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  • Review Article
  • Published:

Precision medicine from the renal cancer genome

Key Points

  • Renal cell carcinoma (RCC) is a heterogeneous group of cancers with different subtypes and varying histological and clinical manifestations

  • Genome-level analysis of constitutional (germline) DNA has identified candidate genetic variants that predispose to RCC

  • Molecular characterization has revealed distinct landscapes of somatic genomic and epigenomic alterations in RCC subtypes, and has advanced our understanding of underlying mechanisms

  • Genomic signatures can provide a molecular diagnosis of RCC and guide therapy selection to target specific molecular aberrations, thereby moving towards precision medicine

  • 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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Figure 1: Pathogenic pathways in clear cell renal cell carcinoma (ccRCC).
Figure 2: The VHL–HIF pathway in clear cell renal cell carcinoma (ccRCC).
Figure 3: Malfunction of the epigenetic machinery contributes to genomic instability and deficiency of the DNA repair system in clear cell renal cell carcinoma (ccRCC).
Figure 4: Activation of the PI3K–mTOR pathway in clear cell renal cell carcinoma (ccRCC).

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References

  1. International Agency for Research on Cancer & WHO. GLOBOCAN 2012: estimated cancer incidence, martality and prevalence worldwide in 2012. Globocan http://globocan.iarc.fr/Pages/summary_table_site_sel.aspx (2016).

  2. Chow, W.-H., Dong, L. M. & Devesa, S. S. Epidemiology and risk factors for kidney cancer. Nat. Rev. Urol. 7, 245–257 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Capitanio, U. & Montorsi, F. Renal cancer. Lancet 387, 894–906 (2016).

    Article  PubMed  Google Scholar 

  4. Levi, F. et al. The changing pattern of kidney cancer incidence and mortality in Europe. BJU Int. 101, 949–958 (2008).

    Article  PubMed  Google Scholar 

  5. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. SEER http://seer.cancer.gov/statfacts/html/kidrp.html (2016).

  6. Theis, R. P., Dolwick Grieb, S. M., Burr, D., Siddiqui, T. & Asal, N. R. Smoking, environmental tobacco smoke, and risk of renal cell cancer: a population-based case–control study. BMC Cancer 8, 387 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Gati, A. et al. Obesity and renal cancer: role of adipokines in the tumor–immune system conflict. Oncoimmunology 3, e27810 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Bergstrom, A. et al. Obesity and renal cell cancer — a quantitative review. Br. J. Cancer 85, 984–990 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Deckers, I. A. et al. Polymorphisms in genes of the renin–angiotensin–aldosterone system and renal cell cancer risk: interplay with hypertension and intakes of sodium, potassium and fluid. Int. J. Cancer 136, 1104–1116 (2015).

    Article  CAS  PubMed  Google Scholar 

  10. Shuch, B. et al. Understanding pathologic variants of renal cell carcinoma: distilling therapeutic opportunities from biologic complexity. Eur. Urol. 67, 85–97 (2015).

    Article  PubMed  Google Scholar 

  11. Drucker, B. J. Renal cell carcinoma: current status and future prospects. Cancer Treat. Rev. 31, 536–545 (2005).

    Article  PubMed  Google Scholar 

  12. Scelo, G. & Brennan, P. The epidemiology of bladder and kidney cancer. Nat. Clin. Pract. Urol. 4, 205–217 (2007).

    Article  PubMed  Google Scholar 

  13. Cancer Genome Atlas Research Network et al. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N. Engl. J. Med. 372, 2481–2498 (2015).

  14. Cancer Genome Atlas Research Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 517, 576–582 (2015).

  15. Cancer Genome Atlas Research Network. Genomic classification of cutaneous melanoma. Cell 161, 1681–1696 (2015).

  16. Srinivasan, R., Ricketts, C. J., Sourbier, C. & Linehan, W. M. New strategies in renal cell carcinoma: targeting the genetic and metabolic basis of disease. Clin. Cancer Res. 21, 10–17 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. McLaughlin, J. K. et al. A population-based case–control study of renal cell carcinoma. J. Natl Cancer Inst. 72, 275–284 (1984).

    CAS  PubMed  Google Scholar 

  18. Schlehofer, B. et al. International renal-cell-cancer study. VI. The role of medical and family history. Int. J. Cancer 66, 723–726 (1996).

