A.N. Shirshova(1), U.A. Boyarskikh(1), M.L. Filipenko(1, 2), V.S. Pokrovsky(3), N.E. Kushlinskii(3) 1-Institute of Chemical Biology and Fundamental Medicine of SB RAS, Akad. Lavrentyeva str., 8, Novosibirsk, 630090, Russian Federation; 2N-ovosibirsk State University, Pirogova str., 2, Novosibirsk, 630090, Russian Federation; 3-N.N.Blokhin National Medical Research Center of Oncology, Kashirskoye shosse, 24, Moscow, 115478, Russian Federation E-mail: [email protected]

The review highlights current data on molecular pathogenesis and potential markers of clear cell renal cell carcinoma, obtained in MultiOmyx studies. Key molecular mechanisms of the pathogenesis of RCC are the loss of functions of the VHL, PBRM1, SETD2, BAP1, KDM5C and CDKN2A genes and the activation of the PI3K-AKT-mTOR cascade. In 91% of cases of sporadic renal cell carcinoma, one VHL allele is lost as a result of deletions of the 3rd chromosome short arm. In 55% of cases, the second VHL allele is inactivated due to somatic mutations. As a result, HIF1-dependent transcription of hypoxia adaptation genes, including VEGF-A, is activated in the cell. Loss of functions of the PBRM1, SETD2, BAP1 and KDM5C genes leads to disruption of chromatin remodeling processes. All genes, with the exception of KDM5C, are located near the VHL gene on the 3rd chromosome. Inactivation of the CDKN2A disrupts the cell cycle control. The pathological activity of the PI3K-AKT-mTOR cascade induces the synthesis of proteins promoting cell division, growth, and survival. Anti-angiogenic and anti-mTOR therapy is the standard treatment for metastatic kidney cancer. Objectively about 40% of patients respond to therapy. Most cases form secondary resistance after 1–1.5 years of successful therapy. Challenge of personalized therapy and prognosis actualize the problem of searching for RCC molecular markers. To date, none of the promising markers, including the key molecules of the RCC pathogenesis and target therapy targets, are recommended for use in clinical practice.
clear cell renal cell carcinoma, pathogenesis, VHL, PBRM1, SETD2, BAP1, KDM5C, CDKN2A, cascade PI3K-AKT-

Список литературы: 
  1. Каприн А.Д., Старинский В.В., Петрова Г.В. (Под ред.) Злокачественные новообразования в России в 2015 году (заболеваемость и смертность). М.: Московский научно-исследовательский онкологический институт им. П.А. Герцена филиал ФГБУ «Национальный медицинский исследовательский радиологический центр» Минздрава России. 2017; 250.
  2. [Kaprin A.D., Starinsky V.V., Petrova G.V. (Ed.) Malignant neoplasms in Russia in 2015 (morbidity and mortality). M : Moscow Research Institute of Oncology. P.A. Herzen is a branch of the National Medical Radiological Research Center of the Ministry of Health of Russia. 2017; 250 (in Russian)]
  3. Holger Moch, Antonio L.. Cubilla, Peter A.. Humphrey, Victor E. Reuter, Thomas M. Ulbright. The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours. Eur. Urol. 2016; 70 (1): 93–105.
  4. Eble J.N., Sauter G., Epstein J.I., Sesterhenn I.A. Pathology and Genetics of Tumours of the Urinary System and Male. Genital Organs. World Health Organization; 1 edition. 2004.
  5. Protzel C., Maruschke M., Hakenberg O.W. Epidemiology, Aetiology, and Pathogenesis of Renal Cell Carcinoma. 2012; Eur. Urol. Supplements. 2012; 11 (3): 52–9.
  6. Алексеев Б.Я., Волкова М.И., Калпинский А.С., Каприн А.Д., Матвеев В.Б., Носов Д.А. Клинические рекомендации по диагностике и лечению рака почки. Правление Ассоциации онкологов России. М., 2014; 38.
  7. [Alekseev B.Y., Volkova M.I., Kalpinsky A.S., Kaprin A.D., Matveev V.B., Nosov D.A. Clinical guidelines for the diagnosis and treatment of kidney cancer. Board of the Association of Oncologists of Russia. M., 2014; 38 (in Russian)]
  8. Doehn C., Grünwald V., Steiner T., Follmann M., Rexer H., Krege S. The Diagnosis, Treatment, and Follow-up of Renal Cell Carcinoma. Dtsch. Arztebl. Int. 2016; 113 (35–36): 590–6.
  9. Han K.R., Janzen N.K., McWhorter V.C., Kim H.L., Pantuck A.J., Zisman A., Figlin R.A., Dorey F.J., Said J.W., Belldegrun A.S. Cystic renal cell carcinoma: Biology and clinical behavior. Urol. Oncol. Semin. Orig. Investig. 2004; 22 (5): 410–4.
  10. Ковалева О.В., Назарова О.Р., Матвеев В.Б., Грачев А.Н. Молекулярные особенности почечноклеточного рака: ранняя диагностика и перспективы терапии. Усп. Мол. Онкол. 2014; 2: 36–43.
  11. [Kovaleva O.V., Nazarova O.R., Matveyev V.B., Grachev A.N. Molecular features of renal cell cancer: early diagnosis and treatment prospects. Uspekhi Molekulyarnoy Onkologii. 2014; 2: 36–43 (in Russian)]
  12. Motzer R.J., Bacik J., Schwartz L.H., Reuter V., Russo P., Marion S., Mazumdar M. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J. Clin. Oncol. 2004; 22 (3): 454–63.
