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Molecular Heterogeneity of Renal Cell Carcinoma

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Urologic Oncology

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Abstract

Renal cell carcinoma (RCC) is characterized by extensive inter- as well as intratumoral heterogeneity (ITH). The range of ITH in clear cell RCC, the most common histological subtype, extends from histopathological features over functional and mutational ITH to topological ITH. Functional and genomic ITH are major determinants of disease progression and therapy resistance since they promote clonal evolution and the ability to overcome selection barriers. This notion applies also to systemic therapeutic interventions, which inevitably result in changes of the molecular architecture of a tumor. This chapter will review the different forms of ITH in RCC including open questions and emerging concepts. The translational relevance of ITH within the conceptual framework of mutation and selection will be discussed.

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References

  • Almendro V, Cheng Y-K, Randles A, Itzkovitz S, Marusyk A, Ametller E, et al. Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of genetic and phenotypic cellular diversity. Cell Rep. 2014a;6(3):514–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Almendro V, Kim HJ, Cheng Y-K, Gönen M, Itzkovitz S, Argani P, et al. Genetic and phenotypic diversity in breast tumor metastases. Cancer Res. 2014b;74(5):1338–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baca SC, Prandi D, Lawrence MS, Mosquera JM, Romanel A, Drier Y, et al. Punctuated evolution of prostate cancer genomes. Cell. 2013;153(3):666–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bi M, Zhao S, Said JW, Merino MJ, Adeniran AJ, Xie Z, et al. Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma. Proc Natl Acad Sci. 2016;113(8):2170–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bousquet G, Bouchtaoui El M, Leboeuf C, Battistella M, Varna M, Ferreira I, et al. Tracking sub-clonal TP53 mutated tumor cells in human metastatic renal cell carcinoma. Oncotarget. 2015;6(22):19279–89.

    Article  PubMed  PubMed Central  Google Scholar 

  • Brannon AR, Reddy A, Seiler M, Arreola A, Moore DT, Pruthi RS, et al. Molecular stratification of clear cell renal cell carcinoma by consensus clustering reveals distinct subtypes and survival patterns. Genes Cancer. 2010;1(2):152–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013;499(7456):43–9.

    Article  Google Scholar 

  • Dalgliesh GL, Furge K, Greenman C, Chen L, Bignell G, Butler A, et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature. 2010;463(7279):360–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Delahunt B, Cheville JC, Martignoni G, Humphrey PA, Magi-Galluzzi C, McKenney J, et al. The International Society of Urological Pathology (ISUP) grading system for renal cell carcinoma and other prognostic parameters. Am J Surg Pathol. 2013;37:1490–504.

    Article  PubMed  Google Scholar 

  • Fox EJ, Loeb LA. Cancer: one cell at a time. Nature. 2014;512(7513):143–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frew IJ, Moch H. A clearer view of the molecular complexity of clear cell renal cell carcinoma. Annu Rev Pathol. 2015;10:263–89.

    Article  CAS  PubMed  Google Scholar 

  • Gao R, Davis A, McDonald TO, Sei E, Shi X, Wang Y, et al. Punctuated copy number evolution and clonal stasis in triple-negative breast cancer. Nat Genet. 2016;48(10):1119–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366(10):883–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gerlinger M, Horswell S, Larkin J, Rowan AJ, Salm MP, Varela I, et al. Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nat Genet. 2014;46(3):225–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gerlinger M, Catto JW, Orntoft TF, Real FX, Zwarthoff EC, Swanton C. Intratumour heterogeneity in urologic cancers: from molecular evidence to clinical implications. Eur Urol. 2015;67(4):729–37.

    Article  CAS  PubMed  Google Scholar 

  • Gnarra JR, Tory K, Weng Y, Schmidt L, Wei MH, Li H, et al. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet. 1994;7(1):85–90.

    Article  CAS  PubMed  Google Scholar 

  • Gnarra JR, Duan DR, Weng Y, Humphrey JS, Chen DY, Lee S, et al. Molecular cloning of the von Hippel-Lindau tumor suppressor gene and its role in renal carcinoma. Biochim Biophys Acta. 1996;1242(3):201–10.