    Article  CAS  PubMed  Google Scholar 

  19. Haas, N. B. & Nathanson, K. L. Hereditary kidney cancer syndromes. Adv. Chronic Kidney Dis. 21, 81–90 (2014).

    Article  PubMed  Google Scholar 

  20. Henrion, M. et al. Common variation at 2q22.3 (ZEB2) influences the risk of renal cancer. Hum. Mol. Genet. 22, 825–831 (2013).

    Article  CAS  PubMed  Google Scholar 

  21. Bertolotto, C. et al. A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature 480, 94–98 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Henrion, M. Y. et al. Common variation at 1q24.1 (ALDH9A1) is a potential risk factor for renal cancer. PLoS ONE 10, e0122589 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Cheli, Y., Ohanna, M., Ballotti, R. & Bertolotto, C. Fifteen-year quest for microphthalmia-associated transcription factor target genes. Pigment Cell. Melanoma Res. 23, 27–40 (2010).

    Article  CAS  PubMed  Google Scholar 

  24. Schodel, J. et al. Common genetic variants at the 11q13.3 renal cancer susceptibility locus influence binding of HIF to an enhancer of cyclin D1 expression. Nat. Genet. 44, 420–425 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Linehan, W. M. Genetic basis of kidney cancer: role of genomics for the development of disease-based therapeutics. Genome Res. 22, 2089–2100 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Benusiglio, P. R. et al. A germline mutation in PBRM1 predisposes to renal cell carcinoma. J. Med. Genet. 52, 426–430 (2015).

    Article  CAS  PubMed  Google Scholar 

  27. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Popova, T. et al. Germline BAP1 mutations predispose to renal cell carcinomas. Am. J. Hum. Genet. 92, 974–980 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Scelo, G. et al. Variation in genomic landscape of clear cell renal cell carcinoma across Europe. Nat. Commun. 5, 5135 (2014).Identification of environmental exposure to aristolochic acid in some regions of central Europe by genome sequencing of ccRCC tumours.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499, 43–49 (2013).Comprehensive landscapes of the genome, DNA methylome and transcriptome of ccRCC, uncovering distinct molecular subtypes.

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

    Article  CAS  PubMed  Google Scholar 

  34. Gnarra, J. R. et al. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat. Genet. 7, 85–90 (1994).

    Article  CAS  PubMed  Google Scholar 

  35. Banks, R. E. et al. Genetic and epigenetic analysis of von Hippel–Lindau (VHL) gene alterations and relationship with clinical variables in sporadic renal cancer. Cancer Res. 66, 2000–2011 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Moore, L. E. et al. Von Hippel–Lindau (VHL) inactivation in sporadic clear cell renal cancer: associations with germline VHL polymorphisms and etiologic risk factors. PLoS Genet. 7, e1002312 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Gossage, L., Eisen, T. & Maher, E. R. VHL, the story of a tumour suppressor gene. Nat. Rev. Cancer 15, 55–64 (2015).

    Article  CAS  PubMed  Google Scholar 

  38. Harris, A. L. Hypoxia — a key regulatory factor in tumour growth. Nat. Rev. Cancer 2, 38–47 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Chan, D. A., Sutphin, P. D., Yen, S. E. & Giaccia, A. J. Coordinate regulation of the oxygen-dependent degradation domains of hypoxia-inducible factor 1α. Mol. Cell. Biol. 25, 6415–6426 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sato, Y. et al. Integrated molecular analysis of clear-cell renal cell carcinoma. Nat. Genet. 45, 860–867 (2013).

    Article  CAS  PubMed  Google Scholar 

  41. Guo, G. et al. Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma. Nat. Genet. 44, 17–19 (2012).

    Article  CAS  Google Scholar 

  42. Hakimi, A. A. et al. TCEB1-mutated renal cell carcinoma: a distinct genomic and morphological subtype. Mod. Pathol. 28, 845–853 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. van Haaften, G. et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat. Genet. 41, 521–523 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kakarougkas, A. et al. Requirement for PBAF in transcriptional repression and repair at DNA breaks in actively transcribed regions of chromatin. Mol. Cell 55, 723–732 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Simon, J. M. et al. Variation in chromatin accessibility in human kidney cancer links H3K36 methyltransferase loss with widespread RNA processing defects. Genome Res. 24, 241–250 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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  PubMed  PubMed Central  Google Scholar 

  49. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Rondinelli, B. et al. Histone demethylase JARID1C inactivation triggers genomic instability in sporadic renal cancer. J. Clin. Invest. 125, 4625–4637 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Velickovic, M., Delahunt, B., McIver, B. & Grebe, S. K. Intragenic PTEN/MMAC1 loss of heterozygosity in conventional (clear-cell) renal cell carcinoma is associated with poor patient prognosis. Mod. Pathol. 15, 479–485 (2002).

