How can we treat cancer more effectively? Traditionally, tumours from the same anatomical site are treated as one tumour entity. This concept has been challenged by recent breakthroughs in cancer genomics and translational research that have enabled molecular tumour profiling. The identification and validation of cancer drivers that are shared between different tumour types, spurred the new paradigm to target driver pathways across anatomical sites by off-label drug use, or within so-called basket or umbrella trials which are designed to test whether molecular alterations in one tumour entity can be extrapolated to all others. However, recent clinical and preclinical studies suggest that there are tissue- and cell type-specific differences in tumorigenesis and the organization of oncogenic signalling pathways. In this Opinion article, we focus on the molecular, cellular, systemic and environmental determinants of organ-specific tumorigenesis and the mechanisms of context-specific oncogenic signalling outputs. Investigation, recognition and in-depth biological understanding of these differences will be vital for the design of next-generation clinical trials and the implementation of molecularly guided cancer therapies in the future.

Tissue-specific tumorigenesis: context matters.

Kidney cancer is not a single disease; it is made up of a number of different types of cancer, including clear cell, type 1 papillary, type 2 papillary, chromophobe, TFE3, TFEB, and oncocytoma. Sporadic, nonfamilial kidney cancer includes clear cell kidney cancer (75%), type 1 papillary kidney cancer (10%), papillary type 2 kidney cancer (including collecting duct and medullary RCC) (5%), the microphalmia-associated transcription (MiT) family translocation kidney cancers (TFE3, TFEB, and MITF), chromophobe kidney cancer (5%), and oncocytoma (5%). Each has a distinct histology, a different clinical course, responds differently to therapy, and is caused by mutation in a different gene. Genomic studies identifying the genes for kidney cancer, including the VHL, MET, FLCN, fumarate hydratase, succinate dehydrogenase, TSC1, TSC2, and TFE3 genes, have significantly altered the ways in which patients with kidney cancer are managed. While seven FDA-approved agents that target the VHL pathway have been approved for the treatment of patients with advanced kidney cancer, further genomic studies, such as whole genome sequencing, gene expression patterns, and gene copy number, will be required to gain a complete understanding of the genetic basis of kidney cancer and of the kidney cancer gene pathways and, most importantly, to provide the foundation for the development of effective forms of therapy for patients with this disease.

/pdf/genetic-basis-of-kidney-cancer-role-of-genomics-for-the-vzkowwr1f8.pdf

Genetic basis of kidney cancer: Role of genomics for the development of disease-based therapeutics

One of the most prevalent forms of post-transcritpional RNA modification is the conversion of adenosine nucleosides to inosine (A-to-I), mediated by the ADAR family of enzymes. The functional requirement and regulatory landscape for the majority of A-to-I editing events are, at present, uncertain. Recent studies have identified key in vivo functions of ADAR enzymes, informing our understanding of the biological importance of A-to-I editing. Large-scale studies have revealed how editing is regulated both in cis and in trans. This review will explore these recent studies and how they broaden our understanding of the functions and regulation of ADAR-mediated RNA editing.

/pdf/rewriting-the-transcriptome-adenosine-to-inosine-rna-editing-17c3dhv0jj.pdf

Rewriting the transcriptome: adenosine-to-inosine RNA editing by ADARs

https://www.europeanurology.com/article/S0302-2838(14)00420-5/pdf/systemic-therapy-for-non-clear-cell-renal-cell-carcinomas-a-systematic-review-and-meta-analysis

Systemic Therapy for Non–clear Cell Renal Cell Carcinomas: A Systematic Review and Meta-analysis

Renal cell carcinoma (RCC) is characterized by an infrequent number of somatic mutations. By contrast, epigenetic aberrations are commonly found in RCC, indicating that epigenetic reprogramming is an important event in RCC development. Epigenetic alterations comprise several different aberrations, such as changes in histone modifications, DNA methylation, and microRNA levels, and occur in the most important signalling pathways in RCC, such as the von Hippel-Lindau disease tumour suppressor (VHL)-hypoxia-inducible factor (HIF) pathway, the WNT-β-catenin pathway, and pathways involved in epithelial-mesenchymal transition. Owing to their involvement in these pathways and frequent occurrence in RCC, epigenetic alterations are regarded as potential biomarkers for the early detection of disease and for prediction of prognosis and treatment response. In addition, most of these alterations are potentially reversible, so they also provide new targets for therapy. At the moment, epigenetic biomarkers for RCC are not being used in clinical practice, but targeted epigenetic therapies are under investigation. Understanding the extent of epigenetic changes occurring in RCC and the mechanisms by which they influence disease progression and treatment response, as well as knowledge of current research on biomarkers and treatments, is crucial to successful clinical translation of epigenetics in RCC.

Epigenetics in renal cell cancer: mechanisms and clinical applications

Renal tumor heterogeneity studies have utilized the von Hippel-Lindau VHL gene to classify disease into molecularly defined subtypes to examine associations with etiologic risk factors and prognosis. The aim of this study was to provide a comprehensive analysis of VHL inactivation in clear cell renal tumors (ccRCC) and to evaluate relationships between VHL inactivation subgroups with renal cancer risk factors and VHL germline single nucleotide polymorphisms (SNPs). VHL genetic and epigenetic inactivation was examined among 507 sporadic RCC/470 ccRCC cases using endonuclease scanning and using bisulfite treatment and Sanger sequencing across 11 CpG sites within the VHL promoter. Case-only multivariate analyses were conducted to identify associations between alteration subtypes and risk factors. VHL inactivation, either through sequence alterations or promoter methylation in tumor DNA, was observed among 86.6% of ccRCC cases. Germline VHL SNPs and a haplotype were associated with promoter hypermethylation in tumor tissue (OR=6.10; 95% CI: 2.28–16.35, p=3.76E-4, p-global=8E-5). Risk of having genetic VHL inactivation was inversely associated with smoking due to a higher proportion of wild-type ccRCC tumors [former: OR=0.70 (0.20–1.31) and current: OR=0.56 (0.32–0.99); P-trend=0.04]. Alteration prevalence did not differ by histopathologic characteristics or occupational exposure to trichloroethylene. ccRCC cases with particular VHL germline polymorphisms were more likely to have VHL inactivation through promoter hypermethylation than through sequence alterations in tumor DNA, suggesting that the presence of these SNPs may represent an example of facilitated epigenetic variation (an inherited propensity towards epigenetic variation) in renal tissue. A proportion of tumors from current smokers lacked VHL alterations and may represent a biologically distinct clinical entity from inactivated cases.

/pdf/von-hippel-lindau-vhl-inactivation-in-sporadic-clear-cell-5ebryewqj3.pdf

Von Hippel-Lindau (VHL) inactivation in sporadic clear cell renal cancer: associations with germline VHL polymorphisms and etiologic risk factors.

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Von Hippel-Lindau (VHL) inactivation in sporadic clear cell renal cancer: associations with germline VHL polymorphisms and etiologic risk factors.