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Clear cell renal cell carcinoma ontogeny and mechanisms of lethality


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.


  1. 1.

    Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394–424 (2018).

    Article  Google Scholar 

  2. 2.

    Jonasch, E., Gao, J. & Rathmell, W. K. Renal cell carcinoma. BMJ 349, g4797 (2014).

    Article  Google Scholar 

  3. 3.

    Hagemeijer, A., Hoehn, W. & Smit, E. M. Cytogenetic analysis of human renal carcinoma cell lines of common origin (NC 65). Cancer Res. 39, 4662–4667 (1979).

    CAS  Google Scholar 

  4. 4.

    Szucs, S., Muller-Brechlin, R., DeRiese, W. & Kovacs, G. Deletion 3p: the only chromosome loss in a primary renal cell carcinoma. Cancer Genet. Cytogenet. 26, 369–373 (1987).

    CAS  Article  Google Scholar 

  5. 5.

    Yoshida, M. A. et al. Rearrangement of chromosome 3 in renal cell carcinoma. Cancer Genet. Cytogenet. 19, 351–354 (1986).

    CAS  Article  Google Scholar 

  6. 6.

    Latif, F. et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260, 1317–1320 (1993).

    CAS  Article  Google Scholar 

  7. 7.

    Varela, I. et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469, 539–542 (2011).

    CAS  Article  Google Scholar 

  8. 8.

    Pena-Llopis, S. et al. BAP1 loss defines a new class of renal cell carcinoma. Nat. Genet. 44, 751–759 (2012).

    CAS  Article  Google Scholar 

  9. 9.

    Dalgliesh, G. L. et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360–363 (2010).

    CAS  Article  Google Scholar 

  10. 10.

    The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499, 43–49 (2013).

  11. 11.

    Klatte, T. et al. Cytogenetic profile predicts prognosis of patients with clear cell renal cell carcinoma. J. Clin. Oncol. 27, 746–753 (2009).

    Article  Google Scholar 

  12. 12.

    La Rochelle, J. et al. Chromosome 9p deletions identify an aggressive phenotype of clear cell renal cell carcinoma. Cancer 116, 4696–4702 (2010).

    Article  Google Scholar 

  13. 13.

    Monzon, F. A. et al. Chromosome 14q loss defines a molecular subtype of clear-cell renal cell carcinoma associated with poor prognosis. Mod. Pathol. 24, 1470–1479 (2011).

    CAS  Article  Google Scholar 

  14. 14.

    Shen, C. et al. Genetic and functional studies implicate HIF1alpha as a 14q kidney cancer suppressor gene. Cancer Discov. 1, 222–235 (2011).

    CAS  Article  Google Scholar 

  15. 15.

    Jiang, F. et al. Construction of evolutionary tree models for renal cell carcinoma from comparative genomic hybridization data. Cancer Res. 60, 6503–6509 (2000).

    CAS  Google Scholar 

  16. 16.

    Brannon, A. R. et al. Molecular stratification of clear cell renal cell carcinoma by consensus clustering reveals distinct subtypes and survival patterns. Genes Cancer 1, 152–163 (2010).

    CAS  Article  Google Scholar 

  17. 17.

    Rini, B. et al. A 16-gene assay to predict recurrence after surgery in localised renal cell carcinoma: development and validation studies. Lancet Oncol. 16, 676–685 (2015).

    CAS  Article  Google Scholar 

  18. 18.

    Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).

    CAS  Article  Google Scholar 

  19. 19.

    Turajlic, S. et al. Deterministic evolutionary trajectories influence primary tumor growth: TRACERx Renal. Cell 173, 595–610.e11 (2018).

    CAS  Article  Google Scholar 

  20. 20.

    Mitchell, T. J. et al. Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx Renal. Cell 173, 611–623.e17 (2018).

    CAS  Article  Google Scholar 

  21. 21.

    Turajlic, S. et al. Tracking cancer evolution reveals constrained routes to metastases: TRACERx Renal. Cell 173, 581–594.e12 (2018).

    CAS  Article  Google Scholar 

  22. 22.

    Monzon, F. A. et al. Whole genome SNP arrays as a potential diagnostic tool for the detection of characteristic chromosomal aberrations in renal epithelial tumors. Mod. Pathol. 21, 599–608 (2008).

    CAS  Article  Google Scholar 

  23. 23.

    Wang, L. et al. Whole-exome sequencing of human pancreatic cancers and characterization of genomic instability caused by MLH1 haploinsufficiency and complete deficiency. Genome Res. 22, 208–219 (2012).

    CAS  Article  Google Scholar 

  24. 24.

    Chiang, Y. C. et al. SETD2 Haploinsufficiency for microtubule methylation is an early driver of genomic instability in renal cell carcinoma. Cancer Res. 78, 3135–3146 (2018).

    CAS  Google Scholar 

  25. 25.

    Fei, S. S. et al. Patient-specific factors influence somatic variation patterns in von Hippel-Lindau disease renal tumours. Nat. Commun. 7, 11588 (2016).

    CAS  Article  Google Scholar 

  26. 26.

    Bakhoum, S. F. & Cantley, L. C. The multifaceted role of chromosomal instability in cancer and its microenvironment. Cell 174, 1347–1360 (2018).

    CAS  Article  Google Scholar 

  27. 27.

    Kalsbeek, D. & Golsteyn, R. M. G2/M-Phase checkpoint adaptation and micronuclei formation as mechanisms that contribute to genomic instability in human cells. Int. J. Mol. Sci. 18, 2344 (2017).

    Article  CAS  Google Scholar 

  28. 28.

    Podrimaj-Bytyqi, A. et al. The frequencies of micronuclei, nucleoplasmic bridges and nuclear buds as biomarkers of genomic instability in patients with urothelial cell carcinoma. Sci. Rep. 8, 17873 (2018).

    CAS  Article  Google Scholar 

  29. 29.

    Lonser, R. R. et al. Von Hippel-Lindau disease. Lancet 361, 2059–2067 (2003).

    CAS  Article  Google Scholar 

  30. 30.

    Ho, T. H. & Jonasch, E. Genetic kidney cancer syndromes. J. Natl Compr. Canc. Netw. 12, 1347–1355 (2014).

    CAS  Article  Google Scholar 

  31. 31.

    Nickerson, M. L. et al. Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin. Cancer Res. 14, 4726–4734 (2008).

    CAS  Article  Google Scholar 

  32. 32.

