Bellacosa, Levy Kopelovich, Alfred G. Knudson

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Tumor suppressor genes and their effector pathways have been identified for many dominantly heritable cancers, enabling efforts to intervene early in the course of disease. Our approach on the subject of early intervention was to investigate gene expression patterns of morphologically normal "one-hit" cells before they become hemizygous or homozygous for the inherited mutant gene which is usually required for tumor formation. Here, we studied histologically non-transformed renal epithelial cells from patients with inherited disorders that predispose to renal tumors, including von Hippel-Lindau (VHL) disease and Tuberous Sclerosis (TSC). As controls, we studied histologically normal cells from non-cancerous renal epithelium of patients with sporadic clear cell renal cell carcinoma (ccRCC). Gene expression analyses of VHLmut/wt or TSC1/2mut/wt versus wild-type (WT) cells revealed transcriptomic alterations previously implicated in the transition to precancerous renal lesions. For example, the gene expression changes in VHLmut/wt cells were consistent with activation of the hypoxia response, associated, in part, with the "Warburg effect". Knockdown of any remaining VHL mRNA using shRNA induced secondary expression changes, such as activation of NFκB and interferon pathways, that are fundamentally important in the development of RCC. We posit that this is a general pattern of hereditary cancer predisposition, wherein haploinsufficiency for VHL or TSC1/2, or potentially othertumor susceptibility genes, is sufficient to promote development of early lesions, while cancer results from inactivation of the remaining normal allele. The gene expression changes identified here are related to the metabolic basis of renal cancer and may constitute suitable targets for early intervention.

Original languageEnglish
Pages (from-to)17628-17642
Number of pages15
Issue number11
StatePublished - 2017


  • Calcium-Binding Proteins/genetics
  • Carcinoma, Renal Cell/genetics
  • Cell Line, Tumor
  • Gene Expression Profiling
  • Gene Knockdown Techniques
  • Genetic Predisposition to Disease/genetics
  • Haploinsufficiency
  • Heterozygote
  • Humans
  • Immunoblotting
  • Kidney Neoplasms/genetics
  • Mutation
  • Oligonucleotide Array Sequence Analysis
  • Real-Time Polymerase Chain Reaction
  • Transcriptome
  • Von Hippel-Lindau Tumor Suppressor Protein/genetics


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