Hereditary renal cell carcinoma syndromes: diagnosis, surveillance and management.

PURPOSE: Genetic factors have been implicated in the pathogenesis of renal cell carcinoma (RCC), with around 3% of cases having a family history. A greater knowledge of the genetics of inherited RCC has the potential to translate into novel therapeutic targets for sporadic RCC. METHODS: A literature review was performed summarising the current knowledge on hereditary RCC diagnosis, surveillance and management. RESULTS: Familial RCC is usually inherited in an autosomal dominant manner, although inherited RCC may present without a relevant family history. A number of familial RCC syndromes have been identified. Familial non-syndromic RCC is suspected when ≥ 2 relatives are affected in the absence of syndromic features, although clear diagnostic criteria are lacking. Young age at onset and bilateral/multicentric tumours are recognised characteristics which should prompt molecular genetic analysis. Surveillance in individuals at risk of inherited RCC aims to prevent morbidity and mortality via early detection of tumours. Though screening and management guidelines for some inherited RCC syndromes (e.g. von Hippel-Lindau disease, Birt-Hogg-Dube syndrome, hereditary leiomyomatosis) are well defined for rare cause of inherited RCC (e.g. germline BAP1 mutations), there is limited information regarding the lifetime RCC risks and the most appropriate screening modalities. CONCLUSION: Increasing knowledge of the natural history and genetic basis has led to characterisation and tailored management of hereditary RCC syndromes. International data sharing of inherited RCC gene variant information may enable evidence-based improvements in the diagnosis, surveillance protocols and management of these rare conditions

Epigenetics of renal cell carcinoma: the path towards new diagnostics and therapeutics

Aberrant DNA methylation, in particular promoter hypermethylation and transcriptional silencing of tumor suppressor genes, has an important role in the development of many human cancers, including renal cell carcinoma (RCC). Indeed, apart from mutations in the well studied von Hippel-Lindau gene (VHL), the mutation frequency rates of known tumor suppressor genes in RCC are generally low, but the number of genes found to show frequent inactivation by promoter methylation in RCC continues to grow. Here, we review the genes identified as epigenetically silenced in RCC and their relationship to pathways of tumor development. Increased understanding of RCC epigenetics provides new insights into the molecular pathogenesis of RCC and opportunities for developing novel strategies for the diagnosis, prognosis and management of RCC

The Unknown Terror: Credit Card Debt Among The American Middle Class

This Capstone focuses on a true crisis that affects many middle class Americans. Credit card debt has become a norm for American society and quietly has terrorized and dismantled the lives of many middle class Americans. From the rolling back of usury laws protecting predatorial interest rates, to many Americans losing jobs and income. This paper discusses the relationship between the reliance on credit cards and crippling debt for many Americans in the middle class

Genetic stratification of inherited and sporadic phaeochromocytoma and paraganglioma: implications for precision medicine.

Over the past two decades advances in genomic technologies have transformed knowledge of the genetic basis of phaeochromocytoma and paraganglioma (PPGL). Though traditional teaching suggested that inherited cases accounted for only 10% of all phaeochromocytoma diagnosis, current estimates are at least three times this proportion. Inherited PPGL is a highly genetically heterogeneous disorder but the most frequently results from inactivating variants in genes encoding subunits of succinate dehydrogenase. Expanding knowledge of the genetics of PPGL has been translated into clinical practice by the provision of widespread testing for inherited PPGL. In this review, we explore how the molecular stratification of PPGL is being utilized to enable more personalized strategies for investigation, surveillance and management of affected individuals and their families. Translating recent genetic research advances into clinical service can not only bring benefits through more accurate diagnosis and risk prediction but also challenges when there is a suboptimal evidence base for the clinical consequences or significance of rare genotypes. In such cases, clinical, biochemical, pathological and functional imaging assessments can all contribute to more accurate interpretation and clinical management.We apologise to all the authors whose work we were unable to cite because of space constraints. We thank Dr Birke Bausch, University of Freiburg, Germany and Anna Roslyakowa, Department of Surgery, Endocrinology Research Center, Moscow, Russia for their expert input. RC acknowledges support from AMEND and GIST Support UK. ERM acknowledges support from European Research Council (Advanced Researcher Award), NIHR (Senior Investigator Award and Cambridge NIHR Biomedical Research Centre) and Cancer Research UK Cambridge Cancer Centre. The views expressed are those of the authors and not necessarily those of the NHS or NIHR. The University of Cambridge has received salary support in respect of EM from the NHS in the East of England through the Clinical Academic Reserve

von Hippel-Lindau Disease: an Update

Funder: University of CambridgeAbstract: Purpose of Review: In this review, we discuss the key molecular and clinical developments in VHL disease that have the potential to impact on the natural history of the disease and improve patient outcomes. Recent Findings: Identifiable mutations in VHL underlie most cases of VHL and define clear genotype-phenotype correlations. Detailed clinical and molecular characterisation has allowed the implementation of lifelong screening programmes that have improved clinical outcomes. Functional characterisation of the VHL protein complex has revealed its role in oxygen sensing and the mechanisms of tumourigenesis that are now being exploited to develop novel therapies for VHL and renal cancer. Summary: The molecular and cellular landscape of VHL-associated tumours is revealing new opportunities to modify the natural history of the disease and develop therapies. Drugs are now entering clinical trials and combined with improved clinical and molecular diagnosis, and lifelong surveillance programmes, further progress towards reducing the morbidity and mortality associated with VHL disease is anticipated