    PubMed  Google Scholar 

  • Greaves M, Maley CC. Clonal evolution in cancer. Nature. 2012;481(7381):306–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haake SM, Brooks SA, Welsh E, Fulp WJ, Chen D-T, Dhillon J, et al. Patients with ClearCode34-identified molecular subtypes of clear cell renal cell carcinoma represent unique populations with distinct comorbidities. Urol Oncol. 2016;34(3):122.e1–7.

    Article  CAS  Google Scholar 

  • Hakimi AA, Pham CG, Hsieh JJ. A clear picture of renal cell carcinoma. Nat Genet. 2013;45(8):849–50.

    Article  CAS  PubMed  Google Scholar 

  • Hatiboglu G, Hohenfellner M, Arslan A, Hadaschik B, Teber D, Radtke JP, et al. Effective downsizing but enhanced intratumoral heterogeneity following neoadjuvant sorafenib in patients with non-metastatic renal cell carcinoma. Langenbecks Arch Surg. 2017;402(4):637–44.

    Google Scholar 

  • Hoefflin R, Lahrmann B, Warsow G, Hübschmann D, Spath C, Walter B, et al. Spatial niche formation but not malignant progression is a driving force for intratumoural heterogeneity. Nat Commun. 2016;7:ncomms11845.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang Y, Gao S, Wu S, Song P, Sun X, Hu X, et al. Multilayered molecular profiling supported the monoclonal origin of metastatic renal cell carcinoma. Int J Cancer. 2014;135(1):78–87.

    Article  CAS  PubMed  Google Scholar 

  • Jones TD, Eble JN, Wang M, MacLennan GT, Jain S, Cheng L. Clonal divergence and genetic heterogeneity in clear cell renal cell carcinomas with sarcomatoid transformation. Cancer. 2005;104(6):1195–203.

    Article  CAS  PubMed  Google Scholar 

  • Kapur P, Peña-Llopis S, Christie A, Zhrebker L, Pavía-Jiménez A, Rathmell WK, 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. 2013;14(2):159–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kovacs G, Akhtar M, Beckwith BJ, Bugert P, Cooper CS, Delahunt B, et al. The Heidelberg classification of renal cell tumours. J Pathol. 1997;183:131–3.

    Article  CAS  PubMed  Google Scholar 

  • Linehan WM. The genetic basis of kidney cancer: implications for management and use of targeted therapeutic approaches. Eur Urol. 2012;61(5):896–8.

    Article  PubMed  PubMed Central  Google Scholar 

  • Linehan WM, Srinivasan R, Schmidt LS. The genetic basis of kidney cancer: a metabolic disease. Nat Rev Urol. 2010;7(5):277–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ljungberg B, Stenling R, Roos G. DNA content in renal cell carcinoma with reference to tumor heterogeneity. Cancer. 1985;56(3):503–8.

    Article  CAS  PubMed  Google Scholar 

  • Lopez JI, Guarch R, Larrinaga G, Corominas-Cishek A, Orozco R. Cell heterogeneity in clear cell renal cell carcinoma. APMIS. 2013;121(12):1187–91.

    Article  PubMed  Google Scholar 

  • Moch H, Schraml P, Bubendorf L, Richter J, Gasser TC, Mihatsch MJ, et al. Intratumoral heterogeneity of von Hippel-Lindau gene deletions in renal cell carcinoma detected by fluorescence in situ hybridization. Cancer Res. 1998;58(11):2304–9.

    CAS  PubMed  Google Scholar 

  • Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM. 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.

    Article  PubMed  Google Scholar 

  • Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356(2):115–24.

    Article  CAS  PubMed  Google Scholar 

  • Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803–13.

    Google Scholar 

  • Nielsen TO, Perou CM. CCR 20th anniversary commentary: the development of breast cancer molecular subtyping. Clin Cancer Res. 2015;21(8):1779–81.

    Article  CAS  PubMed  Google Scholar 

  • Nordenson I, Ljungberg B, Roos G. Chromosomes in renal carcinoma with reference to intratumor heterogeneity. Cancer Genet Cytogenet. 1988;32(1):35–41.

    Article  CAS  PubMed  Google Scholar 

  • Nowell P. The clonal evolution of tumor cell populations. Science. 1976;194:23.

    Article  CAS  PubMed  Google Scholar 

  • Peña-Llopis S, Vega-Rubín-de-Celis S, Liao A, Leng N, Pavía-Jiménez A, Wang S, et al. BAP1 loss defines a new class of renal cell carcinoma. Nat Genet. 2012;44(7):751–9.