    Maxwell, P. H. et al. Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc. Natl Acad. Sci. USA 94, 8104–8109 (1997).

    CAS  Article  Google Scholar 

  33. 33.

    Flamme, I., Krieg, M. & Plate, K. H. Up-regulation of vascular endothelial growth factor in stromal cells of hemangioblastomas is correlated with up-regulation of the transcription factor HRF/HIF-2alpha. Am. J. Pathol. 153, 25–29 (1998).

    CAS  Article  Google Scholar 

  34. 34.

    Krieg, M. et al. Up-regulation of hypoxia-inducible factors HIF-1alpha and HIF-2alpha under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function. Oncogene 19, 5435–5443 (2000).

    CAS  Article  Google Scholar 

  35. 35.

    Maxwell, P. H. et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399, 271–275 (1999).

    CAS  Article  Google Scholar 

  36. 36.

    Keith, B., Johnson, R. S. & Simon, M. C. HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nat. Rev. Cancer 12, 9–22 (2011).

    Article  CAS  Google Scholar 

  37. 37.

    Takahashi, A. et al. Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res. 54, 4233–4237 (1994).

    CAS  Google Scholar 

  38. 38.

    Hu, C. J., Wang, L. Y., Chodosh, L. A., Keith, B. & Simon, M. C. Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol. Cell Biol. 23, 9361–9374 (2003).

    CAS  Article  Google Scholar 

  39. 39.

    Raval, R. R. et al. Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Mol. Cell Biol. 25, 5675–5686 (2005).

    CAS  Article  Google Scholar 

  40. 40.

    Carroll, V. A. & Ashcroft, M. Role of hypoxia-inducible factor (HIF)-1alpha versus HIF-2alpha in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-I, or loss of von Hippel-Lindau function: implications for targeting the HIF pathway. Cancer Res. 66, 6264–6270 (2006).

    CAS  Article  Google Scholar 

  41. 41.

    Kim, J. W., Tchernyshyov, I., Semenza, G. L. & Dang, C. V. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 3, 177–185 (2006).

    Article  CAS  Google Scholar 

  42. 42.

    Semenza, G. L. et al. Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J. Biol. Chem. 271, 32529–32537 (1996).

    CAS  Article  Google Scholar 

  43. 43.

    Zhang, H. et al. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J. Biol. Chem. 283, 10892–10903 (2008).

    CAS  Article  Google Scholar 

  44. 44.

    Bellot, G. et al. Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol. Cell Biol. 29, 2570–2581 (2009).

    CAS  Article  Google Scholar 

  45. 45.

    O’Bryan, J. P. et al. axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase. Mol. Cell Biol. 11, 5016–5031 (1991).

    Article  Google Scholar 

  46. 46.

    Lemke, G. Biology of the TAM receptors. Cold Spring Harb. Perspect. Biol. 5, a009076 (2013).

    Article  CAS  Google Scholar 

  47. 47.

    Lai, C., Gore, M. & Lemke, G. Structure, expression, and activity of Tyro 3, a neural adhesion-related receptor tyrosine kinase. Oncogene 9, 2567–2578 (1994).

    CAS  Google Scholar 

  48. 48.

    Rankin, E. B. et al. Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET. Proc. Natl Acad. Sci. USA 111, 13373–13378 (2014).

    CAS  Article  Google Scholar 

  49. 49.

    Zhou, L. et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene 35, 2687–2697 (2015).

    Article  CAS  Google Scholar 

  50. 50.

    Rankin, E. B. et al. Inactivation of the arylhydrocarbon receptor nuclear translocator (Arnt) suppresses von Hippel-Lindau disease-associated vascular tumors in mice. Mol. Cell Biol. 25, 3163–3172 (2005).

    CAS  Article  Google Scholar 

  51. 51.

    Fu, L., Wang, G., Shevchuk, M. M., Nanus, D. M. & Gudas, L. J. Generation of a mouse model of Von Hippel-Lindau kidney disease leading to renal cancers by expression of a constitutively active mutant of HIF1alpha. Cancer Res. 71, 6848–6856 (2011).

    CAS  Article  Google Scholar 

  52. 52.

    Fu, L., Wang, G., Shevchuk, M. M., Nanus, D. M. & Gudas, L. J. Activation of HIF2alpha in kidney proximal tubule cells causes abnormal glycogen deposition but not tumorigenesis. Cancer Res. 73, 2916–2925 (2013).

    CAS  Article  Google Scholar 

  53. 53.

    Schietke, R. E. et al. Renal tubular HIF-2alpha expression requires VHL inactivation and causes fibrosis and cysts. PLoS One 7, e31034 (2012).

    CAS  Article  Google Scholar 

  54. 54.

    Schonenberger, D. et al. Formation of renal cysts and tumors in vhl/trp53-deficient mice requires HIF1alpha and HIF2alpha. Cancer Res. 76, 2025–2036 (2016).

    CAS  Article  Google Scholar 

  55. 55.

    Zhang, J. & Zhang, Q. VHL and hypoxia signaling: beyond HIF in cancer. Biomedicines 6, 35 (2018).

    Article  CAS  Google Scholar 

  56. 56.

    Guo, J. et al. pVHL suppresses kinase activity of Akt in a proline-hydroxylation-dependent manner. Science 353, 929–932 (2016).

    CAS  Article  Google Scholar 

  57. 57.

    An, J. & Rettig, M. B. Mechanism of von Hippel-Lindau protein-mediated suppression of nuclear factor kappa B activity. Mol. Cell Biol. 25, 7546–7556 (2005).

    CAS  Article  Google Scholar 

  58. 58.

    Yang, H. et al. pVHL acts as an adaptor to promote the inhibitory phosphorylation of the NF-kappaB agonist Card9 by CK2. Mol. Cell 28, 15–27 (2007).

    Article  CAS  Google Scholar 

  59. 59.

    Peri, S., Devarajan, K., Yang, D. H., Knudson, A. G. & Balachandran, S. Meta-analysis identifies NF-kappaB as a therapeutic target in renal cancer. PLoS One 8, e76746 (2013).

    CAS  Article  Google Scholar 

  60. 60.

    Hu, L. et al. TBK1 is a synthetic lethal target in cancer with VHL loss. Cancer Discov. 10, 460–475 (2020).

    CAS  Article  Google Scholar 

  61. 61.

    Metcalf, J. L. et al. K63-ubiquitylation of VHL by SOCS1 mediates DNA double-strand break repair. Oncogene 33, 1055–1065 (2014).