In Vitro Selection of a Single-Stranded DNA Molecular Recognition Element against Clostridium difficile Toxin B and Sensitive Detection in Human Fecal Matter

Toxin B is one of the major virulence factors of Clostridium difficile, a bacterium that is responsible for a significant number of diarrhea cases in acute care settings. Due to the prevalence of C. difficile induced diarrhea, rapid and correct diagnosis is crucial in the disease management. In this study, we have employed a stringent in vitro selection method to identify single-stranded DNA molecular recognition elements (MRE) specific for toxin B. At the end of the 12-round selection, one MRE with high affinity  nM) for toxin B was identified. The selected MRE demonstrated low cross binding activities on negative targets: bovine serum albumin, Staphylococcus aureus alpha toxin, Pseudomonas aeruginosaexotoxin A, and cholera toxin of Vibrio cholera. A modified sandwich ELISA assay was developed utilizing the selected ssDNA MRE as the antigen capturing element and achieved a sensitive detection of 50 nM of toxin B in human fecal preparations

In Vitro

Toxin B is one of the major virulence factors of Clostridium difficile, a bacterium that is responsible for a significant number of diarrhea cases in acute care settings. Due to the prevalence of C. difficile induced diarrhea, rapid and correct diagnosis is crucial in the disease management. In this study, we have employed a stringent in vitro selection method to identify single-stranded DNA molecular recognition elements (MRE) specific for toxin B. At the end of the 12-round selection, one MRE with high affinity (Kd=47.3 nM) for toxin B was identified. The selected MRE demonstrated low cross binding activities on negative targets: bovine serum albumin, Staphylococcus aureus alpha toxin, Pseudomonas aeruginosa exotoxin A, and cholera toxin of Vibrio cholera. A modified sandwich ELISA assay was developed utilizing the selected ssDNA MRE as the antigen capturing element and achieved a sensitive detection of 50 nM of toxin B in human fecal preparations

Analysis of Germline Variants in CDH1, IGFBP3, MMP1, MMP3, STK15 and VEGF in Familial and Sporadic Renal Cell Carcinoma

BACKGROUND:The investigation of rare familial forms of kidney cancer has provided important insights into the biology of sporadic renal cell carcinoma (RCC). In particular, the identification of the von Hippel Lindau (VHL) familial cancer syndrome gene (VHL) provided the basis for the discovery that VHL is somatically inactivated in most sporadic clear cell RCC. Many cases of familial RCC do not have mutations in known RCC susceptibility genes and there is evidence that genetic modifiers may influence the risk of RCC in VHL disease patients. Hence we hypothesised that low-penetrance functional genetic variants in pathways related to the VHL protein (pVHL) function might (a) modify the phenotypic expression of VHL disease and/or (b) predispose to sporadic RCC. METHODOLOGY/PRINCIPAL FINDINGS:We tested this hypothesis for functional polymorphisms in CDH1 (rs16260), IGFBP3 (rs2854744), MMP1 (rs1799750), MMP3 (rs679620), STK15 (rs2273535) and VEGF (rs1570360). We observed that variants of MMP1 and MMP3 were significant modifiers of RCC risk (and risks of retinal angioma and cerebellar haemangioblastoma) in VHL disease patients. In addition, higher frequencies of the MMP1 rs1799750 2G allele (p = 0.017, OR 1.49, 95%CI 1.06-2.08) and the MMP1/MMP3 rs1799750/rs679620 2G/G haplotype (OR 1.45, 95%CI 1.01-2.10) were detected in sporadic RCC patients than in controls (n = 295). CONCLUSIONS/SIGNIFICANCE:These findings (a) represent the first example of genetic modifiers of RCC risk in VHL disease, (b) replicate a previous report of an association between MMP1/MMP3 variants and sporadic RCC and (c) further implicate MMP1/MMP3-related pathways in the pathogenesis of familial and sporadic RCC

Wilms tumour resulting from paternal transmission of a TRIM28 pathogenic variant - A first report

Wilms tumour (nephroblastoma) is a renal embryonal tumour that is frequently caused by constitutional variants in a small range of cancer predisposition genes. TRIM28 has recently been identified as one such gene. Previously, observational data strongly suggested a parent of origin effect, whereby Wilms tumour only occurred following maternal inheritance of a pathogenic genetic variant. However, here we report a child with bilateral Wilms tumour who had inherited a pathogenic TRIM28 variant from their father. This finding suggests that genetic counselling for paternally inherited pathogenic variants in TRIM28 should include discussion of a potential risk of Wilms tumour