    Article  PubMed  Google Scholar 

  52. Shin Lee, J., Seok Kim, H., Bok Kim, Y., Cheol Lee, M. & Soo Park, C. Expression of PTEN in renal cell carcinoma and its relation to tumor behavior and growth. J. Surg. Oncol. 84, 166–172 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. 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).

    Article  CAS  PubMed  Google Scholar 

  54. Sadeqzadeh, E., de Bock, C. E. & Thorne, R. F. Sleeping giants: emerging roles for the fat cadherins in health and disease. Med. Res. Rev. 34, 190–221 (2014).

    Article  CAS  PubMed  Google Scholar 

  55. Morris, L. G. et al. Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation. Nat. Genet. 45, 253–261 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Zang, Z. J. et al. Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. Nat. Genet. 44, 570–574 (2012).

    Article  CAS  PubMed  Google Scholar 

  57. Furukawa, T. et al. Whole exome sequencing reveals recurrent mutations in BRCA2 and FAT genes in acinar cell carcinomas of the pancreas. Sci. Rep. 5, 8829 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Shuch, B. et al. Cytoreductive nephrectomy for kidney cancer with sarcomatoid histology — is up-front resection indicated and, if not, is it avoidable? J. Urol. 182, 2164–2171 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Shuch, B. et al. Impact of pathological tumour characteristics in patients with sarcomatoid renal cell carcinoma. BJU Int. 109, 1600–1606 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Cheville, J. C. et al. Sarcomatoid renal cell carcinoma: an examination of underlying histologic subtype and an analysis of associations with patient outcome. Am. J. Surg. Pathol. 28, 435–441 (2004).

    Article  PubMed  Google Scholar 

  61. Shuch, B., Bratslavsky, G., Linehan, W. M. & Srinivasan, R. Sarcomatoid renal cell carcinoma: a comprehensive review of the biology and current treatment strategies. Oncologist 17, 46–54 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Zbar, B. et al. Hereditary papillary renal cell carcinoma. J. Urol. 151, 561–566 (1994).

    Article  CAS  PubMed  Google Scholar 

  65. Schmidt, L. et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat. Genet. 16, 68–73 (1997).

    Article  CAS  PubMed  Google Scholar 

  66. Schmidt, L. et al. Novel mutations of the MET proto-oncogene in papillary renal carcinomas. Oncogene 18, 2343–2350 (1999).

    Article  CAS  PubMed  Google Scholar 

  67. Durinck, S. et al. Spectrum of diverse genomic alterations define non-clear cell renal carcinoma subtypes. Nat. Genet. 47, 13–21 (2015).

    Article  CAS  PubMed  Google Scholar 

  68. Tomlinson, I. P. et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat. Genet. 30, 406–410 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. Launonen, V. et al. Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc. Natl Acad. Sci. USA 98, 3387–3392 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Grubb, R. L. 3rd et al. Hereditary leiomyomatosis and renal cell cancer: a syndrome associated with an aggressive form of inherited renal cancer. J. Urol. 177, 2074–2079 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Sudarshan, S. et al. Fumarate hydratase deficiency in renal cancer induces glycolytic addiction and hypoxia-inducible transcription factor 1α stabilization by glucose-dependent generation of reactive oxygen species. Mol. Cell. Biol. 29, 4080–4090 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ooi, A. et al. An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell 20, 511–523 (2011).

    Article  CAS  PubMed  Google Scholar 

  73. Ooi, A. et al. CUL3 and NRF2 mutations confer an NRF2 activation phenotype in a sporadic form of papillary renal cell carcinoma. Cancer Res. 73, 2044–2051 (2013).

    Article  CAS  PubMed  Google Scholar 

  74. Cancer Genome Atlas Research Network et al. Comprehensive molecular characterization of papillary renal-cell carcinoma. N. Engl. J. Med. 374, 135–145 (2016).Comprehensive genome-scale analysis of genetic, epigenetic and transcriptome profiles of pRCC, leading to the identification of molecular subtypes associated with different patient outcomes.

  75. Kovac, M. et al. Recurrent chromosomal gains and heterogeneous driver mutations characterise papillary renal cancer evolution. Nat. Commun. 6, 6336 (2015).

    Article  CAS  PubMed  Google Scholar 

  76. Albiges, L. et al. MET is a potential target across all papillary renal cell carcinomas: result from a large molecular study of pRCC with CGH array and matching gene expression array. Clin. Cancer Res. 20, 3411–3421 (2014).