    CAS  Article  Google Scholar 

  62. 62.

    Scanlon, S. E., Hegan, D. C., Sulkowski, P. L. & Glazer, P. M. Suppression of homology-dependent DNA double-strand break repair induces PARP inhibitor sensitivity in VHL-deficient human renal cell carcinoma. Oncotarget 9, 4647–4660 (2018).

    Article  Google Scholar 

  63. 63.

    Espana-Agusti, J., Warren, A., Chew, S. K., Adams, D. J. & Matakidou, A. Loss of PBRM1 rescues VHL dependent replication stress to promote renal carcinogenesis. Nat. Commun. 8, 2026 (2017).

    Article  CAS  Google Scholar 

  64. 64.

    Zhou, L. et al. Abstract: Tip60 dependent DNA homologous recombination repair is impaired in VHL-deficient clear cell renal cell carcinoma. Cancer Res. 78, 1364 (2018).

    Google Scholar 

  65. 65.

    Zhang, J. et al. VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma. Science 361, 290–295 (2018).

    Article  CAS  Google Scholar 

  66. 66.

    Calzada, M. J. et al. Von Hippel-Lindau tumor suppressor protein regulates the assembly of intercellular junctions in renal cancer cells through hypoxia-inducible factor-independent mechanisms. Cancer Res. 66, 1553–1560 (2006).

    CAS  Article  Google Scholar 

  67. 67.

    Stickle, N. H. et al. pVHL modification by NEDD8 is required for fibronectin matrix assembly and suppression of tumor development. Mol. Cell Biol. 24, 3251–3261 (2004).

    CAS  Article  Google Scholar 

  68. 68.

    Ohh, M. et al. The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. Mol. Cell 1, 959–968 (1998).

    CAS  Article  Google Scholar 

  69. 69.

    Kurban, G. et al. Collagen matrix assembly is driven by the interaction of von Hippel-Lindau tumor suppressor protein with hydroxylated collagen IV alpha 2. Oncogene 27, 1004–1012 (2008).

    CAS  Article  Google Scholar 

  70. 70.

    Kurban, G., Hudon, V., Duplan, E., Ohh, M. & Pause, A. Characterization of a von Hippel Lindau pathway involved in extracellular matrix remodeling, cell invasion, and angiogenesis. Cancer Res. 66, 1313–1319 (2006).

    CAS  Article  Google Scholar 

  71. 71.

    Clifford, S. C. & Maher, E. R. Von Hippel-Lindau disease: clinical and molecular perspectives. Adv. Cancer Res. 82, 85–105 (2001).

    CAS  Article  Google Scholar 

  72. 72.

    Hoffman, M. A. et al. Von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF. Hum. Mol. Genet. 10, 1019–1027 (2001).

    CAS  Article  Google Scholar 

  73. 73.

    Tang, N., Mack, F., Haase, V. H., Simon, M. C. & Johnson, R. S. pVHL function is essential for endothelial extracellular matrix deposition. Mol. Cell Biol. 26, 2519–2530 (2006).

    CAS  Article  Google Scholar 

  74. 74.

    Lolkema, M. P. et al. Tumor suppression by the von Hippel-Lindau protein requires phosphorylation of the acidic domain. J. Biol. Chem. 280, 22205–22211 (2005).

    CAS  Article  Google Scholar 

  75. 75.

    German, P. et al. Phosphorylation-dependent cleavage regulates von Hippel Lindau proteostasis and function. Oncogene 35, 4973–4980 (2016).

    CAS  Article  Google Scholar 

  76. 76.

    Hergovich, A., Lisztwan, J., Barry, R., Ballschmieter, P. & Krek, W. Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL. Nat. Cell Biol. 5, 64–70 (2003).

    CAS  Article  Google Scholar 

  77. 77.

    Schermer, B. et al. The von Hippel-Lindau tumor suppressor protein controls ciliogenesis by orienting microtubule growth. J. Cell Biol. 175, 547–554 (2006).

    CAS  Article  Google Scholar 

  78. 78.

    Esteban, M. A., Harten, S. K., Tran, M. G. & Maxwell, P. H. Formation of primary cilia in the renal epithelium is regulated by the von Hippel-Lindau tumor suppressor protein. J. Am. Soc. Nephrol. 17, 1801–1806 (2006).

    CAS  Article  Google Scholar 

  79. 79.

    Lutz, M. S. & Burk, R. D. Primary cilium formation requires von Hippel-Lindau gene function in renal-derived cells. Cancer Res. 66, 6903–6907 (2006).

    CAS  Article  Google Scholar 

  80. 80.

    Devlin, L. A. & Sayer, J. A. Renal ciliopathies. Curr. Opin. Genet. Dev. 56, 49–60 (2019).

    CAS  Article  Google Scholar 

  81. 81.

    Hasanov, E. et al. Ubiquitination and regulation of AURKA identifies a hypoxia-independent E3 ligase activity of VHL. Oncogene 36, 3450–3463 (2017).

    CAS  Article  Google Scholar 

  82. 82.

    Thoma, C. R. et al. VHL loss causes spindle misorientation and chromosome instability. Nat. Cell Biol. 11, 994–1001 (2009).

    CAS  Article  Google Scholar 

  83. 83.

    Hell, M. P., Duda, M., Weber, T. C., Moch, H. & Krek, W. Tumor suppressor VHL functions in the control of mitotic fidelity. Cancer Res. 74, 2422–2431 (2014).

    CAS  Article  Google Scholar 

  84. 84.

    Hell, M. P. et al. miR-28-5p promotes chromosomal instability in VHL-associated cancers by inhibiting Mad2 translation. Cancer Res. 74, 2432–2443 (2014).

    CAS  Article  Google Scholar 

  85. 85.

    Janku, F., Yap, T. A. & Meric-Bernstam, F. Targeting the PI3K pathway in cancer: are we making headway? Nat. Rev. Clin. Oncol. 15, 273–291 (2018).

    CAS  Article  Google Scholar 

  86. 86.

    Horiguchi, A., Oya, M., Uchida, A., Marumo, K. & Murai, M. Elevated Akt activation and its impact on clinicopathological features of renal cell carcinoma. J. Urol. 169, 710–713 (2003).

    CAS  Article  Google Scholar 

  87. 87.

    Sourbier, C. et al. The phosphoinositide 3-kinase/Akt pathway: a new target in human renal cell carcinoma therapy. Cancer Res. 66, 5130–5142 (2006).

