Molecular Diagnostics in Renal Cancer

  • Barkha Singhal Sanganeria
  • Radhieka Misra
  • Kamla Kant Shukla


Renal cancer is an aggressive and incurable disease with a worldwide prevalence that ranks it to be twelfth most common type of cancer. According to world cancer statistics, around 338,000 new kidney cancer incidences are diagnosed annually. Renal cancer is caused by various sporadic or familial mutations that lead to the accumulation of genomic aberrations enough to impair cell proliferation and differentiation. Epigenetic factors such as hypermethylation also adds up to the malignancy. Kidney heterogeneity makes it really tough to treat renal cancer since (a) different cells are affected in different types of renal cancer, and (b) diagnosis is very incidental and the symptoms appear only in the advance stages. Kidney cancer can be detected by conventional methods based on tumor morphology and tissue histology, while radical nephrectomy or more recently nephron-sparing surgery is the only treatment available in advance cancer stages. Evolvement of molecular techniques and integration in transcriptomics, proteomics and metabolomics, has lead to the quantification of a wide range of chemical fingerprints left behind by alterations caused by different types of renal cancer at earlier stages. These non-invasive biomarkers has the potential to detect renal cancer before they metastasize, improve cancer diagnosis, prognosis, and provide more personalized and targeted therapies in patient care. In this chapter, we have summarized the various molecular techniques and renal cancer biomarkers available to detect early stages with a possibility to have clinical implications in near future.


Renal cancer diagnosis Renal cancer biomarkers Clear cell carcinoma RCC Renal molecular diagnosis Molecular techniques Immunoassay NGS Non-invasive biomarkers 


  1. 1.
    Ferlay J, Soerjomataram I, Mea E. GLOBOCAN 2012 v1.0, cancer incidence and mortality worldwide: IARC CancerBase No. 11. Lyon: International Agency for Research on Cancer; 2013. p. 1.0.Google Scholar
  2. 2.
    Bray F, Ren JS, Masuyer E, Ferlay J. Global estimates of cancer prevalence for 27 sites in the adult population in 2008. Int J Cancer. 2013;132(5):1133–45.PubMedGoogle Scholar
  3. 3.
    Linehan W, et al. Molecular diagnosis and therapy of kidney cancer. Annu Rev Med. 2010;61:329–43.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Pastore AL, et al. Serum and urine biomarkers for human renal cell carcinoma. Dis Mark. 2015;2015:251403.Google Scholar
  5. 5.
    Leppert JT, Pantuck AJ, Figlin RA, Belldegrun AS. The role of molecular markers in the staging of renal cell carcinoma. BJU Int. 2007;99(5b):1208–11.PubMedGoogle Scholar
  6. 6.
    Audenet F, Yates D, Cancel-Tassin G, Cussenot O, Rouprêt M. Genetic pathways involved in carcinogenesis of clear cell renal cell carcinoma: genomics towards personalized medicine. BJU Int. 2012;109:1864–70.PubMedGoogle Scholar
  7. 7.
    Daniel CR, et al. Large prospective investigation of meat intake, related mutagens, and risk of renal cell carcinoma. Am J Clin Nutr. 2012;95(1):155–62.PubMedGoogle Scholar
  8. 8.
    T P, et al. Body size and risk of renal cell carcinoma in the European prospective investigation into cancer and nutrition (EPIC). Int J Cancer. 2006;118(3):728–38.Google Scholar
  9. 9.
    Xu Y, et al. The impact of smoking on survival in renal cell carcinoma: a systematic review and meta-analysis. Tumor Biol. 2014;35(7):6633–40.Google Scholar
  10. 10.
    Sanfilippo KM, et al. Hypertension and obesity and the risk of kidney cancer in 2 large cohorts of US men and women. Hypertension. 2014;63(5):934–41.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Hu J, et al. Renal cell carcinoma and occupational exposure to chemicals in Canada. Occup Med. 2002;52(3):157–64.Google Scholar
  12. 12.