    Article  CAS  PubMed  Google Scholar 

  77. Choueiri, T. K. et al. Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. J. Clin. Oncol. 31, 181–186 (2013).

    Article  CAS  PubMed  Google Scholar 

  78. Lopez-Beltran, A. et al. 2009 update on the classification of renal epithelial tumors in adults. Int. J. Urol. 16, 432–443 (2009).

    Article  PubMed  Google Scholar 

  79. Nickerson, M. L. et al. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt–Hogg–Dube syndrome. Cancer Cell 2, 157–164 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Vocke, C. D. et al. High frequency of somatic frameshift BHD gene mutations in Birt–Hogg–Dube-associated renal tumors. J. Natl Cancer Inst. 97, 931–935 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Davis, C. F. et al. The somatic genomic landscape of chromophobe renal cell carcinoma. Cancer Cell 26, 319–330 (2014).Genome-wide analysis of somatic genetic, epigenetic and transcriptome alterations in chRCC, which identified an association between eosinophilic tumours and mutations in mitochondrial genes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Rathmell, K. W., Chen, F. & Creighton, C. J. Genomics of chromophobe renal cell carcinoma: implications from a rare tumor for pan-cancer studies. Oncoscience 2, 81–90 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Moch, H., Montironi, R., Lopez-Beltran, A., Cheng, L. & Mischo, A. Oncotargets in different renal cancer subtypes. Curr. Drug Targets 16, 125–135 (2015).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  85. Land, S. C. & Tee, A. R. Hypoxia-inducible factor 1α is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif. J. Biol. Chem. 282, 20534–20543 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  87. Rini, B. I., Campbell, S. C. & Escudier, B. Renal cell carcinoma. Lancet 373, 1119–1132 (2009).

    Article  CAS  PubMed  Google Scholar 

  88. Singer, E. A., Gupta, G. N. & Srinivasan, R. Update on targeted therapies for clear cell renal cell carcinoma. Curr. Opin. Oncol. 23, 283–289 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  89. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  91. Battelli, C. & Cho, D. C. mTOR inhibitors in renal cell carcinoma. Therapy 8, 359–367 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Vera-Badillo, F. E. et al. Systemic therapy for non-clear cell renal cell carcinomas: a systematic review and meta-analysis. Eur. Urol. 67, 740–749 (2015).

    Article  PubMed  Google Scholar 

  93. Gore, M. E. et al. Final results from the large sunitinib global expanded-access trial in metastatic renal cell carcinoma. Br. J. Cancer 113, 12–19 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Chen, F. et al. Multilevel genomics-based taxonomy of renal cell carcinoma. Cell Rep. 14, 2476–2489 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Brugarolas, J. Molecular genetics of clear-cell renal cell carcinoma. J. Clin. Oncol. 32, 1968–1976 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Jelakovic, B. et al. Renal cell carcinomas of chronic kidney disease patients harbor the mutational signature of carcinogenic aristolochic acid. Int. J. Cancer 136, 2967–2972 (2015).

    Article  CAS  PubMed  Google Scholar 

  97. Nortier, J. L. et al. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). N. Engl. J. Med. 342, 1686–1692 (2000).

    Article  CAS  PubMed  Google Scholar 

  98. Turesky, R. J. et al. Aristolochic acid exposure in Romania and implications for renal cell carcinoma. Br. J. Cancer 114, 76–80 (2016).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Helleday, T., Eshtad, S. & Nik-Zainal, S. Mechanisms underlying mutational signatures in human cancers. Nat. Rev. Genet. 15, 585–598 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Hakimi, A. A. et al. Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: a report by MSKCC and the KIRC TCGA research network. Clin. Cancer Res. 19, 3259–3267 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Liao, L., Testa, J. R. & Yang, H. The roles of chromatin-remodelers and epigenetic modifiers in kidney cancer. Cancer Genet. 208, 206–214 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Ricketts, C. J. & Linehan, W. M. Gender specific mutation incidence and survival associations in clear cell renal cell carcinoma (CCRCC). PLoS ONE 10, e0140257 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. 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).

    Article  CAS  PubMed  Google Scholar 

  106. Joseph, R. W. et al. Clear cell renal cell carcinoma subtypes identified by BAP1 and PBRM1 expression. J. Urol. 195, 180–187 (2016).

    Article  CAS  PubMed  Google Scholar 

  107. Pawlowski, R. et al. Loss of PBRM1 expression is associated with renal cell carcinoma progression. Int. J. Cancer 132, E11–E17 (2013).