    CAS  Article  Google Scholar 

  88. 88.

    Yang, J. et al. Targeting PI3K in cancer: mechanisms and advances in clinical trials. Mol. Cancer 18, 26 (2019).

    Article  Google Scholar 

  89. 89.

    Kim, J. et al. Cytoplasmic sequestration of p27 via AKT phosphorylation in renal cell carcinoma. Clin. Cancer Res. 15, 81–90 (2009).

    CAS  Article  Google Scholar 

  90. 90.

    Haase, V. H., Glickman, J. N., Socolovsky, M. & Jaenisch, R. Vascular tumors in livers with targeted inactivation of the von Hippel-Lindau tumor suppressor. Proc. Natl Acad. Sci. USA 98, 1583–1588 (2001).

    CAS  Article  Google Scholar 

  91. 91.

    Hickey, M. M., Lam, J. C., Bezman, N. A., Rathmell, W. K. & Simon, M. C. Von Hippel-Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2alpha signaling and splenic erythropoiesis. J. Clin. Invest. 117, 3879–3889 (2007).

    CAS  Google Scholar 

  92. 92.

    Lee, C. M. et al. VHL Type 2B gene mutation moderates HIF dosage in vitro and in vivo. Oncogene 28, 1694–1705 (2009).

    CAS  Article  Google Scholar 

  93. 93.

    Gnarra, J. R. et al. Defective placental vasculogenesis causes embryonic lethality in VHL-deficient mice. Proc. Natl Acad. Sci. USA 94, 9102–9107 (1997).

    CAS  Article  Google Scholar 

  94. 94.

    Frew, I. J. & Moch, H. A clearer view of the molecular complexity of clear cell renal cell carcinoma. Annu. Rev. Pathol. 10, 263–289 (2015).

    CAS  Article  Google Scholar 

  95. 95.

    Rankin, E. B., Tomaszewski, J. E. & Haase, V. H. Renal cyst development in mice with conditional inactivation of the von Hippel-Lindau tumor suppressor. Cancer Res. 66, 2576–2583 (2006).

    CAS  Article  Google Scholar 

  96. 96.

    Mathia, S. et al. Action of hypoxia-inducible factor in liver and kidney from mice with Pax8-rtTA-based deletion of von Hippel-Lindau protein. Acta Physiol. 207, 565–576 (2013).

    CAS  Article  Google Scholar 

  97. 97.

    Schley, G. et al. Hypoxia-inducible transcription factors stabilization in the thick ascending limb protects against ischemic acute kidney injury. J. Am. Soc. Nephrol. 22, 2004–2015 (2011).

    CAS  Article  Google Scholar 

  98. 98.

    Lubensky, I. A. et al. Allelic deletions of the VHL gene detected in multiple microscopic clear cell renal lesions in von Hippel-Lindau disease patients. Am. J. Pathol. 149, 2089–2094 (1996).

    CAS  Google Scholar 

  99. 99.

    Paraf, F. et al. Renal lesions in von Hippel-Lindau disease: immunohistochemical expression of nephron differentiation molecules, adhesion molecules and apoptosis proteins. Histopathology 36, 457–465 (2000).

    CAS  Article  Google Scholar 

  100. 100.

    Albers, J. et al. Combined mutation of Vhl and Trp53 causes renal cysts and tumours in mice. EMBO Mol. Med. 5, 949–964 (2013).

    CAS  Article  Google Scholar 

  101. 101.

    Frew, I. J. et al. pVHL and PTEN tumour suppressor proteins cooperatively suppress kidney cyst formation. EMBO J. 27, 1747–1757 (2008).

    CAS  Article  Google Scholar 

  102. 102.

    Harlander, S. et al. Combined mutation in Vhl, Trp53 and Rb1 causes clear cell renal cell carcinoma in mice. Nat. Med. 23, 869–877 (2017).

    CAS  Article  Google Scholar 

  103. 103.

    Gu, Y. F. et al. Modeling renal cell carcinoma in mice: Bap1 and Pbrm1 inactivation drive tumor grade. Cancer Discov. 7, 900–917 (2017).

    CAS  Article  Google Scholar 

  104. 104.

    Nargund, A. M. et al. The SWI/SNF protein PBRM1 restrains VHL-loss-driven clear cell renal cell carcinoma. Cell Rep. 18, 2893–2906 (2017).

    CAS  Article  Google Scholar 

  105. 105.

    Lee, H. et al. BAF180 regulates cellular senescence and hematopoietic stem cell homeostasis through p21. Oncotarget 7, 19134–19146 (2016).

    Article  Google Scholar 

  106. 106.

    de Cubas, A. A. & Rathmell, W. K. Epigenetic modifiers: activities in renal cell carcinoma. Nat. Rev. Urol. 15, 599–614 (2018).

    Article  Google Scholar 

  107. 107.

    Thompson, M. Polybromo-1: the chromatin targeting subunit of the PBAF complex. Biochimie 91, 309–319 (2009).

    CAS  Article  Google Scholar 

  108. 108.

    Pulice, J. L. & Kadoch, C. Composition and function of mammalian SWI/SNF Chromatin remodeling complexes in human disease. Cold Spring Harb. Symp. Quant. Biol. 81, 53–60 (2016).

    Article  Google Scholar 

  109. 109.

    Kim, S. H. et al. The prognostic value of BAP1, PBRM1, pS6, PTEN, TGase2, PD-L1, CA9, PSMA, and Ki-67 tissue markers in localized renal cell carcinoma: a retrospective study of tissue microarrays using immunohistochemistry. PLoS One 12, e0179610 (2017).

    Article  CAS  Google Scholar 

  110. 110.

    Wang, Z. et al. Sarcomatoid renal cell carcinoma has a distinct molecular pathogenesis, driver mutation profile, and transcriptional landscape. Clin. Cancer Res. 23, 6686–6696 (2017).

    CAS  Article  Google Scholar 

  111. 111.

    Gao, W., Li, W., Xiao, T., Liu, X. S. & Kaelin, W. G. Jr. Inactivation of the PBRM1 tumor suppressor gene amplifies the HIF-response in VHL−/− clear cell renal carcinoma. Proc. Natl Acad. Sci. USA 114, 1027–1032 (2017).

    CAS  Article  Google Scholar 

  112. 112.

    Liao, L. et al. Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer. eLife 7, e37925 (2018).

    Article  Google Scholar 

  113. 113.

