Clinical and Translational Oncology

, Volume 10, Issue 11, pp 697–712

Origin of renal cell carcinomas

  • Manuel Valladares Ayerbes
  • Guadalupe Aparicio Gallego
  • Silvia Díaz Prado
  • Paula Jiménez Fonseca
  • Rosario García Campelo
  • Luis Miguel Antón Aparicio
Educational Series

Abstract

Cancer is a heritable disorder of somatic cells: environment and heredity are both important in the carcinogenic process. The primal force is the “two hits” of Knudson’s hypothesis, which has proved true for many tumours, including renal cell carcinoma. Knudson et al. [1, 2] recognised that familial forms of cancer might hold the key to the identification of important regulatory elements known as tumour-suppressor genes. Their observations (i.e., that retinoblastoma tend to be multifocal in familial cases and unifocal in sporadic presentation) led them to propose a two-hit theory of carcinogenesis. Furthermore, Knudson postulated that patients with the familial form of the cancer would be born with one mutant allele and that all cells in that organ or tissue would be at risk, accounting for early onset and the multifocal nature of the disease. In contrast, sporadic tumours would develop only if a mutation occurred in both alleles within the same cell, and, as each event would be expected to occur with low frequency, most tumours would develop late in life and in a unifocal manner [3, 4]. The kidney is affected in a variety of inherited cancer syndromes. For most of them, both the oncogene/tumour-suppressor gene involved and the respective germline mutations have been identified. Each of the inherited syndromes predisposes to distinct types of renal carcinoma. Families with hereditary predisposition to cancer continue to provide a unique opportunity for the identification and characterisation of genes involved in carcinogenesis. A surprising number of genetic syndromes predispose to the development of renal cell carcinoma, and genes associated with five of these syndromes have been already identified: VHL, MET, FH, BHD and HRPT2. Few cancers have as many different types of genetic predisposition as renal cancer, although to date only a small proportion of renal cell cancers can be explained by genetic predisposition.