  13. Mehdi A., Riazalhosseini Y. Epigenome Aberrations: Emerging Driving Factors of the Clear Cell Renal Cell Carcinoma. Int. J. Mol. Sci. 2017; 18 (8): E1774.
  14. Ricketts C.J., De Cubas A.A., Fan H., Smith C.C., Lang M., Reznik E., Bowlby R., Gibb E.A., Akbani R., Beroukhim R., Bottaro D.P., Choueiri T.K., Gibbs R.A., Godwin A.K., Haake S., Hakimi A.A., Henske E.P., Hsieh J.J., Ho T.H., Kanchi R.S., Krishnan B., Kwiatkowski D.J., Lui W., Merino M.J., Mills G.B., Myers J., Nickerson M.L., Reuter V.E., Schmidt L.S., Shelley C.S., Shen H., Shuch B., Signoretti S., Srinivasan R., Tamboli P., Thomas G., Vincent B.G., Vocke C.D., Wheeler D.A., Yang L., Kim W.Y., Robertson A.G.; Cancer Genome Atlas Research Network, Spellman P.T., Rathmell W.K., Linehan W.M. The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma. Cell Rep. 2018; 23 (12): 313–26. e5.
  15. Yao M., Latif F., Orcutt M.L., Kuzmin I., Stackhouse T., Zhou F.W., Tory K., Duh F.M., Richards F., Maher E, LaForgia S., Huebner K., Le Pasilier D., Linehan M., Lerman M., Zbar В. von Hippel-Lindau disease: identification of deletion mutations by pulsed-field gel electrophoresis. Hum. Genet. 1993; 92 (6): 605–14.
  16. Latif F., Tory K., Gnarra J., Yao M., Duh F.M., Orcutt M.L., Stackhouse T., Kuzmin I., Modi W., Geil L. Schmidt L., Zhou F., Li H., Wei M.H., Chen F., Glenn G., Choyke P., Walther M.C., Weng Y., Duan D.S.R., Dean M., Glavac D., Richards F., Crossey P.A., Ferguson-Smith M.A., Le Paslier D., Chumakov I., Cohen D., Chinault A.C., Maher E.R., Linehan W.M., Zbar B., Lerman M.I. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993; 260 (5112): 1317–20.
  17. Cohen A.J., Li F.P., Berg S., Marchetto D.J., Tsai S., Jacobs S.C., Brown R.S. Hereditary Renal-Cell Carcinoma Associated with a Chromosomal Translocation. N. Engl. J. Med. 1979; 301 (11): 592–5.
  18. Kim W.Y., Kaelin W.G. Role of VHL gene mutation in human cancer. J. Clin. Oncol. 2004; 22 (24): 4991–5004.
  19. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013; 499 (7456): 43–9.
  20. Mandriota S.J., Turner K.J., Davies D.R., Murray P.G., Morgan N.V., Sowter H.M., Wykoff C.C., Maher E.R., Harris A.L., Ratcliffe P.J., Maxwell P.H. HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron. Cancer Cell. 2002; 1 (5): 459–68.
  21. Raval R.R., Lau K.W., Tran M.G., Sowter H.M., Mandriota S.J., Li J.L., Pugh C.W., Maxwell P.H., Harris A.L., Ratcliffe P.J. Contrasting Properties of Hypoxia-Inducible Factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-Associated Renal Cell Carcinoma. Mol. Cell. Biol. 2005; 25 (13): 5675–86.
  22. 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. 2003; 23 (24): 9361–74.
  23. Covello K.L., Kehler J., Yu H., Gordan J.D., Arsham A.M., Hu C.J., Labosky P.A., Simon M.C., Keith B. HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev. 2006; 20 (5): 557–70.
  24. Shen C., Beroukhim R., Schumacher S.E., Zhou J., Chang M., Signoretti S., Kaelin W.G. Jr. Genetic and Functional Studies Implicate HIF1 as a 14q Kidney Cancer Suppressor Gene. Cancer Discov. 2011; 1 (3): 222–35.
  25. Schödel J., Grampp S., Maher E.R., Moch H., Ratcliffe P.J., Russo P., Mole D.R. Hypoxia, Hypoxia-inducible Transcription Factors, and Renal Cancer. Eur. Urol. 2016; 69 (4): 646–57.
  26. Maxwell P.H., Wiesener M.S., Chang G.W., Clifford S.C., Vaux E.C., Cockman M.E., Wykoff C.C., Pugh C.W., Maher E.R., Ratcliffe P.J. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999; 399 (6733): 271–5.
  27. Yan Q., Bartz S., Mao M., Li L., Kaelin W.G. The Hypoxia-Inducible Factor 2α N-Terminal and C-Terminal Transactivation Domains Cooperate To Promote Renal Tumorigenesis In Vivo. Mol. Cell. Biol. 2007; 27 (6): 2092–102.
  28. Bracken C.P., Fedele A.O., Linke S., Balrak W., Lisy K., Whitelaw M.L., Peet D.J. Cell-specific Regulation of Hypoxia-inducible Factor (HIF)-1α and HIF-2α Stabilization and Transactivation in a Graded Oxygen Environment. J. Biol. Chem. 2006; 281 (32): 22575–85.
  29. Kaelin Jr, W.G. The von Hippel–Lindau tumour suppressor protein: O2 sensing and cancer. Nat. Rev. Cancer. 2008; 8 (11): 865–73.