    Liu, X. D. et al. PBRM1 loss defines a nonimmunogenic tumor phenotype associated with checkpoint inhibitor resistance in renal carcinoma. Nat. Commun. 11, 2135 (2020).

    CAS  Article  Google Scholar 

  114. 114.

    Cai, W. et al. PBRM1 acts as a p53 lysine-acetylation reader to suppress renal tumor growth. Nat. Commun. 10, 5800 (2019).

    CAS  Article  Google Scholar 

  115. 115.

    Xue, Y. et al. The human SWI/SNF-B chromatin-remodeling complex is related to yeast rsc and localizes at kinetochores of mitotic chromosomes. Proc. Natl Acad. Sci. USA 97, 13015–13020 (2000).

    CAS  Article  Google Scholar 

  116. 116.

    Huang, J., Hsu, J. M. & Laurent, B. C. The RSC nucleosome-remodeling complex is required for Cohesin’s association with chromosome arms. Mol. Cell 13, 739–750 (2004).

    CAS  Article  Google Scholar 

  117. 117.

    Baetz, K. K., Krogan, N. J., Emili, A., Greenblatt, J. & Hieter, P. The ctf13-30/CTF13 genomic haploinsufficiency modifier screen identifies the yeast chromatin remodeling complex RSC, which is required for the establishment of sister chromatid cohesion. Mol. Cell Biol. 24, 1232–1244 (2004).

    CAS  Article  Google Scholar 

  118. 118.

    Brownlee, P. M., Chambers, A. L., Cloney, R., Bianchi, A. & Downs, J. A. BAF180 promotes cohesion and prevents genome instability and aneuploidy. Cell Rep. 6, 973–981 (2014).

    CAS  Article  Google Scholar 

  119. 119.

    Clark, D. J. et al. Integrated proteogenomic characterization of clear cell renal cell carcinoma. Cell 179, 964–983.e31 (2019).

    CAS  Article  Google Scholar 

  120. 120.

    Hakimi, A. A. et al. Transcriptomic profiling of the tumor microenvironment reveals distinct subgroups of clear cell renal cell cancer — data from a randomized phase III trial. Cancer Discov. 9, 510–525 (2019).

    CAS  Article  Google Scholar 

  121. 121.

    Jensen, D. E. et al. BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene 16, 1097–1112 (1998).

    CAS  Article  Google Scholar 

  122. 122.

    Kapur, P. et al. Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation. Lancet Oncol. 14, 159–167 (2013).

    CAS  Article  Google Scholar 

  123. 123.

    Scheuermann, J. C. et al. Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB. Nature 465, 243–247 (2010).

    CAS  Article  Google Scholar 

  124. 124.

    Endoh, M. et al. Histone H2A mono-ubiquitination is a crucial step to mediate PRC1-dependent repression of developmental genes to maintain ES cell identity. PLoS Genet. 8, e1002774 (2012).

    CAS  Article  Google Scholar 

  125. 125.

    Dey, A. et al. Loss of the tumor suppressor BAP1 causes myeloid transformation. Science 337, 1541–1546 (2012).

    CAS  Article  Google Scholar 

  126. 126.

    Cejas, P. et al. Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors. Nat. Med. 25, 1260–1265 (2019).

    CAS  Article  Google Scholar 

  127. 127.

    Peng, J. et al. Stabilization of MCRS1 by BAP1 prevents chromosome instability in renal cell carcinoma. Cancer Lett. 369, 167–174 (2015).

    CAS  Article  Google Scholar 

  128. 128.

    Kobayashi, A. et al. Six2 defines and regulates a multipotent self-renewing nephron progenitor population throughout mammalian kidney development. Cell Stem Cell 3, 169–181 (2008).

    CAS  Article  Google Scholar 

  129. 129.

    Wang, S. S. et al. Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis. Proc. Natl Acad. Sci. USA 111, 16538–16543 (2014).

    CAS  Article  Google Scholar 

  130. 130.

    Joseph, R. W. et al. Loss of BAP1 protein expression is an independent marker of poor prognosis in patients with low-risk clear cell renal cell carcinoma. Cancer 120, 1059–1067 (2014).

    CAS  Article  Google Scholar 

  131. 131.

    Hsieh, J. J. et al. Genomic biomarkers of a randomized trial comparing first-line everolimus and sunitinib in patients with metastatic renal cell carcinoma. Eur. Urol. 71, 405–414 (2017).

    CAS  Article  Google Scholar 

  132. 132.

    Farley, M. N. et al. A novel germline mutation in BAP1 predisposes to familial clear-cell renal cell carcinoma. Mol. Cancer Res. 11, 1061–1071 (2013).

    CAS  Article  Google Scholar 

  133. 133.

    Lickwar, C. R. et al. The Set2/Rpd3S pathway suppresses cryptic transcription without regard to gene length or transcription frequency. PLoS One 4, e4886 (2009).

    Article  CAS  Google Scholar 

  134. 134.

    Hacker, K. E. et al. Structure/function analysis of recurrent mutations in SETD2 protein reveals a critical and conserved role for a SET domain residue in maintaining protein stability and histone H3 Lys-36 trimethylation. J. Biol. Chem. 291, 21283–21295 (2016).

    CAS  Article  Google Scholar 

  135. 135.

    Fahey, C. C. & Davis, I. J. SETting the stage for cancer development: SETD2 and the consequences of lost methylation. Cold Spring Harb. Perspect. Med. 7, a026468 (2017).

    Article  CAS  Google Scholar 

  136. 136.

    Park, I. Y. et al. Dual chromatin and cytoskeletal remodeling by SETD2. Cell 166, 950–962 (2016).

    CAS  Article  Google Scholar 

  137. 137.

    Giaccia, A. J. A new chromatin-cytoskeleton link in cancer. Mol. Cancer Res. 14, 1173–1175 (2016).

    CAS  Article  Google Scholar 

  138. 138.

    Seervai, R. N. H. et al. SETD2 is an actin lysine methyltransferase. Preprint at bioRxiv (2020).

  139. 139.

    Karki, M. et al. A cytoskeletal function for PBRM1 reading methylated microtubules. Preprint at bioRxiv (2020).

  140. 140.

    Pilie, P. G., Tang, C., Mills, G. B. & Yap, T. A. State-of-the-art strategies for targeting the DNA damage response in cancer. Nat. Rev. Clin. Oncol. 16, 81–104 (2019).

    CAS  Article  Google Scholar 

  141. 141.

    Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    CAS  Article  Google Scholar 

  142. 142.

    Dere, R., Perkins, A. L., Bawa-Khalfe, T., Jonasch, D. & Walker, C. L. β-catenin links von Hippel-Lindau to aurora kinase A and loss of primary cilia in renal cell carcinoma. J. Am. Soc. Nephrol. 26, 553–564 (2014).

    Article  CAS  Google Scholar 

  143. 143.

    Zhang, M. et al. HDAC6 deacetylates and ubiquitinates MSH2 to maintain proper levels of MutSalpha. Mol. Cell 55, 31–46 (2014).

    Article  CAS  Google Scholar 

  144. 144.

    Li, F. et al. The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSalpha. Cell 153, 590–600 (2013).

    CAS  Article  Google Scholar 

  145. 145.

    Naqvi, R. A. et al. Hypermethylation analysis of mismatch repair genes (hmlh1 and hmsh2) in locally advanced breast cancers in Indian women. Hum. Pathol. 39, 672–680 (2008).

    CAS  Article  Google Scholar 

  146. 146.

    Altavilla, G., Fassan, M., Busatto, G., Orsolan, M. & Giacomelli, L. Microsatellite instability and hMLH1 and hMSH2 expression in renal tumors. Oncol. Rep. 24, 927–932 (2010).

    CAS  Article  Google Scholar 

  147. 147.

    Jasin, M. & Rothstein, R. Repair of strand breaks by homologous recombination. Cold Spring Harb. Perspect. Biol. 5, a012740 (2013).

    Article  CAS  Google Scholar 

  148. 148.

    Hall, J. M. et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250, 1684–1689 (1990).

    CAS  Article  Google Scholar 

  149. 149.

    Hall, J. M. et al. Closing in on a breast cancer gene on chromosome 17q. Am. J. Hum. Genet. 50, 1235–1242 (1992).

    CAS  Google Scholar 

  150. 150.

    Wooster, R. et al. Identification of the breast cancer susceptibility gene BRCA2. Nature 378, 789–792 (1995).

    CAS  Article  Google Scholar 

  151. 151.

    Antoniou, A. C. et al. Breast-cancer risk in families with mutations in PALB2. N. Engl. J. Med. 371, 497–506 (2014).

    Article  CAS  Google Scholar 

  152. 152.

    Swift, M., Morrell, D., Massey, R. B. & Chase, C. L. Incidence of cancer in 161 families affected by ataxia-telangiectasia. N. Engl. J. Med. 325, 1831–1836 (1991).

    CAS  Article  Google Scholar 

  153. 153.

    Bindra, R. S. et al. Down-regulation of Rad51 and decreased homologous recombination in hypoxic cancer cells. Mol. Cell Biol. 24, 8504–8518 (2004).

    CAS  Article  Google Scholar 

  154. 154.

    Bindra, R. S. et al. Hypoxia-induced down-regulation of BRCA1 expression by E2Fs. Cancer Res. 65, 11597–11604 (2005).

    CAS  Article  Google Scholar 

  155. 155.

    Scanlon, S. E. & Glazer, P. M. Hypoxic stress facilitates acute activation and chronic downregulation of fanconi anemia proteins. Mol. Cancer Res. 12, 1016–1028 (2014).

    CAS  Article  Google Scholar 

  156. 156.

    Roe, J. S. et al. Phosphorylation of von Hippel-Lindau protein by checkpoint kinase 2 regulates p53 transactivation. Cell Cycle 10, 3920–3928 (2011).

    CAS  Article  Google Scholar 

  157. 157.

    Tang, J. et al. Acetylation limits 53BP1 association with damaged chromatin to promote homologous recombination. Nat. Struct. Mol. Biol. 20, 317–325 (2013).

    CAS  Article  Google Scholar 

  158. 158.

    Sun, Y., Jiang, X., Chen, S., Fernandes, N. & Price, B. D. A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM. Proc. Natl Acad. Sci. USA 102, 13182–13187 (2005).

    CAS  Article  Google Scholar 

  159. 159.

    Pfister, S. X. et al. SETD2-dependent histone H3K36 trimethylation is required for homologous recombination repair and genome stability. Cell Rep. 7, 2006–2018 (2014).

    CAS  Article  Google Scholar 

  160. 160.

    Carvalho, S. et al. SETD2 is required for DNA double-strand break repair and activation of the p53-mediated checkpoint. eLife 3, e02482 (2014).

    Article  CAS  Google Scholar 

  161. 161.

    Aymard, F. et al. Transcriptionally active chromatin recruits homologous recombination at DNA double-strand breaks. Nat. Struct. Mol. Biol. 21, 366–374 (2014).

    CAS  Article  Google Scholar 

  162. 162.

    Kanu, N. et al. SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair. Oncogene 34, 5699–5708 (2015).

    CAS  Article  Google Scholar 

  163. 163.

    Li, L. & Wang, Y. Cross-talk between the H3K36me3 and H4K16ac histone epigenetic marks in DNA double-strand break repair. J. Biol. Chem. 292, 11951–11959 (2017).

    Article  Google Scholar 

  164. 164.

    Ismail, I. H. et al. Germline mutations in BAP1 impair its function in DNA double-strand break repair. Cancer Res. 74, 4282–4294 (2014).

    CAS  Article  Google Scholar 

  165. 165.

    Peng, G. et al. Genome-wide transcriptome profiling of homologous recombination DNA repair. Nat. Commun. 5, 3361 (2014).

    Article  CAS  Google Scholar 

  166. 166.

    Pilie, P. G. et al. Homologous repair deficiency in VHL-mutated clear cell renal cell carcinoma. J. Clin. Oncol. 36, 585 (2018).

    Article  Google Scholar 

  167. 167.

    Carter, S. L., Eklund, A. C., Kohane, I. S., Harris, L. N. & Szallasi, Z. A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat. Genet. 38, 1043–1048 (2006).

    CAS  Article  Google Scholar 

  168. 168.

    McGranahan, N., Burrell, R. A., Endesfelder, D., Novelli, M. R. & Swanton, C. Cancer chromosomal instability: therapeutic and diagnostic challenges. EMBO Rep. 13, 528–538 (2012).

    CAS  Article  Google Scholar 

  169. 169.

    Gordan, J. D. et al. HIF-alpha effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. Cancer Cell 14, 435–446 (2008).

    CAS  Article  Google Scholar 

  170. 170.

