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Genomic profiling in renal cell carcinoma

Nature Reviews Nephrology volume 16, pages 435–451 (2020)Cite this article

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Abstract

The treatment landscape of metastatic renal cell carcinoma (RCC) has been revolutionized over the past two decades, bringing forth an era in which more than a dozen therapeutic agents are now available to treat patients. As a consequence, personalized care has become a critical part of developing effective treatment guidelines and improving patient outcomes. One of the most important emerging aspects of precision medicine in cancer is matching patients and treatments based on the genomic characteristics of an individual and their tumour. Despite the lack of a single genomic predictor of treatment response or prognostication feature in RCC, emerging research suggests that the identification of such markers remains promising. Mutations in VHL and alterations in its downstream pathways are the mainstay of RCC development and progression. However, the predictive value of VHL mutations has been questioned. Further research has examined mutations in genes involved in chromosome remodelling (for example, PBRM1, BAP1 and SETD2), DNA methylation and DNA damage repair, all of which have been associated with clinical outcomes. Here, we provide a comprehensive overview of genomic evidence in the context of RCC and its potential predictive and prognostic value.

Key points

  • Renal cell carcinoma (RCC) is a complex disease entity with different histological subtypes characterized by distinct clinical and pathophysiological features; genomic research has identified relevant alterations associated with each RCC subtype.

  • In the past two decades, new insights into the mechanisms that underlie the development and progression of RCC have expanded treatment options; genomic data might guide treatment choices by enabling individuals to be matched with therapeutics that specifically target the genomic and molecular alterations present in their tumours.

  • Despite a mechanistic link between VHL alterations and RCC, alterations in this driver gene are not clearly associated with clinical outcomes.

  • Growing evidence supports the prognostic value of chromatin remodelling genes, such as PBRM1 and BAP1; alterations in PBRM1 also seem to have predictive value in responses to immunotherapy.

  • Concerning non-clear cell RCC, investigations are underway to identify the clinical role of alterations in genes such as MET in papillary RCC, TERT, TP53 and PTEN in chromophobe RCC, NF2 in collecting duct RCC and EZH2 in medullary subtypes of RCC.

  • The unique genomic and clinical features of a patient have a complex effect on disease progression and responses to treatment — this variability must be addressed when assessing potential prognostic and predictive factors in RCC.

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Fig. 1: Evolution of therapies in the metastatic RCC armamentarium.
Fig. 2: Location and cell of origin of RCC histological subtypes.
Fig. 3: Functional consequences of chromosome 3p loss.

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Authors and Affiliations

  1. Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA

    Nazli Dizman & Sumanta K. Pal

  2. University of California San Francisco (UCSF) School of Medicine, San Francisco, CA, USA

    Errol J. Philip

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All authors researched data for the article, wrote the manuscript, made substantial contributions to discussions of the content and reviewed or edited the manuscript before submission.

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Correspondence to Sumanta K. Pal.

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S.K.P. consults for Genentech, Aveo, Eisai, Roche, Pfizer, Novartis, Exelixis, Ipsen, BMS and Astellas. N.D. and E.J.P. declare no competing interests.

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Glossary

Chromothripsis

The shattering of a chromosome and reassembly of its fragments in a different order and orientation.

Loss of heterozygosity

A chromosomal event involving the loss of one allele of a gene or a chromosomal region.

Fuhrman grade

A scoring system based on pathological appearance (that is, diameter, shape and characteristics of nuclei) of renal cell carcinoma cells.

Rhabdoid pathological features

Pathological characteristics that may be present in RCC cells and include a large and prominent nucleus, and prominent eosinophilic inclusion bodies.

Microsatellite instability

The tendency to accumulate abnormally high rates of mutations owing to defects in DNA mismatch repair.

Nude mice

Laboratory mice with impaired T cell-mediated immunity due to the absence of a thymus.

TNM stage

A cancer staging system based on tumour extent, nodal involvement and the presence of metastatic disease.

Genomic hybridization studies

Genetic method used to analyse copy number variations.

Spindle cells

Narrow and elongated, spindle-shaped cells that can be present in sarcoma.

Adjuvant therapies

Cancer therapies used with the intention of avoiding disease recurrence after complete resection of a tumour.

Neoadjuvant settings

Treatment settings in which a cancer therapeutic is given to a patient with the intention of decreasing tumour burden before definitive surgery.

Allelic imbalance

Instance in which two alleles of a gene have different levels of expression.

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Dizman, N., Philip, E.J. & Pal, S.K. Genomic profiling in renal cell carcinoma. Nat Rev Nephrol 16, 435–451 (2020). https://doi.org/10.1038/s41581-020-0301-x

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