Key Points
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Renal cell carcinoma (RCC) is a heterogeneous group of cancers with different subtypes and varying histological and clinical manifestations
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Genome-level analysis of constitutional (germline) DNA has identified candidate genetic variants that predispose to RCC
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Molecular characterization has revealed distinct landscapes of somatic genomic and epigenomic alterations in RCC subtypes, and has advanced our understanding of underlying mechanisms
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Genomic signatures can provide a molecular diagnosis of RCC and guide therapy selection to target specific molecular aberrations, thereby moving towards precision medicine
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Genome analysis of RCC tumours has uncovered previously unrecognized environmental exposures with possible consequences for intervention
Abstract
Genomics is revolutionizing our understanding of the molecular basis of renal cell carcinoma (RCC). The advent of unbiased genome-wide association studies has led to the discovery of previously unrecognized genetic predisposing factors that impact an individual's risk of developing RCC. Moreover, large-scale investigations of somatic alterations of the genomic and transcriptomic landscapes in tumours using next-generation sequencing technology have revealed new information on the molecular pathways that are characteristically disrupted in various RCC subtypes. Sequencing studies have revealed that epigenetic machinery and chromatin remodelling complexes are disrupted in >80% of clear cell RCC tumours, the most common form of the disease. The growing knowledge of subtype-specific molecular abnormalities arising from genomics has opened new avenues towards the development of molecular diagnostics for RCC subtypes, and for the rational design of therapeutic approaches tailored to patients based on the molecular profiles of their tumours. Genomic studies have also pinpointed a possible role of environmental exposure to aristolochic acid, a nephrotoxin, in the genesis of the disease in some regions of central Europe. In this Review, we discuss the impact of genomics in identifying the genes and environmental exposures involved in disease susceptibility, and in discovering the molecular pathways that are disrupted somatically in different RCC subtypes. Further, we explore the possibilities provided by this genomic knowledge in providing a precision medicine approach for diagnosing and treating RCC.
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Acknowledgements
The authors' work was supported by a grant from Génome Québec, le Ministère de l'Enseignement supérieur, de la Recherche, de la Science et de la Technologie (MESRST) Québec and McGill University.
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Y.R. and M.L. researched the data for the article, contributed equally to discussions of the content, wrote the article and reviewed or edited the manuscript before submission.
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Glossary
- Loss of heterozygosity
-
Human chromosomes and genes have two alleles or copies, each of which is inherited from one parent. Loss of heterozygosity happens when one of the two alleles of a gene is deleted, and often results in the somatic loss of the wild-type allele in cancer.
- Copy number variation
-
Alterations in the number of copies of a gene or a larger genomic region (such as a segment of a chromosome or an entire chromosome) in the genotype of an individual.
- Non-synonymous mutations
-
DNA mutations that alter the identity and sequence of amino acids in the encoded protein.
- Aneuploidy
-
A genetic defect characterized by the presence of an abnormal number of chromosomes.
- Sarcomatoid features
-
Histologic features that contain foci of high-grade malignant spindle cells in RCC tumours.
- Fusion genes
-
A fusion gene is formed by joining parts of two separate genes. Fusion genes are common in cancers and result from structural abnormalities that involve one or more chromosomes.
- CpG island methylator phenotype
-
Widespread hypermethylation of CpG islands at gene promoters.
- Mutational load
-
The abundance of mutations or of a specific type of mutation in the genome.
- Indels
-
A class of mutations caused by insertion or deletion of a small number of nucleotides (ranging from 1–1,000 base pairs) in the genome.
- Subclonal
-
Mutations that are not present in the entire population of cancerous cells within a tumour bulk.
- Switch events
-
Changes in the identity of the most abundant spliced variant of a gene in tumour tissue compared to normal tissue in the same patient.
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Riazalhosseini, Y., Lathrop, M. Precision medicine from the renal cancer genome. Nat Rev Nephrol 12, 655–666 (2016). https://doi.org/10.1038/nrneph.2016.133
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DOI: https://doi.org/10.1038/nrneph.2016.133
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