    Article  CAS  PubMed  Google Scholar 

  108. da Costa, W. H. et al. Polybromo-1 (PBRM1), a SWI/SNF complex subunit is a prognostic marker in clear cell renal cell carcinoma. BJU Int. 113, E157–E163 (2014).

    Article  CAS  PubMed  Google Scholar 

  109. 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).

    Article  CAS  PubMed  Google Scholar 

  110. Schutz, F. A. et al. Single nucleotide polymorphisms and risk of recurrence of renal-cell carcinoma: a cohort study. Lancet Oncol. 14, 81–87 (2013).

    Article  CAS  PubMed  Google Scholar 

  111. Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).Study demonstrating intratumoral genetic heterogeneity in ccRCC and its effect on the activity of relevant cancer pathways.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Gerlinger, M. et al. Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nat. Genet. 46, 225–233 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Gerlinger, M. et al. Intratumour heterogeneity in urologic cancers: from molecular evidence to clinical implications. Eur. Urol. 67, 729–737 (2015).

    Article  CAS  PubMed  Google Scholar 

  114. Yap, T. A., Gerlinger, M., Futreal, P. A., Pusztai, L. & Swanton, C. Intratumor heterogeneity: seeing the wood for the trees. Sci. Transl Med. 4, 127ps10 (2012).

    Article  CAS  PubMed  Google Scholar 

  115. Wei, E. Y. & Hsieh, J. J. A river model to map convergent cancer evolution and guide therapy in RCC. Nat. Rev. Urol. 12, 706–712 (2015).

    Article  CAS  PubMed  Google Scholar 

  116. Kim, K. T. et al. Application of single-cell RNA sequencing in optimizing a combinatorial therapeutic strategy in metastatic renal cell carcinoma. Genome Biol. 17, 80 (2016).Characterization of ccRCC intratumoral heterogeneity at the transcriptome level involving different targetable pathways, suggesting combinatorial targeted therapies based on molecular profiles.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Choueiri, T. K. et al. von Hippel–Lindau gene status and response to vascular endothelial growth factor targeted therapy for metastatic clear cell renal cell carcinoma. J. Urol. 180, 860–865 (2008).

    Article  CAS  PubMed  Google Scholar 

  118. Dornbusch, J. et al. Analyses of potential predictive markers and survival data for a response to sunitinib in patients with metastatic renal cell carcinoma. PLoS ONE 8, e76386 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Garcia-Donas, J. et al. Single nucleotide polymorphism associations with response and toxic effects in patients with advanced renal-cell carcinoma treated with first-line sunitinib: a multicentre, observational, prospective study. Lancet Oncol. 12, 1143–1150 (2011).

    Article  CAS  PubMed  Google Scholar 

  120. Beuselinck, B. et al. Single-nucleotide polymorphisms associated with outcome in metastatic renal cell carcinoma treated with sunitinib. Br. J. Cancer 108, 887–900 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Garcia-Donas, J. et al. Prospective study assessing hypoxia-related proteins as markers for the outcome of treatment with sunitinib in advanced clear-cell renal cell carcinoma. Ann. Oncol. 24, 2409–2414 (2013).

    Article  CAS  PubMed  Google Scholar 

  122. Huang, D. et al. Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma. Cancer Res. 70, 1063–1071 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Xu, C. F. et al. IL8 polymorphisms and overall survival in pazopanib- or sunitinib-treated patients with renal cell carcinoma. Br. J. Cancer 112, 1190–1198 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Diekstra, M. H. et al. Association of single nucleotide polymorphisms in IL8 and IL13 with sunitinib-induced toxicity in patients with metastatic renal cell carcinoma. Eur. J. Clin. Pharmacol. 71, 1477–1484 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Kwiatkowski, D. J. et al. Mutations in TSC1, TSC2, and MTOR are associated with response to rapalogs in patients with metastatic renal cell carcinoma. Clin. Cancer Res. 22, 2445–2452 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Voss, M. H. et al. Tumor genetic analyses of patients with metastatic renal cell carcinoma and extended benefit from mTOR inhibitor therapy. Clin. Cancer Res. 20, 1955–1964 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Quinn, D. I. & Lara, P. N. Jr. Renal-cell cancer — targeting an immune checkpoint or multiple kinases. N. Engl. J. Med. 373, 1872–1874 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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Authors

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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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Correspondence to Yasser Riazalhosseini or Mark Lathrop.

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PowerPoint slides

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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