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Clear cell renal cell carcinoma ontogeny and mechanisms of lethality

Nature Reviews Nephrology volume 17, pages 245–261 (2021)Cite this article

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Abstract

The molecular features that define clear cell renal cell carcinoma (ccRCC) initiation and progression are being increasingly defined. The TRACERx Renal studies and others that have described the interaction between tumour genomics and remodelling of the tumour microenvironment provide important new insights into the molecular drivers underlying ccRCC ontogeny and progression. Our understanding of common genomic and chromosomal copy number abnormalities in ccRCC, including chromosome 3p loss, provides a mechanistic framework with which to organize these abnormalities into those that drive tumour initiation events, those that drive tumour progression and those that confer lethality. Truncal mutations in ccRCC, including those in VHL, SET2, PBRM1 and BAP1, may engender genomic instability and promote defects in DNA repair pathways. The molecular features that arise from these defects enable categorization of ccRCC into clinically and therapeutically relevant subtypes. Consideration of the interaction of these subtypes with the tumour microenvironment reveals that specific mutations seem to modulate immune cell populations in ccRCC tumours. These findings present opportunities for disease prevention, early detection, prognostication and treatment.

Key points

  • Chromosome 3p loss is an almost universal finding in both hereditary and sporadic clear cell renal cell carcinoma (ccRCC).

  • The near ubiquitous loss of a second copy of VHL seems to provide a selective advantage for cells, as well as leading to defects in DNA repair and an increase in genomic instability.

  • Secondarily mutated genes in ccRCC, including PBRM1, SETD2 and BAP1, as well as copy number changes in chromosomes 9p and 14q, are associated with prognostically important molecular and phenotypic characteristics that can be used to classify tumours into subgroups.

  • Tumour genomic features are associated with distinct immune phenotypes; for example, PBRM1 mutations are associated with reduced infiltration of T cells.

  • Efforts are underway to link genomic features to specific therapeutic strategies for patients with ccRCC.

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Fig. 1: Key discoveries in ccRCC genomics.
Fig. 2: Key events in clear cell renal cell carcinoma progression.
Fig. 3: Non-HIF targets of VHL.
Fig. 4: Factors influencing mismatch repair in ccRCC.
Fig. 5: Factors influencing homologous recombination repair in clear cell renal cell carcinoma.
Fig. 6: Alterations in the immune microenvironment in clear cell renal cell carcinoma.

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Authors and Affiliations

  1. Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Eric Jonasch

  2. Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, USA

    Cheryl Lyn Walker

  3. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    W. Kimryn Rathmell

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The authors contributed equally to all aspects of the article.

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Correspondence to Eric Jonasch.

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Competing interests

E.J. has received research funding from Exelixis, Novartis, Peloton and Pfizer and consulting fees from Eisai, Exelixis, Genentech, Ipsen, Novartis, Peloton, Pfizer and Roche. The other authors declare no competing interests.

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Nature Reviews Nephrology thanks O. Iliopoulos, S. Turajlic and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Haploinsufficient

A situation in which one copy of a gene is inactivated; for such haploinsufficient genes, gene function is thus altered in heterozygotes, as the remaining (functional) copy does not produce sufficient gene product for normal function.

Von Hippel–Lindau (VHL) disease

A hereditary condition associated with the development of cysts and tumours in multiple organs.

Chromothripsis

A phenomenon by which tens to thousands of chromosomal rearrangements occur; chromothripsis may result from a single catastrophic event during the life history of a cell.

Micronuclei

The small nucleus that forms when a chromosome or a fragment of a chromosome is not incorporated into one of the daughter nuclei during mitosis. It is usually a sign of genotoxic events and chromosomal instability.

Aneugens

Substances that cause a daughter cell to have an abnormal number of chromosomes.

Clastogens

Mutagenic agents that give rise to or induce disruption or breakages of chromosomes.

Chromosome bridges

Attachments of the telomeric ends of sister chromatids during mitosis, specifically during anaphase, preventing segregation into respective daughter cells.

Cytokinesis

The physical process of cell division, which divides the cytoplasm of a parental cell into two daughter cells.

Aneuploidy

An abnormal number of chromosomes in a cell.

Replication stress

Any condition that compromises the faithful duplication of the genome once per cell cycle.

Acetyl-lysine reader

A protein that recognizes acetylated lysine residues in promoters and enhancers and has an active role in gene transcription.

Kinetochore

A large protein complex that assembles at the centromere of a chromosome and functions to connect the chromosome to microtubules in the mitotic spindle.

Genome instability index

An estimate of the proportion of the genome with aberrant copy number compared with the median ploidy, weighted on a per chromosome basis.

Intratumoural heterogeneity

(ITH). The presence of distinct tumour cell populations within the same tumour specimen.

Cryptic transcription

Transcripts initiated from intragenic promoters that are usually not accessible to transcriptional machinery.

DNA mismatch repair

A process for recognizing and repairing erroneous insertion, deletion and misincorporation of bases that can arise during DNA replication and recombination, or through DNA damage.

Microsatellite instability

Genetic predisposition to mutation that results from impaired DNA mismatch repair.

Lynch syndrome

An inherited disorder that arises from germline genetic defects in mismatch repair components and increases the risk of many types of cancer, particularly cancers of the colon.

Non-homologous end joining

(NHEJ). A pathway that repairs double-strand breaks in DNA without the need for a homologous template.

Homologous recombination repair

(HRR). A DNA repair process in which an intact DNA molecule is used as a template for the repair process, in particular during the S phase.

Cell cycle checkpoint

Control mechanisms in the eukaryotic cell cycle that ensure its proper progression.

Microhomology repair

An error-prone, alternative form of non-homologous end joining that involves alignment of microhomologous sequences internal to the broken ends before joining.

PARP inhibitors

A group of pharmacological inhibitors of the enzyme poly(ADP-ribose) polymerase (PARP).

Somatic copy number alterations

(SCNAs). Somatic changes to chromosome structure that result in gain or loss of copies of sections of DNA.

Circulating tumour DNA

(ctDNA). DNA in the bloodstream that comes from cancerous cells and tumours.

Synthetic lethality

The concept whereby the simultaneous mutation of two genes leads to the lethality of a cell, but the mutation of one alone is viable.

cGAS–STING pathway

A component of the innate immune system that functions to detect the presence of cytosolic DNA and triggers the expression of inflammatory genes.

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Jonasch, E., Walker, C.L. & Rathmell, W.K. Clear cell renal cell carcinoma ontogeny and mechanisms of lethality. Nat Rev Nephrol 17, 245–261 (2021). https://doi.org/10.1038/s41581-020-00359-2

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