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

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.

SUBMITTER: Peri S

PROVIDER: S-EPMC5392274 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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

Peri Suraj S Caretti Elena E Tricarico Rossella R Devarajan Karthik K Cheung Mitchell M Sementino Eleonora E Menges Craig W CW Nicolas Emmanuelle E Vanderveer Lisa A LA Howard Sharon S Conrad Peggy P Crowell James A JA Campbell Kerry S KS Ross Eric A EA Godwin Andrew K AK Yeung Anthony T AT Clapper Margie L ML Uzzo Robert G RG Henske Elizabeth P EP Ricketts Christopher J CJ Vocke Cathy D CD Linehan W Marston WM Testa Joseph R JR Bellacosa Alfonso A Kopelovich Levy L Knudson Alfred G AG

Oncotarget 20170301 11

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 ...[more]

PMID: 27682873

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Project description:Familial adenomatous polyposis (FAP) is an inherited syndrome caused by a heterozygous adenomatous polyposis coli (APC) germline mutation, associated with a profound lifetime risk for colorectal cancer. While it is well accepted that tumorigenic transformation is initiated following acquisition of a second mutation and loss of function of the APC gene, the role of heterozygous APC mutation in this process is yet to be discovered. This work aimed to explore whether a heterozygous APC mutation induces molecular defects underlying tumorigenic transformation and how different APC germline mutations predict disease severity. Three FAP-human embryonic stem cell lines (FAP1/2/3-hESC lines) carrying germline mutations at different locations of the APC gene, and two control hESC lines free of the APC mutation, were differentiated into colon organoids and analyzed by immunohistochemistry and RNA sequencing. In addition, data regarding the genotype and clinical phenotype of the embryo donor parents were collected from medical records. FAP-hESCs carrying a complete loss-of-function of a single APC allele (FAP3) generated complex and molecularly mature colon organoids, which were similar to controls. In contrast, FAP-hESCs carrying APC truncation mutations (FAP1 and FAP2) generated only few cyst-like structures and cell aggregates of various shape, occasionally with luminal parts, which aligned with their failure to upregulate critical differentiation genes early in the process, as shown by RNA sequencing. Abnormal disease phenotype was shown also in non-pathological colon of FAP patients by the randomly distribution of proliferating cells throughout the crypts, compared to their focused localization in the lower part of the crypt in healthy/non-FAP patients. Genotype/phenotype analysis revealed correlations between the colon organoid maturation potential and FAP severity in the carrier parents. In conclusion, this study suggest that a single truncated APC allele is sufficient to initiate early molecular tumorigenic activity. In addition, the results hint that patient-specific hESC-derived colon organoids can probably predict disease severity among FAP patients.

Project description:IntroductionDiffusion-weighted magnetic resonance imaging is increasingly available for investigation of canine brain diseases. Apparent diffusion coefficient (ADC) of normal canine brains is reported only in small numbers of subjects. The aim of the study was to investigate the ADC of different anatomical regions in the morphologically normal brain in a large population of canine patients in clinical setting. Additionally, possible influence on the ADC value of patient-related factors like sex, age and body weight, difference between the left and right side of the cerebral hemispheres, and between gray and white matter were investigated.MethodsBrain magnetic resonance studies including diffusion-weighted images of dogs presented at the Vetsuisse Faculty-University Zurich between 2015 and 2020 were reviewed retrospectively. Only morphologically normal brain magnetic resonance studies of dogs presented with neurological signs or non-neurological signs were included. Apparent diffusion coefficient values of 12 regions of interest (ROIs) in each hemisphere and an additional region in the cerebellar vermis were examined in each dog.ResultsA total of 321 dogs (including 247 dogs with neurological signs and 62 dogs with non-neurological signs) of various breeds, sex and age were included. Apparent diffusion coefficient significantly varied among most anatomical brain regions. A significantly higher ADC was measured in the gray [median 0.79 (range 0.69-0.90) × 10-3 mm2/s] compared to the white matter [median 0.70 (range 0.63-0.85) × 10-3 mm2/s]. No significant differences were found between the left and right cerebral hemispheres in most of the regions, neither between sexes, different reproductive status, and not consistently between body weight groups. Age was correlated first with a decrease from dogs <1 year of age to middle-age (⩾3 to <8 years) dogs and later with an increase of ADC values in dogs ⩾8 years.DiscussionApparent diffusion coefficient values of 25 ROIs were described in 321 morphologically normal canine brains in clinical setting. Apparent diffusion coefficient differences depending on the brain anatomical region are present. Apparent diffusion coefficient differences among age classes are present, likely consistent with brain maturation and aging. The described data can be a reference for future studies in clinical settings on the canine brain.

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

Publications

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

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