  30. Koshiji M., Kageyama Y., Pete E.A., Horikawa I., Barrett J.C., Huang L.E. HIF-1alpha induces cell cycle arrest by functionally counteracting Myc. EMBO J. 2004; 23 (9): 1949–56.
  31. Keefe S.M., Nathanson K.L., Kimryn Rathmell W. The Molecular Biology of Renal Cell Carcinoma. Semin. Oncol. 2013; 40 (4): 421–8.
  32. Ferrara N., Gerber H.-P., LeCouter J. The biology of VEGF and its receptors. Nat. Med. 2003; 9 (6): 669–76.
  33. Asahara T., Takahashi T., Masuda H., Kalka C., Chen D., Iwaguro H., Inai Y., Silver M., Isner J.M. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J. 1999; 18 (14): 3964–72.
  34. Носов Д.А., Волкова М.И., Гладков О.А., Харкевич Д.Ю. Практические рекомендации по лекарственному лечению почечноклеточного рака. Russco. 2017; 404–10.
  35. [Nosov D.A., Volkova M.I., Gladkov O.A., Kharkevich D.Yu. Practical recommendations for the treatment of renal cell carcinoma. Russco. 2017; 404–10 (in Russian)]
  36. Ohh M., Yauch R.L., Lonergan K.M., Whaley J.M., Stemmer-Rachamimov A.O., Louis D.N., Gavin B.J., Kley N., Kaelin W.G.Jr, Iliopoulos O. The von Hippel-Lindau Tumor Suppressor Protein Is Required for Proper Assembly of an Extracellular Fibronectin Matrix. Mol. Cell. 1998; 1 (7): 959–68.
  37. 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. 2006; 26 (7): 2519–30.
  38. Rozario T., DeSimone D.W. The extracellular matrix in development and morphogenesis: A dynamic view. Dev. Biol. 2010; 341 (1): 126–40.
  39. Venning F.A., Wullkopf L., Erler J.T. Targeting ECM Disrupts Cancer Progression. Front. Oncol. 2015; 5: 224.
  40. Wipff P.-J., Hinz B. Integrins and the activation of latent transforming growth factor β1 An intimate relationship. Eur. J. Cell Biol. 2008; 87 (8–9): 601–15.
  41. Cox T.R., Erler J.T. Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer. Dis. Model. Mech. 2011; 4 (2): 165–78.
  42. Bonnans C., Chou J., Werb Z. Remodelling the extracellular matrix in development and disease. Nat. Rev. Mol. Cell Biol. 2014; 15 (12): 786–801.
  43. Sottile J. Regulation of angiogenesis by extracellular matrix. Biochim. Biophys. Acta. 2004; 1654 (1): 13–22.
  44. Lubensky I.A, Gnarra J.R., Bertheau P., Walther M.M., Linehan W.M., Zhuang Z. Allelic deletions of the VHL gene detected in multiple microscopic clear cell renal lesions in von Hippel-Lindau disease patients. Am. J. Pathol. 1996; 149 (6): 2089–94.
  45. Lutz M.S., Burk R.D. Primary Cilium Formation Requires von Hippel-Lindau Gene Function in Renal-Derived Cells. Cancer Res. 2006; 66 (14): 6903–7.
  46. 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. 2006; 17 (7): 1801–6.
  47. Schermer B., Ghenoiu C., Bartram M., Müller R.U., Kotsis F., Höhne M., Kühn W., Rapka M., Nitschke R., Zentgraf H., Fliegauf M., Omran H., Walz G., Benzing T. The von Hippel-Lindau tumor suppressor protein controls ciliogenesis by orienting microtubule growth. J. Cell Biol. 2006; 175 (4): 547–54.
  48. Lolkema M.P., Mans D.A., Ulfman L.H., Volpi S., Voest E.E., Giles R.H. Allele-specific regulation of primary cilia function by the von Hippel–Lindau tumor suppressor. Eur. J. Hum. Genet. 2008; 16 (1): 73–8.
  49. Masliah-Planchon J., Bièche I., Guinebretière J.-M., Bourdeaut F., Delattre O. SWI/SNF Chromatin Remodeling and Human Malignancies. Annu. Rev. Pathol. Mech. Dis. 2015; 10: 145–71.
  50. Alver B.H., Kim K.H., Lu P., Wang X., Manchester H.E., Wang W., Haswell J.R., Park P.J, Roberts C.W. The SWI/SNF chromatin remodelling complex is required for maintenance of lineage specific enhancers. Nat. Commun. 2017; 8: 14648.
  51. Tang L., Nogales E., Ciferri C. Structure and function of SWI/SNF chromatin remodeling complexes and mechanistic implications for transcription. Prog. Biophys. Mol. Biol. 2010; 102 (2–3): 122–8.
  52. Piva F., Santoni M., Matrana M.R., Satti S., Giulietti M., Occhipinti G., Massari F., Cheng L., Lopez-Beltran A., Scarpelli M., Principato G., Cascinu S., Montironi R. BAP1, PBRM1 and SETD2 in clear-cell renal cell carcinoma: molecular diagnostics and possible targets for personalized therapies. Expert Rev. Mol. Diagn. 2015; 15 (9): 1201–10.
  53. Kakarougkas A., Ismail A., Chambers A.L., Riballo E., Herbert A.D., Künzel J., Löbrich M., Jeggo P.A., Downs J.A. Requirement for PBAF in Transcriptional Repression and Repair at DNA Breaks in Actively Transcribed Regions of Chromatin. Mol. Cell. 2014; 55 (5): 723–32.