    Muglia VF, Prando A. Renal cell carcinoma: histological classification and correlation with imaging findings. Radiol Bras. 2015;48(3):166–74.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Cairns P. Renal cell carcinoma. Cancer Biomark. 2011;9(1–6):461–73.PubMedCentralGoogle Scholar
  14. 14.
  15. 15.
    Haase VH. The VHL/HIF oxygen-sensing pathway and its relevance to kidney disease. Kidney Int. 2006;69(8):1302–7.PubMedGoogle Scholar
  16. 16.
    Organ S, Tsao M. An overview of the c-MET signaling pathway. Ther Adv Med Oncol. 2011;3(1 Suppl):S7–S19.PubMedPubMedCentralGoogle Scholar
  17. 17.
    L S, et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet. 1997;16(1):68–73.Google Scholar
  18. 18.
    Linehan WM, Srinivasan R, Schmidt LS. The genetic basis of kidney cancer: a metabolic disease. Nat Rev Urol. 2010;5:277.Google Scholar
  19. 19.
    Linehan WM, Walther MM, Zbar B. The genetic basis of cancer of the kidney. J Urol. 2003;170(6 Part 1):2163.PubMedGoogle Scholar
  20. 20.
    Menko FH, et al. Hereditary leiomyomatosis and renal cell cancer (HLRCC). Renal cancer risk, surveillance and treatment. Fam Cancer. 2014;13(4):637–44.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Schneider M, et al. Early onset renal cell carcinoma in an adolescent girl with germline FLCN exon 5 deletion. Fam Cancer. 2018;17(1):135–9. Cite as(1):135–9.PubMedGoogle Scholar
  22. 22.
    Pavlovich C, et al. Renal tumors in the Birt-Hogg-Dubé syndrome. Am J Surg Pathol. 2002;26(12):1542–52.PubMedGoogle Scholar
  23. 23.
    Ramakrishnan S, Ellis L, Pili R. Histone modifications: implications in renal cell carcinoma. Epigenomics. 2013;5(4):453–62.PubMedGoogle Scholar
  24. 24.
    Shenoy N, et al. Role of DNA methylation in renal cell carcinoma. J Hematol Oncol. 2015;8:88.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Tunuguntla HS, Jorda M. Diagnostic and prognostic molecular markers in renal cell carcinoma. J Urol. 2008;179(6):2096.PubMedGoogle Scholar
  26. 26.
    Eichelberg C, Junker K, Ljungberg B, Moch H. Diagnostic and prognostic molecular markers for renal cell carcinoma: a critical appraisal of the current state of research and clinical applicability. Eur Urol. 2009;55(4):851–63.PubMedGoogle Scholar
  27. 27.
    DI Carlo A. Evaluation of neutrophil gelatinase-associated lipocalin (NGAL), matrix metalloproteinase-9 (MMP-9) and their complex MMP-9/NGAL in sera and urine of patients with kidney tumors. Oncol Lett. 2013;5(5):1677–81.Google Scholar
  28. 28.
    Won KH, et al. 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.Google Scholar
  29. 29.
    Bonventre J. Kidney injury molecule-1 (KIM-1): a urinary biomarker and much more. Nephrol Dial Transplant. 2009;24(11):3265–8.PubMedGoogle Scholar
  30. 30.
    Jeremiah JM, Amy NL, Jingqin L, Evan DK. Urinary biomarkers for the early diagnosis of kidney cancer. Mayo Clin Proc. 2010;85(5):413–21.Google Scholar
  31. 31.
    Rajandram R, et al. Tumour necrosis factor receptor-associated factor-1 (TRAF-1) expression is increased in renal cell carcinoma patient serum but decreased in cancer tissue compared with normal: potential biomarker significance. Pathology. 2014;46(6):518–22.PubMedGoogle Scholar
  32. 32.
    Bennett NC, et al. Patient samples of renal cell carcinoma show reduced expression of TRAF1 compared with normal kidney and functional studies in vitro indicate TRAF1 promotes apoptosis: potential for targeted therapy. Pathology. 2012;44(5):453–9.PubMedGoogle Scholar
  33. 33.
