Oncotarget

Research Papers:

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. Ricketts, Cathy D. Vocke, W. Marston Linehan, Joseph R. Testa, Alfonso Bellacosa _, Levy Kopelovich and Alfred G. Knudson

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Oncotarget. 2017; 8:17628-17642. https://doi.org/10.18632/oncotarget.12192

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Abstract

Suraj Peri1, Elena Caretti2, Rossella Tricarico2, Karthik Devarajan1, Mitchell Cheung3, Eleonora Sementino3, Craig W. Menges3, Emmanuelle Nicolas3, Lisa A. Vanderveer4, Sharon Howard5, Peggy Conrad6, James A. Crowell7, Kerry S. Campbell5, Eric A. Ross1, Andrew K. Godwin8, Anthony T. Yeung4, Margie L. Clapper4, Robert G. Uzzo3,9, Elizabeth P. Henske10, Christopher J. Ricketts11, Cathy D. Vocke11, W. Marston Linehan11, Joseph R. Testa3,9, Alfonso Bellacosa2, Levy Kopelovich12 and Alfred G. Knudson3

1 Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA, USA

2 Cancer Epigenetics, Fox Chase Cancer Center, Philadelphia, PA, USA

3 Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA, USA

4 Cancer Prevention and Control, Fox Chase Cancer Center, Philadelphia, PA, USA

5 Blood Cell Development and Function, Fox Chase Cancer Center, Philadelphia, PA, USA

6 University of California San Francisco, San Francisco, CA, USA

7 Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, NCI, Rockville, MD, USA

8 Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA

9 Kidney Cancer Programs, Fox Chase Cancer Center, Philadelphia, PA, USA

10 Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, NCI, Bethesda, MD, USA

11 Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute Bethesda, MD, USA

12 Department of Medicine, Weill Cornell Medical College, New York, NY, USA

Correspondence to:

Alfonso Bellacosa, email:

Joseph R. Testa, email:

Levy Kopelovich, email:

Keywords: VHL, TSC1, TSC2, transcriptomics, primary kidney epithelial cells

Received: August 31, 2016 Accepted: September 07, 2016 Published: September 22, 2016

Abstract

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 other tumor 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.


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