  54. Brownlee P.M., Chambers A.L., Cloney R., Bianchi A., Downs J.A. BAF180 Promotes Cohesion and Prevents Genome Instability and Aneuploidy. Cell Rep. 2014; 6 (6): 973–81.
  55. Burrows A.E., Smogorzewska A., Elledge S. J. Polybromo-associated BRG1-associated factor components BRD7 and BAF180 are critical regulators of p53 required for induction of replicative senescence. Proc. Natl. Acad. Sci. USA. 2010; 107 (32): 14280–5.
  56. Xia W., Nagase S., Montia A.G., Kalachikov S.M., Keniry M., Su T., Memeo L., Hibshoosh H., Parsons R. BAF180 Is a Critical Regulator of p21 Induction and a Tumor Suppressor Mutated in Breast Cancer. Cancer Res. 2008; 68 (6): 1667–74.
  57. Carvalho S., Raposo A.C., Martins F.B., Grosso A.R., Sridhara S.C., Rino J., Carmo-Fonseca M., de Almeida S.F. Histone methyltransferase SETD2 coordinates FACT recruitment with nucleosome dynamics during transcription. 2013; 41 (5): 2881–93.
  58. Li J., Duns G., Westers H., Sijmons R., van den Berg A., Kok K. SETD2: an epigenetic modifier with tumor suppressor functionality. Oncotarget. 2016; 7 (31): 50719–34.
  59. Pfister S.X, Ahrabi S., Zalmas L.P., Sarkar S., Aymard F., Bachrati C.Z., Helleday T., Legube G., La Thangue N.B., Porter A.C., Humphrey T.C. SETD2-Dependent Histone H3K36 Trimethylation Is Required for Homologous Recombination Repair and Genome Stability. Cell Rep. 2014; 7 (6): 2006–18.
  60. Pai C.-C., Deegan R.S., Subramanian L., Gal C., Sarkar S., Blaikley E.J., Walker C., Hulme L., Bernhard E., Codlin S., Bähler J., Allshire R., Whitehall S., Humphrey T.C. A histone H3K36 chromatin switch coordinates DNA double-strand break repair pathway choice. Nat. Commun. 2014; 5: 4091.
  61. Rondinelli B., Rosano D., Antonini E., Frenquelli M., Montanini L., Huang D., Segalla S., Yoshihara K., Amin S.B., Lazarevic D., The B.T., Verhaak R.G., Futreal P.A., Di Croce L., Chin L., Cittaro D., Tonon G. Histone demethylase JARID1C inactivation triggers genomic instability in sporadic renal cancer. J. Clin. Invest. 2015; 125 (12): 4625–37.
  62. Guo X., Zhang Q. The Emerging Role of Histone Demethylases in Renal Cell Carcinoma. J. Kidney Cancer VHL. 2017; 4 (2): 1–5.
  63. Dalgliesh G.L., Furge K., Greenman C., Chen L., Bignell G., Butler A., Davies H., Edkins S., Hardy C., Latimer C., Teague J., Andrews J., Barthorpe S., Beare D., Buck G., Campbell P.J., Forbes S., Jia M., Jones D., Knott H., Kok C.Y., Lau K.W., Leroy C., Lin M.L., McBride D.J., Maddison M., Maguire S., McLay K., Menzies A., Mironenko T., Mulderrig L., Mudie L., O’Meara S., Pleasance E., Rajasingham A., Shepherd R., Smith R., Stebbings L., Stephens P., Tang G., Tarpey P.S., Turrell K., Dykema K.J., Khoo S.K., Petillo D., Wondergem B., Anema J., Kahnoski R.J., Teh B.T., Stratton M.R., Futreal P.A. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature. 2010; 463 (7279): 360–3.
  64. Jensen D.E., Proctor M., Marquis S.T., Gardner H.P., Ha S.I., Chodosh L.A., Ishov A.M., Tommerup N., Vissing H., Sekido Y., Minna J., Borodovsky A., Schultz D.C., Wilkinson K.D., Maul G.G., Barlev N., Berger S.L., Prendergast G.C., Rauscher F.J. 3rd. BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene. 1998; 16 (19): 1097–112.
  65. Yu H., Pak H., Hammond-Martel I., Ghram M., Rodrigue A., Daou S., Barbour H., Corbeil L., Hébert J., Drobetsky E., Masson J.Y., Di Noia J.M., Affar el B. Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair. Proc. Natl. Acad. Sci. USA. 2014; 111 (1): 285–90.
  66. Machida Y.J., Machida Y., Vashisht A.A., Wohlschlegel J.A., Dutta A. The deubiquitinating enzyme BAP1 regulates cell growth via interaction with HCF-1. J. Biol. Chem. 2009; 284 (49): 34179–88.
  67. Yu H., Mashtalir N., Daou S., Hammond-Martel I., Ross J., Sui G., Hart G.W., Rauscher F.J. 3rd, Drobetsky E., Milot E., Shi Y., Affar el B. The ubiquitin carboxyl hydrolase BAP1 forms a ternary complex with YY1 and HCF-1 and is a critical regulator of gene expression. Mol. Cell. Biol. 2010; 30 (21): 5071–85.
  68. Misaghi S., Ottosen S., Izrael-Tomasevic A., Arnott D., Lamkanfi M., Lee J., Liu J., O’Rourke K., Dixit V.M., Wilson A.C. Association of C-terminal ubiquitin hydrolase BRCA1-associated protein 1 with cell cycle regulator host cell factor 1. Mol. Cell. Biol. 2009; 29 (8): 2181–92.