Keywords

Stem cell Stem cell markers Bone marrow stem cells 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Knudson AG (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 69:820–823CrossRefGoogle Scholar
  2. 2.
    Knudson AG, Strong LC (1976) Mutation and cancer: a model for Wilms’ tumor of the kidney. J Natl Cancer Inst 48:313–324Google Scholar
  3. 3.
    Zimmer M, Iliopoulos O (2003) Molecular genetics of kidney cancer. Cancer Treat Res 116:3–27PubMedGoogle Scholar
  4. 4.
    Pavlovich CP, Schmidt LS (2004) Searching for the hereditary causes of renal-cell carcinoma. Nat Rev Cancer 4:381–393PubMedCrossRefGoogle Scholar
  5. 5.
    Al-Awqati Q, Oliver JA (2002) Stem cells in the kidney. Kidney Int 61:387–395PubMedCrossRefGoogle Scholar
  6. 6.
    Savage COS (1994) The biology of the glomerulus: endothelial cells. Kidney Int 45:314–319PubMedCrossRefGoogle Scholar
  7. 7.
    Johnson RJ, Floege J, Yoshimura A et al (1992) The activated mesangial cell: a glomerular “myofibroblast”. J Am Soc Nephrol 2[Suppl 10]: S190–19PubMedGoogle Scholar
  8. 8.
    El Nahas AM, Muchaneta-Kubara EC, Essawy M, Soylemezoglu O (1997) Renal fibrosis: insights into pathogenesis and treatment. Int J Biochem Cell Biol 29:55–62PubMedCrossRefGoogle Scholar
  9. 9.
    Lidhal P, Hellstrom M, Kalen M et al (1998) Paracrine PDGF-B/PDGF-R beta signalling controls mesangial development in kidney glomeruli. Development 125:3313–3322Google Scholar
  10. 10.
    Naruse K, Fujieda M, Miyazaki E et al (1999) CD34 expression as a novel marker of transformed mesangial cells in biopsied glomerular diseases. J Pathol 189:105–111PubMedCrossRefGoogle Scholar
  11. 11.
    Simmons PJ, Torok-Storb B (1991) CD34 expression by stromal precursors in normal human adult bone marrow. Blood 78:2848–2853PubMedGoogle Scholar
  12. 12.
    Ng YY, Fan JM, Mu W et al (1999) Glomerular epithelial-myofibroblast transdifferentiation in the evolution of glomerular crescent formation. Nephrol Dial Transpl 14:2860–2872CrossRefGoogle Scholar
  13. 13.
    Jernigan SJ, Eddy AA (2000) Experimental insights into the mechanisms of tubulointerstitial scarring. In: El Nahas AM, Anderson S, Harris KPG (eds) Mechanisms and management of progressive renal failure. Oxford University Press, London, pp 104–145Google Scholar
  14. 14.
    Fan JM, Ng YY, Hill PA et al (1999) Transforming growth factor-beta regulates tubular epithelial myofibroblast transdifferentiation in vitro. Kidney Int 56:1455–1467PubMedCrossRefGoogle Scholar
  15. 15.
    Zeisberg M, Strutz F, Muller GA (2000) Renal fibrosis: an update. Curr Opin Nephrol Hypert 10: 315–320CrossRefGoogle Scholar
  16. 16.
    Lineham WM, Lerman MI, Zbar B (1995) Identification of the von Hippel-Lindau (VHL) gene: its role in renal cancer. JAMA 273:564–570CrossRefGoogle Scholar
  17. 17.
    Glenn GM, Choyke PL, Zbar B, Lineham WM (1990) Von Hippel-Lindau disease: clinical review and molecular genetics. In: Anderson E (ed.) Problems in urologic surgery: benign and malignant tumors of the kidney. J.B. Lippincott, Philadelphia, pp 312–330Google Scholar
  18. 18.
    Poston CD, Jaffe GS, Lubensky IA et al (1995) Characterization of the renal pathology of a familial form of renal cell carcinoma associated with von Hippel-Lindau disease: clinical and molecular genetics implications. J Urol 153:22–26PubMedCrossRefGoogle Scholar
  19. 19.
    Cohen AJ, Li FP, Berg S et al (1979) Hereditary renal-cell carcinoma associated with a chromosomal translocation. New Engl J Med 301:592–595PubMedCrossRefGoogle Scholar
  20. 20.
    Kovacs G, Brusa P, De Riese W (1989) Tissuespecific expression of a constitutional 3;6 translocation: development of multiple bilateral renal-cell carcinomas. Int J Cancer 43:422–427PubMedCrossRefGoogle Scholar
  21. 21.
    Zbar B, Tory K, Marine M et al (1994) Hereditary papillary renal cell carcinoma. J Urol 151:561–566PubMedGoogle Scholar
  22. 22.
    Zbar B, Glenn G, Lubensky I et al (1995) Hereditary papillary renal cell carcinoma: clinical studies in 10 families. J Urol 153:907–912PubMedCrossRefGoogle Scholar
  23. 23.
    Weirich G, Glenn G, Junker K et al (1998) Familial renal oncocytoma: clinicopathological study of 5 families. J Urol 160:335–340PubMedCrossRefGoogle Scholar
  24. 24.
    Tory K, Brauch H, Linehan M et al (1989) Specific genetic change in tumors associated with von Hippel-Lindau disease. J Natl Cancer Inst 81: 1097–1101PubMedCrossRefGoogle Scholar
  25. 25.
    Shi G, Cannizzaro LA (1996) Mapping of 29 YAC clones and identification of 3 YACs spanning the translocation t(3;8) (p14.2;q24.1) breakpoint at 8q24.1 in hereditary renal cell carcinoma. Cytogenet Cell Genet 75:180–185PubMedCrossRefGoogle Scholar
  26. 26.
    Bodmer D, Eleveld MJ, Ligtenberg MJ et al (1998) An alternative route for multistep tumorigenesis in a novel case of hereditary renal cell carcinoma and a t(2;3)(q35;q21) chromosomal translocation. Am J Hum Genet 62:1475–1483PubMedCrossRefGoogle Scholar
  27. 27.
    Wang N, Perkins KL (1984) Involvement of band 3p14 in t(3;8) hereditary renal carcinoma. Cancer Genet Cytogenet 11:479–481PubMedCrossRefGoogle Scholar
  28. 28.