    Hofbauer S, et al. Pretherapeutic gamma-glutamyltransferase is an independent prognostic factor for patients with renal cell carcinoma. Br J Cancer. 2014;111(8):1526–31.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Ramp U, et al. Apoptosis induction in renal cell carcinoma by TRAIL and γ-radiation is impaired by deficient caspase-9 cleavage. Br J Cancer. 2003;88(11):1800–7.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Déjosez M, et al. Sensitivity to TRAIL/APO-2L-mediated apoptosis in human renal cell carcinomas and its enhancement by topotecan. Cell Death Differ. 2000;7(11):1127–36.PubMedGoogle Scholar
  36. 36.
    I Y, et al. Serum M65 as a biomarker for metastatic renal cell carcinoma. Clin Genitourin Cancer. 2013;11(3):290–6.Google Scholar
  37. 37.
    Frew IJ, Moch H. A clearer view of the molecular complexity of clear cell renal cell carcinoma. Annu Rev Pathol Mech Dis. 2015;10(1):263–89.Google Scholar
  38. 38.
    Tanaka T, Kitamura H, Torigoe T, et al. Autoantibody against hypoxia-inducible factor prolyl hydroxylase-3 is a potential serological marker for renal cell carcinoma. J Cancer Res Clin Oncol. 2011;137(5):789–94.PubMedGoogle Scholar
  39. 39.
    Takacova M, et al. Carbonic anhydrase IX is a clinically significant tissue and serum biomarker associated with renal cell carcinoma. Oncol Lett. 2013;5(1):191–7.PubMedGoogle Scholar
  40. 40.
    Silva D, et al. Serum tissue factor as a biomarker for renal clear cell carcinoma. Int Braz J Urol. 2018;44(1):38–44.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Tan W, et al. Role of inflammatory related gene expression in clear cell renal cell carcinoma development and clinical outcomes. J Urol. 2011;186(5):2071–7.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Iqbal MA, Akhtar M, Al Dayel F, Ulmer C, Paterson MC. Use of fish analysis for diagnosis of renal cell carcinoma subtypes. Ann Saudi Med. 1999;19(6):495–500.PubMedGoogle Scholar
  43. 43.
    Kim S, et al. Usefulness of a break-apart FISH assay in the diagnosis of Xp11.2 translocation renal cell carcinoma. Virchows Arch. 2011;459(3):299–306.PubMedGoogle Scholar
  44. 44.
    Pradhan D, et al. Validation and utilization of a TFE3 break-apart FISH assay for Xp11.2 translocation renal cell carcinoma and alveolar soft part sarcoma. Diagn Pathol. 2015;10(1):179.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Pflueger D, et al. Identification of molecular tumor markers in renal cell carcinomas with TFE3 protein expression by RNA sequencing. Neoplasia. 2013;15(11):1231–40.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Hahn AW, et al. Correlation of genomic alterations assessed by next-generation sequencing (NGS) of tumor tissue DNA and circulating tumor DNA (ctDNA) in metastatic renal cell carcinoma (mRCC): potential clinical implications. Oncotarget. 2017;8(20):33614–20.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Di Napoli A, Signoretti S. Tissue biomarkers in renal cell carcinoma: issues and solutions. Cancer. 2009;115(10 Suppl):2290–7.PubMedGoogle Scholar
  48. 48.
    Barr ML, et al. PAX-8 expression in renal tumours and distant sites: a useful marker of primary and metastatic renal cell carcinoma? J Clin Pathol. 2014;68(1):12–7.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Knoepp S, Kunju LP, Roh MH. Utility of PAX8 and PAX2 immunohistochemistry in the identification of renal cell carcinoma in diagnostic cytology. Diagn Cytopathol. 2012;40(8):667–72.PubMedGoogle Scholar
  50. 50.
    Miettinen M, Lasota J. KIT (CD117): a review on expression in normal and neoplastic tissues, and mutations and their clinicopathologic correlation. Appl Immunohistochem Mol Morphol. 2005;13(3):205–20.PubMedGoogle Scholar
  51. 51.