  69. Daou S., Hammond-Martel I., Mashtalir N., Barbour H., Gagnon J., Iannantuono N.V., Nkwe N.S., Motorina A., Pak H., Yu H., Wurtele H., Milot E., Mallette F.A., Carbone M., Affar el B. The BAP1/ASXL2 Histone H2A Deubiquitinase Complex Regulates Cell Proliferation and Is Disrupted in Cancer. J. Biol. Chem. 2015; 290 (48): 28643–Sahtoe D.D., van Dijk W.J., Ekkebus R., Ovaa H., Sixma T.K. BAP1/ASXL1 recruitment and activation for H2A deubiquitination. Nat. Commun. 2016; 7: 10292.
  70. Zhou W., Zhu P., Wang J., Pascual G., Ohgi K.A., Lozach J., Glass C.K., Rosenfeld M.G. Histone H2A monoubiquitination represses transcription by inhibiting RNA polymerase II transcriptional elongation. Mol. Cell. 2008; 29 (1): 69–80.
  71. Pavri R., Zhu B., Li G., Trojer P., Mandal S., Shilatifard A., Reinberg D. Histone H2B Monoubiquitination Functions Cooperatively with FACT to Regulate Elongation by RNA Polymerase II. Cell. 2006; 125 (4): 703–17.
  72. Pilarski R., Rai K., Cebulla C., Abdel-Rahman M. BAP1 Tumor Predisposition Syndrome. GeneReviews® (University of Washington, Seattle, 1993).
  73. Zhao R., Choi B.Y., Lee M.-H., Bode A.M., Dong Z. Implications of Genetic and Epigenetic Alterations of CDKN2A (p16(INK4a)) in Cancer. EBioMedicine 2016; 8: 30–39.
  74. Huang J., Manning B.D. The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem. J. 2008; 412 (2): 179–90.
  75. Yu L., McPhee C.K., Zheng L., Mardones G.A., Rong Y., Peng J., Mi N., Zhao Y., Liu Z., Wan F., Hailey D.W., Oorschot V., Klumperman J., Baehrecke E.H., Lenardo M.J. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature. 2010; 465 (7300): 942–6.
  76. Saxton R.A., Sabatini D.M. mTOR Signaling in Growth, Metabolism, and Disease. Cell. 2017; 168 (6): 960–76.
  77. Martini M., De Santis M.C., Braccini L., Gulluni F., Hirsch E. PI3K/AKT signaling pathway and cancer: an updated review. Ann. Med. 2014; 46 (6): 372–83.
  78. Cancer Genome Atlas Research Network, Linehan W.M., Spellman P.T., Ricketts C.J., Creighton C.J., Fei S.S., Davis C., Wheeler D.A., Murray B.A., Schmidt L., Vocke C.D., Peto M., Al Mamun A.A., Shinbrot E., Sethi A., Brooks S., Rathmell W.K., Brooks A.N., Hoadley K.A., Robertson A.G., Brooks D., Bowlby R., Sadeghi S., Shen H., Weisenberger D.J., Bootwalla M., Baylin S.B., Laird P.W., Cherniack A.D., Saksena G., Haake S., Li J., Liang H., Lu Y., Mills G.B., Akbani R., Leiserson M.D., Raphael B.J., Anur P., Bottaro D., Albiges L., Barnabas N., Choueiri T.K., Czerniak B., Godwin A.K., Hakimi A.A., Ho T.H., Hsieh J., Ittmann M., Kim W.Y., Krishnan B., Merino M.J., Mills Shaw K.R., Reuter V.E., Reznik E., Shelley C.S., Shuch B., Signoretti S., Srinivasan R., Tamboli P., Thomas G., Tickoo S., Burnett K., Crain D., Gardner J., Lau K., Mallery D., Morris S., Paulauskis J.D., Penny R.J., Shelton C., Shelton W.T., Sherman M., Thompson E., Yena P., Avedon M.T., Bowen J., Gastier-Foster J.M., Gerken M., Leraas K.M., Lichtenberg T.M., Ramirez N.C., Santos T., Wise L., Zmuda E., Demchok J.A., Felau I., Hutter C.M., Sheth M., Sofia H.J., Tarnuzzer R., Wang Z., Yang L., Zenklusen J.C., Zhang J., Ayala B., Baboud J., Chudamani S., Liu J., Lolla L., Naresh R., Pihl T., Sun Q., Wan Y., Wu Y., Ally A., Balasundaram M., Balu S., Beroukhim R., Bodenheimer T., Buhay C., Butterfield Y.S., Carlsen R., Carter S.L., Chao H., Chuah E., Clarke A., Covington K.R., Dahdouli M., Dewal N., Dhalla N., Doddapaneni H.V., Drummond J.A., Gabriel S.B., Gibbs R.A., Guin R., Hale W., Hawes A., Hayes D.N., Holt R.A., Hoyle A.P., Jefferys S.R., Jones S.J., Jones C.D., Kalra D., Kovar C., Lewis L., Li J., Ma Y., Marra M.A., Mayo M., Meng S., Meyerson M., Mieczkowski P.A., Moore R.A., Morton D., Mose L.E., Mungall A.J., Muzny D., Parker J.S., Perou C.M., Roach J., Schein J.E., Schumacher S.E., Shi Y., Simons J.V., Sipahimalani P., Skelly T., Soloway M.G., Sougnez C., Tam A., Tan D., Thiessen N., Veluvolu U., Wang M., Wilkerson M.D., Wong T., Wu J., Xi L., Zhou J., Bedford J., Chen F., Fu Y., Gerstein M., Haussler D., Kasaian K., Lai P., Ling S., Radenbaugh A., Van Den Berg D., Weinstein J.N., Zhu J., Albert M., Alexopoulou I., Andersen J.J., Auman J.T., Bartlett J., Bastacky S., Bergsten J., Blute M.L., Boice L., Bollag R.J., Boyd J., Castle E., Chen Y.B., Cheville J.C., Curley E., Davies B., DeVolk A., Dhir R., Dike L., Eckman J., Engel J., Harr J., Hrebinko R., Huang M., Huelsenbeck-Dill L., Iacocca M., Jacobs B., Lobis M., Maranchie J.K., McMeekin S., Myers J., Nelson J., Parfitt J., Parwani A., Petrelli N., Rabeno B., Roy S., Salner A.L., Slaton J., Stanton M., Thompson R.H., Thorne L., Tucker K., Weinberger P.M., Winemiller C., Zach L.A., Zuna R. Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma. N. Engl. J. Med. 2016; 374 (2): 135–45.