    Wolfer, A. et al. MYC regulation of a “poor-prognosis” metastatic cancer cell state. Proc. Natl Acad. Sci. USA 107, 3698–3703 (2010).

    CAS  Article  Google Scholar 

  171. 171.

    Jamal-Hanjani, M., Quezada, S. A., Larkin, J. & Swanton, C. Translational implications of tumor heterogeneity. Clin. Cancer Res. 21, 1258–1266 (2015).

    CAS  Article  Google Scholar 

  172. 172.

    Malouf, G. G. et al. Genomic characterization of renal cell carcinoma with sarcomatoid dedifferentiation pinpoints recurrent genomic alterations. Eur. Urol. 70, 348–357 (2016).

    CAS  Article  Google Scholar 

  173. 173.

    Bi, M. et al. Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma. Proc. Natl Acad. Sci. USA 113, 2170–2175 (2016).

    CAS  Article  Google Scholar 

  174. 174.

    Hinshaw, D. C. & Shevde, L. A. The tumor microenvironment innately modulates cancer progression. Cancer Res. 79, 4557–4566 (2019).

    CAS  Article  Google Scholar 

  175. 175.

    Chevrier, S. et al. An immune atlas of clear cell renal cell carcinoma. Cell 169, 736–749 e718 (2017).

    CAS  Article  Google Scholar 

  176. 176.

    Senbabaoglu, Y. et al. Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures. Genome Biol. 17, 231 (2016).

    Article  CAS  Google Scholar 

  177. 177.

    Ko, J. S. et al. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin. Cancer Res. 15, 2148–2157 (2009).

    CAS  Article  Google Scholar 

  178. 178.

    Wang, T. et al. An empirical approach leveraging tumorgrafts to dissect the tumor microenvironment in renal cell carcinoma identifies missing link to prognostic inflammatory factors. Cancer Discov. 8, 1142–1155 (2018).

    CAS  Article  Google Scholar 

  179. 179.

    Miao, D. et al. Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science 359, 801–806 (2018).

    CAS  Article  Google Scholar 

  180. 180.

    McDermott, D. F. et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat. Med. 24, 749–757 (2018).

    CAS  Article  Google Scholar 

  181. 181.

    Bindea, G. et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 39, 782–795 (2013).

    CAS  Article  Google Scholar 

  182. 182.

    Yoshihara, K. et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat. Commun. 4, 2612 (2013).

    Article  CAS  Google Scholar 

  183. 183.

    Winslow, S., Leandersson, K., Edsjo, A. & Larsson, C. Prognostic stromal gene signatures in breast cancer. Breast Cancer Res. 17, 23 (2015).

    Article  CAS  Google Scholar 

  184. 184.

    Heng, D. Y. et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J. Clin. Oncol. 27, 5794–5799 (2009).

    CAS  Article  Google Scholar 

  185. 185.

    Seung, S. K., Shu, H. K., McDermott, M. W., Sneed, P. K. & Larson, D. A. Stereotactic radiosurgery for malignant melanoma to the brain. Surg. Clin. North Am. 76, 1399–1411 (1996).

    CAS  Article  Google Scholar 

  186. 186.

    Braun, D. A. et al. Clinical validation of PBRM1 alterations as a marker of immune checkpoint inhibitor response in renal cell carcinoma. JAMA Oncol. 5, 1631–1633 (2019).

    Article  Google Scholar 

  187. 187.

    Zisman, A. et al. Improved prognostication of renal cell carcinoma using an integrated staging system. J. Clin. Oncol. 19, 1649–1657 (2001).

    CAS  Article  Google Scholar 

  188. 188.

    Frank, I. et al. An outcome prediction model for patients with clear cell renal cell carcinoma treated with radical nephrectomy based on tumor stage, size, grade and necrosis: the SSIGN score. J. Urol. 168, 2395–2400 (2002).

    Article  Google Scholar 

  189. 189.

    Kattan, M. W., Reuter, V., Motzer, R. J., Katz, J. & Russo, P. A postoperative prognostic nomogram for renal cell carcinoma. J. Urol. 166, 63–67 (2001).

    CAS  Article  Google Scholar 

  190. 190.

    Bettegowda, C. et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci. Transl. Med. 6, 224ra224 (2014).

    Article  CAS  Google Scholar 

  191. 191.

    Cohen, J. D. et al. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science 359, 926–930 (2018).

    CAS  Article  Google Scholar 

  192. 192.

    Pal, S. K. et al. Evolution of circulating tumor DNA profile from first-line to subsequent therapy in metastatic renal cell carcinoma. Eur. Urol. 72, 557–564 (2017).

    CAS  Article  Google Scholar 

  193. 193.

    Merker, J. D. et al. Circulating tumor DNA analysis in patients with cancer: American Society of Clinical Oncology and College of American Pathologists joint review. Arch. Pathol. Lab. Med. 142, 1242–1253 (2018).

    CAS  Article  Google Scholar 

  194. 194.

    Rouzier, R. et al. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin. Cancer Res. 11, 5678–5685 (2005).

    CAS  Article  Google Scholar 

  195. 195.

    Travis, W. D. et al. The 2015 World Health Organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J. Thorac. Oncol. 10, 1243–1260 (2015).

    Article  Google Scholar 

  196. 196.

    Turcotte, S. et al. A molecule targeting VHL-deficient renal cell carcinoma that induces autophagy. Cancer Cell 14, 90–102 (2008).

    CAS  Article  Google Scholar 

  197. 197.

    Ding, Z. et al. Genetic and pharmacological strategies to refunctionalize the von Hippel Lindau R167Q mutant protein. Cancer Res. 74, 3127–3136 (2014).

    CAS  Article  Google Scholar 

  198. 198.

    Ding, Z. et al. Agents that stabilize mutated von Hippel-Lindau (VHL) protein: results of a high-throughput screen to identify compounds that modulate VHL proteostasis. J. Biomol. Screen. 17, 572–580 (2012).

    CAS  Article  Google Scholar 

  199. 199.

    Gameiro, P. A. et al. In vivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation. Cell Metab. 17, 372–385 (2013).

    CAS  Article  Google Scholar 

  200. 200.

    US National Library of Medicine. (2019).

  201. 201.

    US National Library of Medicine. (2019).

  202. 202.

    Courtney, K. D. et al. Phase I dose-escalation trial of PT2385, a first-in-class hypoxia-inducible factor-2alpha antagonist in patients with previously treated advanced clear cell renal cell carcinoma. J. Clin. Oncol. 36, 867–874 (2018).