    Ahmed EA, Youssif ME. Immunohistochemical study of c-KIT (CD117) expression in renal cell carcinoma. J Egypt Natl Canc Inst. 2009;21(2):121–32.PubMedGoogle Scholar
  52. 52.
    Martignoni G, et al. Validation of 34betaE12 immunoexpression in clear cell papillary renal cell carcinoma as a sensitive biomarker. Pathology. 2017;49(1):10–8.PubMedGoogle Scholar
  53. 53.
    Farber N, et al. Renal cell carcinoma: the search for a reliable biomarker. Transl Cancer Res. 2017;6(3):620–32.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Slade L, Pulinilkunnil T. The MiTF/TFE family of transcription factors: master regulators of organelle signaling, metabolism, and stress adaptation. Mol Cancer Res. 2017 15(12):1637–43.Google Scholar
  55. 55.
    Alshenawy HA. Immunohistochemical panel for differentiating renal cell carcinoma with clear and papillary features. Pathol Oncol Res. 2015;21(4):893–9.PubMedGoogle Scholar
  56. 56.
    Lee HJ, et al. Combination of immunohistochemistry, FISH and RT-PCR shows high incidence of Xp11 translocation RCC: comparison of three different diagnostic methods. Oncotarget. 2017;8(19):30756–65.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Kim K, et al. Urine metabolomics analysis for kidney cancer detection and biomarker discovery. Mol Cell Proteomics. 2009;8(3):558–70.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Kind T, Tolstikov V, Fiehn O, Weiss R. A comprehensive urinary metabolomic approach for identifying kidney cancer. Anal Biochem. 2007;363(2):185–95.PubMedGoogle Scholar
  59. 59.
    Rogers M, et al. Proteomic profiling of urinary proteins in renal cancer by surface enhanced laser desorption ionization and neural-network analysis. Cancer Res. 2003;63(20):6971–83.PubMedGoogle Scholar
  60. 60.
    Fischer K, Theil G, Hoda R, Fornara P. Serum amyloid a: a biomarker for renal cancer. Anticancer Res. 2012;32(5):1801–4.PubMedGoogle Scholar
  61. 61.
    Wulfken L, et al. MicroRNAs in renal cell carcinoma: diagnostic implications of serum miR-1233 levels. PLoS One. 2011;6(9):e25787.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Wang C, et al. A panel of five serum miRNAs as a potential diagnostic tool for early-stage renal cell carcinoma. Sci Rep. 2015;5(1):7610.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Li M, et al. MicroRNAs in renal cell carcinoma: a systematic review of clinical implications (review). Oncol Rep. 2015;33(4):1571–8.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Li M, Wang Y, Cheng L, Niu W, Zhao G, Raju JK, et al. Long non-coding RNAs in renal cell carcinoma: a systematic review and clinical implications. Oncotarget. 2017;8(29):48424–35.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Yu G, et al. LncRNAs expression signatures of renal clear cell carcinoma revealed by microarray. PLoS One. 2012;7(8):e42377.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Ellinger J, et al. The long non-coding RNA lnc-ZNF180–2 is a prognostic biomarker in patients with clear cell renal cell carcinoma. Am J Cancer Res. 2015;5(9):2799–807.PubMedPubMedCentralGoogle Scholar
  67. 67.
    Ball MW, et al. Circulating tumor DNA as a marker of therapeutic response in patients with renal cell carcinoma: a pilot study. Clin Genitourin Cancer. 2016;14(5):e515–20.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Cohen RJ. Pathology of clear cell renal cell carcinoma; 2016.

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Barkha Singhal Sanganeria
    • 1
  • Radhieka Misra
    • 2
  • Kamla Kant Shukla
    • 3
  1. 1.Centre for Transplant and Renal ResearchWestmead Institute for Medical ResearchWestmeadAustralia
  2. 2.Era’s Lucknow Medical College and HospitalLucknowIndia
  3. 3.Department of BiochemistryAll India Institute of Medical SciencesJodhpurIndia

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