  79. Davis C.F., Ricketts C.J., Wang M., Yang L., Cherniack A.D., Shen H., Buhay C., Kang H., Kim S.C., Fahey C.C., Hacker K.E., Bhanot G., Gordenin D.A., Chu A., Gunaratne P.H., Biehl M., Seth S., Kaipparettu B.A., Bristow C.A., Donehower L.A., Wallen E.M., Smith A.B., Tickoo S.K., Tamboli P., Reuter V., Schmidt L.S., Hsieh J.J., Choueiri T.K., Hakimi A.A.; The Cancer Genome Atlas Research Network, Chin L., Meyerson M., Kucherlapati R., Park W.Y., Robertson A.G., Laird P.W., Henske E.P., Kwiatkowski D.J., Park P.J., Morgan M., Shuch B., Muzny D., Wheeler D.A., Linehan W.M., Gibbs R.A., Rathmell W.K., Creighton C.J. The Somatic Genomic Landscape of Chromophobe Renal Cell Carcinoma. Cancer Cell 2014; 26: 319–30.
  80. Tan P.H., Cheng L., Rioux-Leclercq N., Merino M.J., Netto G., Reuter V.E., Shen S.S., Grignon D.J., Montironi R., Egevad L., Srigley J.R., Delahunt B., Moch H., ISUP Renal Tumor Panel. Renal tumors: diagnostic and prognostic biomarkers. Am. J. Surg. Pathol. 2013; 37 (10): 1518–31.
  81. Yin C., Wang N. Kidney injury molecule-1 in kidney disease. Ren. Fail. 2016; 38 (10): 1567–73.
  82. Mijuskovic M., Stanojevic I., Milovic N., Cerovic S., Petrovic D., Maksic D., Kovacevic B., Andjelic T., Aleksic P., Terzic B., Djukic M., Vojvodic D. Tissue and urinary KIM-1 relate to tumor characteristics in patients with clear renal cell carcinoma. Int. Urol. Nephrol. 2018; 50 (1): 63–70.
  83. Morrissey J.J., London A.N., Luo J., Kharasch E.D. Urinary biomarkers for the early diagnosis of kidney cancer. Mayo Clin. Proc. 2010; 85 (5): 413–21.
  84. Han W.K., Alinani A., Wu C.L., Michaelson D., Loda M., McGovern F.J., Thadhani R., Bonventre J.V. Human kidney injury molecule-1 is a tissue and urinary tumor marker of renal cell carcinoma. J. Am. Soc. Nephrol. 2005; 16 (4): 1126–34.
  85. Zhang P.L., Mashni J.W., Sabbisetti V.S., Schworer C.M., Wilson G.D., Wolforth S.C., Kernen K.M., Seifman B.D., Amin M.B., Geddes T.J., Lin F., Bonventre J.V., Hafron J.M. Urine kidney injury molecule-1: a potential non-invasive biomarker for patients with renal cell carcinoma. Int. Urol. Nephrol. 2014; 46 (2): 379–88.
  86. Shalabi A., Abassi Z., Awad H., Halachmi S., Moskovitz B., Kluger Y., Nativ O. Urinary NGAL and KIM-1: potential association with histopathologic features in patients with renal cell carcinoma. World J. Urol. 2013; 31 (6): 1541–5.
  87. Morrissey J.J., Kharasch E.D. The Specificity of Urinary Aquaporin 1 and Perilipin 2 to Screen for Renal Cell Carcinoma. J. Urol. 2013; 189 (5): 1913–20.
  88. Morrissey J.J., Mobley J., Song J., Vetter J., Luo J., Bhayani S., Figenshau R.S., Kharasch E.D. Urinary Concentrations of Aquaporin-1 and Perilipin-2 in Patients With Renal Cell Carcinoma Correlate With Tumor Size and Stage but not Grade. Urology. 2014; 83 (1): 9–14.
  89. Morrissey J.J., Mobley J., Figenshau R.S., Vetter J., Bhayani S., Kharasch E.D. Urine Aquaporin 1 and Perilipin 2 Differentiate Renal Carcinomas From Other Imaged Renal Masses and Bladder and Prostate Cancer. Mayo Clin. Proc. 2015; 90 (1): 35–42.
  90. Kaya K., Ayan S., Gokce G., Kilicarslan H., Yildiz E., Gultekin E.Y. Urinary nuclear matrix protein 22 for diagnosis of renal cell carcinoma. Scand. J. Urol. Nephrol. 2005; 39 (1): 25–9.