    CAS  Article  Google Scholar 

  203. 203.

    Chen, W. et al. Targeting renal cell carcinoma with a HIF-2 antagonist. Nature 539, 112–117 (2016).

    CAS  Article  Google Scholar 

  204. 204.

    US National Library of Medicine. (2020).

  205. 205.

    US National Library of Medicine. (2020).

  206. 206.

    Jonasch, E. et al. An open-label phase II study to evaluate PT2977 for the treatment of von Hippel-Lindau disease-associated renal cell carcinoma. J. Clin. Oncol. 37, TPS680 (2019).

    Article  Google Scholar 

  207. 207.

    Jonasch, E. et al. Phase II study of the oral HIF-2α inhibitor MK-6482 for Von Hippel-Lindau disease-associated renal cell carcinoma. J. Clin. Oncol. 38, 5003–5003 (2020).

    Article  Google Scholar 

  208. 208.

    LaFave, L. M. et al. Loss of BAP1 function leads to EZH2-dependent transformation. Nat. Med. 21, 1344–1349 (2015).

    CAS  Article  Google Scholar 

  209. 209.

    Schoumacher, M. et al. Uveal melanoma cells are resistant to EZH2 inhibition regardless of BAP1 status. Nat. Med. 22, 577–578 (2016).

    CAS  Article  Google Scholar 

  210. 210.

    Pfister, S. X. et al. Inhibiting WEE1 selectively kills histone H3K36me3-deficient cancers by dNTP starvation. Cancer Cell 28, 557–568 (2015).

    CAS  Article  Google Scholar 

  211. 211.

    Terzo, E. A. et al. SETD2 loss sensitizes cells to PI3Kbeta and AKT inhibition. Oncotarget 10, 647–659 (2019).

    Article  Google Scholar 

  212. 212.

    Motzer, R. J. et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372, 449–456 (2008).

    CAS  Article  Google Scholar 

  213. 213.

    Hudes, G. et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med. 356, 2271–2281 (2007).

    CAS  Article  Google Scholar 

  214. 214.

    Jonasch, E. et al. A randomized phase 2 study of MK-2206 versus everolimus in refractory renal cell carcinoma. Ann. Oncol. 28, 804–808 (2017).

    CAS  Article  Google Scholar 

  215. 215.

    Ibrahim, Y. H. et al. PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. Cancer Discov. 2, 1036–1047 (2012).

    CAS  Article  Google Scholar 

  216. 216.

    Juvekar, A. et al. Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer. Cancer Discov. 2, 1048–1063 (2012).

    CAS  Article  Google Scholar 

  217. 217.

    Escudier, B. et al. A randomized, controlled, double-blind phase III study (AVOREN) of bevacizumab/interferon-α2a vs placebo/interferon-α2a as first-line therapy in metastatic renal cell carcinoma. J. Clin. Oncol. 25, 3 (2007).

    Article  Google Scholar 

  218. 218.

    Rini, B. I. et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J. Clin. Oncol. 26, 5422–5428 (2008).

    CAS  Article  Google Scholar 

  219. 219.

    Rini, B. I. et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 378, 1931–1939 (2012).

    Article  CAS  Google Scholar 

  220. 220.

    Motzer, R. J. et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N. Engl. J. Med. 356, 115–124 (2007).

    CAS  Article  Google Scholar 

  221. 221.

    Choueiri, T. K. et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373, 1814–1823 (2015).

    CAS  Article  Google Scholar 

  222. 222.

    Escudier, B. et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N. Engl. J. Med. 356, 125–134 (2007).

    CAS  Article  Google Scholar 

  223. 223.

    Sternberg, C. N. et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J. Clin. Oncol. 28, 1061–1068 (2010).

    CAS  Article  Google Scholar 

  224. 224.

    Motzer, R. J. et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N. Engl. J. Med. 369, 722–731 (2013).

    CAS  Article  Google Scholar 

  225. 225.

    Jonasch, E. et al. Phase II study of two weeks on, one week off sunitinib scheduling in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 36, 1588–1593 (2018).

    CAS  Article  Google Scholar 

  226. 226.

    Jonasch, E. et al. Pilot trial of sunitinib therapy in patients with von Hippel-Lindau disease. Ann. Oncol. 22, 2661–2666 (2011).

    CAS  Article  Google Scholar 

  227. 227.

    Kawakami, F. et al. Programmed cell death ligand 1 and tumor-infiltrating lymphocyte status in patients with renal cell carcinoma and sarcomatoid dedifferentiation. Cancer 123, 4823–4831 (2017).

    CAS  Article  Google Scholar 

  228. 228.

    Joseph, R. W. et al. PD-1 and PD-L1 expression in renal cell carcinoma with sarcomatoid differentiation. Cancer Immunol. Res. 3, 1303–1307 (2015).

    CAS  Article  Google Scholar 

  229. 229.

    Raychaudhuri, R. et al. Immune check point inhibition in sarcomatoid renal cell carcinoma: a new treatment paradigm. Clin. Genitourin. Cancer 15, e897–e901 (2017).

    Article  Google Scholar 

  230. 230.

    Paolino, M. et al. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature 507, 508–512 (2014).

    CAS  Article  Google Scholar 

  231. 231.

    Paolino, M. & Penninger, J. M. The role of TAM family receptors in immune cell function: implications for cancer therapy. Cancers 8, 97 (2016).

    Article  CAS  Google Scholar 

  232. 232.

    US National Library of Medicine. (2020).

  233. 233.

    Heemskerk, B., Kvistborg, P. & Schumacher, T. N. The cancer antigenome. EMBO J. 32, 194–203 (2013).

    CAS  Article  Google Scholar 

  234. 234.

    Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).

    CAS  Article  Google Scholar 

  235. 235.

    Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017).

    CAS  Article  Google Scholar 

  236. 236.

    Motzer, R. J. et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373, 1803–1813 (2015).

    CAS  Article  Google Scholar 

  237. 237.

    Motzer, R. J. et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N. Engl. J. Med. 378, 1277–1290 (2018).

    CAS  Article  Google Scholar 

  238. 238.

    Woo, S. R., Corrales, L. & Gajewski, T. F. The STING pathway and the T cell-inflamed tumor microenvironment. Trends Immunol. 36, 250–256 (2015).

    CAS  Article  Google Scholar 

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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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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.


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.


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.


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


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.


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


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.


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 (2020).

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