    Article  PubMed  PubMed Central  Google Scholar 

  • Polyak K, Haviv I, Campbell IG. Co-evolution of tumor cells and their microenvironment. Trends Genet. 2009;25(1):30–8.

    Article  CAS  PubMed  Google Scholar 

  • Sato Y, Yoshizato T, Shiraishi Y, Maekawa S, Okuno Y, Kamura T, et al. Integrated molecular analysis of clear-cell renal cell carcinoma. Nat Genet. 2013;45(8):860–7.

    Article  CAS  PubMed  Google Scholar 

  • Schödel J, Grampp S, Maher ER, Moch H, Ratcliffe PJ, Russo P, et al. Hypoxia, hypoxia-inducible transcription factors, and renal cancer. Eur Urol. 2016;69(4):646–57.

    Article  PubMed  Google Scholar 

  • Shaw G. The silent disease. Nature. 2016;537(7620):S98–9.

    Article  CAS  PubMed  Google Scholar 

  • Stewart GD, O’Mahony FC, Laird A, Eory L, Lubbock ALR, Mackay A, et al. Sunitinib treatment exacerbates intratumoral heterogeneity in metastatic renal cancer. Clin Cancer Res. 2015;21(18):4212–23.

    Article  CAS  PubMed  Google Scholar 

  • Varela I, Tarpey P, Raine K, Huang D, Ong CK, Stephens P, et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature. 2011;469(7331):539–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Voss MH, Hakimi AA, Pham CG, Brannon AR, Chen Y-B, Cunha LF, et al. Tumor genetic analyses of patients with metastatic renal cell carcinoma and extended benefit from mTOR inhibitor therapy. Clin Cancer Res. 2014;20(7):1955–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Waclaw B, Bozic I, Pittman ME, Hruban RH, Vogelstein B, Nowak MA. A spatial model predicts that dispersal and cell turnover limit intratumour heterogeneity. Nature. 2015;525(7568):261–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu X, Hou Y, Yin X, Bao L, Tang A, Song L, et al. Single-cell exome sequencing reveals single-nucleotide mutation characteristics of a kidney tumor. Cell. 2012;148(5):886–95.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Work in the authors’ laboratory is supported by the Medical Faculty Heidelberg. W. H. is recipient of a fellowship from the China Scholarship Council.

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Authors and Affiliations

  1. Department of Urology and Section of Molecular Urooncology, University of Heidelberg School of Medicine, Medical Faculty Heidelberg, 69120, Heidelberg, Germany

    Weibin Hou, Rouven Hoefflin, Markus Hohenfellner & Stefan Duensing

  2. Department of Hematology and Oncology, University of Freiburg School of Medicine, Hugstetter Strasse 55, 79106, Freiburg, Germany

    Rouven Hoefflin

  3. Department of Medical Oncology, Section of Translational Urooncology, University of Heidelberg School of Medicine, National Center for Tumor Diseases (NCT) Heidelberg, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany

    Carsten Grüllich

Authors
  1. Weibin Hou
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  2. Rouven Hoefflin
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  3. Carsten Grüllich
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  4. Markus Hohenfellner
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  5. Stefan Duensing
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Corresponding author

Correspondence to Stefan Duensing .

Editor information

Editors and Affiliations

  1. Dept. of Urology & Urologic Oncology, Hannover Medical School, Hannover, Germany

    Axel S. Merseburger

  2. Dept. of Urology, University of Regensburg St. Josef Medical Centre, Regensburg, Germany

    Maximilian Burger

Section Editor information

  1. Klinik für Urologie, Ratzeburger Allee 160, 23538, Lübeck, Germany

    Mario W. Kramer

  2. Department of Urology, University Hospital Schleswig-Holstein, Ratzeburger Allee 160, 23538, Lübeck, Germany

    Axel S. Merseburger

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Hou, W., Hoefflin, R., Grüllich, C., Hohenfellner, M., Duensing, S. (2017). Molecular Heterogeneity of Renal Cell Carcinoma. In: Merseburger, A., Burger, M. (eds) Urologic Oncology. Springer, Cham. https://doi.org/10.1007/978-3-319-42603-7_59-1

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  • DOI: https://doi.org/10.1007/978-3-319-42603-7_59-1

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  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-42603-7

  • Online ISBN: 978-3-319-42603-7

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