  91. Ozer G., Altinel M., Kocak B., Yazicioglu A., Gonenc F. Value of urinary NMP-22 in patients with renal cell carcinoma. Urology. 2002; 60 (4): 593–7.
  92. Huang S., Rhee E., Patel H., Park E., Kaswick J. Urinary NMP22 and renal cell carcinoma. Urology. 2000; 55 (2): 227–30.
  93. Eggener S.E., Yossepowitch O., Pettus J.A., Snyder M.E., Motzer R.J., Russo P. Renal Cell Carcinoma Recurrence After Nephrectomy for Localized Disease: Predicting Survival From Time of Recurrence. J. Clin. Oncol. 2006; 24 (19): 3101–6.
  94. Kim B.J., Kim J.H., Kim H.S., Zang D.Y. Prognostic and predictive value of VHL gene alteration in renal cell carcinoma: a meta-analysis and review. Oncotarget. 2017; 8 (8): 13979–85.
  95. Salinas-Sánchez A.S., Serrano-Oviedo L., Nam-Cha S.Y., Roche-Losada O., Sánchez-Prieto R., Giménez-Bachs J.M. Prognostic Value of the VHL, HIF-1α, and VEGF Signaling Pathway and Associated MAPK (ERK1/2 and ERK5) Pathways in Clear-Cell Renal Cell Carcinoma. A Long-Term Study. Clin. Genitourin. Cancer. 2017; 15 (6): 923–33.
  96. Smits K.M., Schouten L.J., van Dijk B.A., Hulsbergen-van de Kaa C.A., Wouters K.A., Oosterwijk E., van Engeland M., van den Brandt P.A. Genetic and Epigenetic Alterations in the von Hippel-Lindau Gene: the Influence on Renal Cancer Prognosis. Clin. Cancer Res. 2008; 14 (3): 782–7.
  97. Kondo K., Yao M., Yoshida M., Kishida T., Shuin T., Miura T., Moriyama M., Kobayashi K., Sakai N., Kaneko S., Kawakami S., Baba M., Nakaigawa N., Nagashima Y., Nakatani Y., Hosaka M. Comprehensive mutational analysis of the VHL gene in sporadic renal cell carcinoma: relationship to clinicopathological parameters. Genes. Chromosomes Cancer. 2002; 34 (1): 58–68.
  98. Giménez-Bachs J.M., Salinas-Sánchez A.S., Sánchez-Sánchez F., Lorenzo-Romero J.G., Donate-Moreno M.J., Pastor-Navarro H., Garcia-Olmo D.C., Escribano-Martinez J., Virseda-Rodriguez J.A. Determination of vhl Gene Mutations in Sporadic Renal Cell Carcinoma. Eur. Urol. 2006; 49 (6): 1051–7.
  99. Kim J.H., Jung C.W., Cho Y.H., Lee J., Lee H., Kim H.Y., Park J., Park J.O., Kim K., Kim W.S., Park Y.S., Im Y.H., Kang W.K., Park K. Somatic VHL alteration and its impact on prognosis in patients with clear cell renal cell carcinoma. Oncol. Rep. 2005; 13 (5): 859–64.
  100. Choueiri T.K., Vaziri S.A., Jaeger E., Elson P., Wood L., Bhalla I.P., Small E.J., Weinberg V., Sein N., Simko J., Golshayan A.R., Sercia L., Zhou M., Waldman F.M., Rini B.I., Bukowski R.M., Ganapathi R. von Hippel-Lindau Gene Status and Response to Vascular Endothelial Growth Factor Targeted Therapy for Metastatic Clear Cell Renal Cell Carcinoma. J. Urol. 2008; 180 (3): 860–6.
  101. Gad S., Sultan-Amar V., Meric J.-B., Izzedine H., Khayat D., Richard S., Rixe O. Somatic von Hippel-Lindau (VHL) gene analysis and clinical outcome under antiangiogenic treatment in metastatic renal cell carcinoma: preliminary results. Target. Oncol. 2007; 2 (1): 3–6.
  102. Yao M., Yoshida M., Kishida T., Nakaigawa N., Baba M., Kobayashi K., Miura T., Moriyama M., Nagashima Y., Nakatani Y., Kubota Y., Kondo K. VHL tumor suppressor gene alterations associated with good prognosis in sporadic clear-cell renal carcinoma. J. Natl. Cancer Inst. 2002; 94 (20): 1569–75.
  103. Patard J.J., Fergelot P., Karakiewicz P.I., Klatte T., Trinh Q.D., Rioux-Leclercq N., Said J.W., Belldegrun A.S., Pantuck A.J. Low CAIX expression and absence of VHL gene mutation are associated with tumor aggressiveness and poor survival of clear cell renal cell carcinoma. Int. J. Cancer. 2008; 123 (2): 395–400.
  104. Klatte T., Rao P.N., de Martino M., LaRochelle J., Shuch B., Zomorodian N., Said J., Kabbinavar F.F., Belldegrun A.S., Pantuck A.J. Cytogenetic Profile Predicts Prognosis of Patients With Clear Cell Renal Cell Carcinoma. J. Clin. Oncol. 2009; 27 (5): 746–53.
  105. Kroeger N., Klatte T., Chamie K., Rao P.N., Birkhäuser F.D., Sonn G.A., Riss J., Kabbinavar F.F., Belldegrun A.S., Pantuck A.J. Deletions of chromosomes 3p and 14q molecularly subclassify clear cell renal cell carcinoma. Cancer. 2013; 119 (8): 1547–54.
