Haploinsufficiency in tumor predisposition syndromes: altered genomic transcription in morphologically normal cells heterozygous for VHL or TSC mutation.
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.
Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA, USA.
Suraj
S
Peri
Cancer Epigenetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
Elena
E
Caretti
Cancer Epigenetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
Rossella
R
Tricarico
Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA, USA.
Karthik
K
Devarajan
Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA, USA.
Mitchell
M
Cheung
Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA, USA.
Eleonora
E
Sementino
Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA, USA.
Craig W
CW
Menges
Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA, USA.
Emmanuelle
E
Nicolas
Cancer Prevention and Control, Fox Chase Cancer Center, Philadelphia, PA, USA.
Lisa A
LA
Vanderveer
Blood Cell Development and Function, Fox Chase Cancer Center, Philadelphia, PA, USA.
Sharon
S
Howard
University of California San Francisco, San Francisco, CA, USA.
Peggy
P
Conrad
Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, NCI, Rockville, MD, USA.
James A
JA
Crowell
Blood Cell Development and Function, Fox Chase Cancer Center, Philadelphia, PA, USA.
Kerry S
KS
Campbell
Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA, USA.
Eric A
EA
Ross
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
Andrew K
AK
Godwin
Cancer Prevention and Control, Fox Chase Cancer Center, Philadelphia, PA, USA.
Anthony T
AT
Yeung
Cancer Prevention and Control, Fox Chase Cancer Center, Philadelphia, PA, USA.
Margie L
ML
Clapper
Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA, USA.|Kidney Cancer Programs, Fox Chase Cancer Center, Philadelphia, PA, USA.
Robert G
RG
Uzzo
Brigham and Women's Hospital, Harvard Medical School, Boston, MA, NCI, Bethesda, MD, USA.
Elizabeth P
EP
Henske
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute Bethesda, MD, USA.
Christopher J
CJ
Ricketts
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute Bethesda, MD, USA.
Cathy D
CD
Vocke
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute Bethesda, MD, USA.
W Marston
WM
Linehan
Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA, USA.|Kidney Cancer Programs, Fox Chase Cancer Center, Philadelphia, PA, USA.
Joseph R
JR
Testa
Cancer Epigenetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
Alfonso
A
Bellacosa
Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Levy
L
Kopelovich
Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA, USA.
Alfred G
AG
Knudson
D002135:Calcium-Binding Proteins / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000235:genetics; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D057895:Haploinsufficiency; D006579:Heterozygote; D006801:Humans; D015151:Immunoblotting; D007680:Kidney Neoplasms / Q000235:genetics; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
D002135:Calcium-Binding Proteins; C486009:TESC protein, human; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human
TSC1; TSC2; VHL; primary kidney epithelial cells; transcriptomics
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