  106. Schraml P., Struckmann K., Hatz F., Sonnet S., Kully C., Gasser T., Sauter G., Mihatsch M.J., Moch H. VHL mutations and their correlation with tumour cell proliferation, microvessel density, and patient prognosis in clear cell renal cell carcinoma. J. Pathol. 2002; 196 (2): 186–93.
  107. Banks R.E., Tirukonda P., Taylor C., Hornigold N., Astuti D., Cohen D., Maher E.R., Stanley A.J., Harnden P., Joyce A., Knowles M., Selby P.J. Genetic and Epigenetic Analysis of von Hippel-Lindau (VHL) Gene Alterations and Relationship with Clinical Variables in Sporadic Renal Cancer. Cancer Res. 2006; 66 (4): 2000–11.
  108. Joseph R.W., Kapur P., Serie D.J., Parasramka M., Ho T.H., Cheville J.C., Frenkel E., Parker A.S., Brugarolas J. Clear Cell Renal Cell Carcinoma Subtypes Identified by BAP1 and PBRM1 Expression. J. Urol. 2016; 195 (1): 180–7.
  109. Kapur P., Peña-Llopis S., Christie A., Zhrebker L., Pavia-Jiménez A., Rathmell W.K., Xie X.J., Brugarolas J. Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation. Lancet Oncol. 2013; 14 (2): 159–67.
  110. Sato Y., Yoshizato T., Shiraishi Y., Maekawa S., Okuno Y., Kamura T., Shimamura T., Sato-Otsubo A., Nagae G., Suzuki H., Nagata Y., Yoshida K., Kon A., Suzuki Y., Chiba K., Tanaka H., Niida A., Fujimoto A., Tsunoda T., Morikawa T., Maeda D., Kume H., Sugano S., Fukayama M., Aburatani H., Sanada M., Miyano S., Homma Y., Ogawa S. Integrated molecular analysis of clear-cell renal cell carcinoma. Nat. Genet. 2013; 45 (8): 860–7.
  111. Hakimi A.A., Ostrovnaya I., Reva B., Schultz N., Chen Y.B., Gonen M., Liu H., Takeda S., Voss M.H., Tickoo S.K., Reuter V.E., Russo P., Cheng E.H., Sander C., Motzer R.J., Hsieh J.J.; ccRCC Cancer Genome Atlas (KIRC TCGA) Research Network investigators. 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. 2013; 19 (12): 3259–67.
  112. Gulati S., Martinez P., Joshi T., Birkbak N.J., Santos C.R., Rowan A.J., Pickering L., Gore M., Larkin J., Szallasi Z., Bates P.A., Swanton C., Gerlinger M. Systematic evaluation of the prognostic impact and intratumour heterogeneity of clear cell renal cell carcinoma biomarkers. Eur. Urol. 2014; 66 (5): 936–48.
  113. Shen H., Liu Q., Li M., Yang P. The prognostic value of vascular endothelial growth factor in patients with renal cell carcinoma: a systematic review of the literature and meta-analysis. Clin. Invest. Med. 2017; 40 (2): 40–8.
  114. Thompson R.H., Gillett M.D., Cheville J.C., Lohse C.M., Dong H., Webster W.S., Krejci K.G., Lobo J.R., Sengupta S., Chen L., Zincke H., Blute M.L., Strome S.E., Leibovich B.C., Kwon E.D. Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. Proc. Natl. Acad. Sci. USA. 2004; 101 (49): 17174–9.
  115. Yao S., Chen L. PD-1 as an immune modulatory receptor. Cancer J. 2014; 20 (4): 262–4.
  116. Dong Y., Sun Q., Zhang X. PD-1 and its ligands are important immune checkpoints in cancer. Oncotarget. 2017;8 (2): 2171–86.
  117. Swann J.B., Smyth M.J. Immune surveillance of tumors. J. Clin. Invest. 2007; 117 (5): 1137–46.
  118. Thompson R.H., Dong H., Kwon E.D. Implications of B7-H1 Expression in Clear Cell Carcinoma of the Kidney for Prognostication and Therapy. Clin. Cancer Res. 2007; 13 (2 Pt 2): 709–15.
  119. Choueiri T.K., Figueroa D.J., Fay A.P., Signoretti S., Liu Y., Gagnon R., Deen K., Carpenter C., Benson P., Ho T.H., Pandite L., de Souza P., Powles T., Motzer R.J. Correlation of PD-L1 tumor expression and treatment outcomes in patients with renal cell carcinoma receiving sunitinib or pazopanib: results from COMPARZ, a randomized controlled trial. Clin. Cancer Res. 2015; 21 (5): 1071–7.
  120. Choueiri T.K., Fay A.P., Gray K.P., Callea M., Ho T.H., Albiges L., Bellmunt J., Song J., Carvo I., Lampron M., Stanton M.L., Hodi F.S., McDermott D.F., Atkins M.B., Freeman G.J., Hirsch M.S., Signoretti S. PD-L1 expression in nonclear-cell renal cell carcinoma. Ann. Oncol. 2014; 25 (11): 2178–84.
  121. Frigola X., Inman B.A., Lohse C.M., Krco C.J., Cheville J.C., Thompson R.H., Leibovich B., Blute M.L., Dong H., Kwon E.D. Identification of a soluble form of B7-H1 that retains immunosuppressive activity and is associated with aggressive renal cell carcinoma. Clin. Cancer Res. 2011; 17 (7): 1915–23.
  122. Thompson R.H., Kuntz S.M., Leibovich B.C., Dong H., Lohse C.M., W