    Schmidt L, Duh FM, Chen F et al (1997) Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet 16:68–73PubMedCrossRefGoogle Scholar
  29. 29.
    Schmidt LS, Warren MB, Nickerson ML et al (2001) Birt Hogg Dubé syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2. Am J Hum Genet 69:876–882PubMedCrossRefGoogle Scholar
  30. 30.
    Nickerson ML, Warrem MR, Toro JR et al (2002) Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with Birt-Hogg-Dubé syndrome. Cancer Cell 2:157–164PubMedCrossRefGoogle Scholar
  31. 31.
    Kiuru M, Launonen V, Hietala M et al (2001) Familial cutaneous leiomyomatosis is a two-hit condition associated with renal cell cancer of characteristic histopathology. Am J Pathol 159:825–829PubMedGoogle Scholar
  32. 32.
    Isaacs JT, Jung YJ, Mole DR et al (2005) HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 8:143–153PubMedCrossRefGoogle Scholar
  33. 33.
    Couch V, Lindor NM, Karnes PS, Michels VV (2000) Von Hippel-Lindau disease. Mayo Clin Proc 75:265–272PubMedCrossRefGoogle Scholar
  34. 34.
    Maher ER, Iselius L, Yater JR et al (1991) Von Hippel-Lindau disease: a genetic study. J Med Genet 28:443–447PubMedCrossRefGoogle Scholar
  35. 35.
    Lenehan WM, Zbar B, Klausner RD (2001) Renal carcinoma. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) Metabolic and molecular basis of inherited disease. McGraw-Hill, New YorkGoogle Scholar
  36. 36.
    Tory K, Braauch H, Linehan WM et al (1989) Specific genetic change in tumors associated with von Hippel-Lindau disease. J Natl Cancer Inst 81:1097–1101PubMedCrossRefGoogle Scholar
  37. 37.
    Latif F, Tory K, Gnarra J et al (1993) Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260:1317–1320PubMedCrossRefGoogle Scholar
  38. 38.
    Iliopoulos O, Eng C (2000) Genetics and clinical aspects of familial renal neoplasms. Semin Oncol 27:138–149PubMedGoogle Scholar
  39. 39.
    Seizinger BR, Rouleau GA, Ozellius LJ et al (1988) Von Hippel-Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma. Nature 332:268–269PubMedCrossRefGoogle Scholar
  40. 40.
    Lubensky IA, Gnarra JR, Bertheau P et al (1996) Allelic deletions of the VHL gene detected in multiple microscopic clear cell renal lesions in von Hippel-Lindau disase patients. Am J Pathol 149:2089–2094PubMedGoogle Scholar
  41. 41.
    Hosoe S, Brauch H, Latif F et al (1990) Localization of the von Hippel-Lindau disease gene to a small region of chromosome 3. Genomics 8:634–640PubMedCrossRefGoogle Scholar
  42. 42.
    Richars FM, Maher ER, Latif F et al (1993) Detailed genetic mapping of the von Hippel-Lindau disease tumor suppressor gene. J Med Genet 30: 104–107CrossRefGoogle Scholar
  43. 43.
    Chen F, Kishida T, Yao M et al (1995) Mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. Hum Mutat 5:66–75PubMedCrossRefGoogle Scholar
  44. 44.
    Abar B, Kishida T, Chen F et al (1996) Germline mutations in the von Hippel-Lindau disease (VHL) gene in families from North America, Europe and Japan. Hum Mutat 8:349–357Google Scholar
  45. 45.
    Walther MM, Enquist EG, Jennings SB et al (1999) Molecular genetics of renal cell carcinoma. In Vogelzang NJ, Scardino PT, Shipley WU et al (eds) Comprehensive textbook of genitourinary oncology. Williams/Wilkins, Baltimore, pp 116–128Google Scholar
  46. 46.
    Bottaro DP, Rubin JS, Faletto DL et al (1991) Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 251:802–804PubMedCrossRefGoogle Scholar
  47. 47.
    Huang Z, Park WS, Pack S et al (1998) Trisomy 7-harboring nonrandom duplication of the mutant MET allele in hereditary papillary renal carcinomas. Nat Genet 20:66–69CrossRefGoogle Scholar
  48. 48.
    Kovacs G, Ishikawa I (1993) High incidence of papillary renal cell tumours in patients on chronic haemodialysis. Histopathology 22:135–139PubMedCrossRefGoogle Scholar
  49. 49.
    Zambrano NR, Lubensky IA, Merino MJ et al (1999) Histopathology and molecular genetics of renal tumors: toward unification of a classification system. J Urol 162:1246–1258PubMedCrossRefGoogle Scholar
  50. 50.
    Kovacs G, Tory K, Kovacs A (1994) Development of papillary renal cell tumours is associated with a loss of Y-chromosome-specific DNA sequences. J Pathol 173:39–44PubMedCrossRefGoogle Scholar
  51. 51.
    Thrash-Bingham CA, Salazar H, Freed JJ et al (1995) Genomic alterations and instabilities in renal cell carcinomas and their relationship to tumor pathology. Cancer Res 55:6189–6195PubMedGoogle Scholar
  52. 52.
    Tonk V, Wilson KS, Timmons CF et al (1995) Renal carcinoma with translocation (X;1): further evidence for cytogenetically defined subtype. Cancer Genet Cytogenet 81:72–75PubMedCrossRefGoogle Scholar
  53. 53.
    Kovacs G, Szucs S, Deriese W, Baumgartel H (1978) Specific chromosomal aberration in human renal cell carcinoma. Int J Cancer 40:171–178CrossRefGoogle Scholar
  54. 54.
    Zbar B, Glenn G, Lubensky I et al (1995) Hereditary papillary renal cell carcinoma: clinical studies in 10 families. J Urol 153:907–912PubMedCrossRefGoogle Scholar
  55. 55.
    Duh FM, Scherer SW, Tsui LC et al (1997) Gene structure of the human MET proto-oncogene. Oncogene 15:1583–1586PubMedCrossRefGoogle Scholar
  56. 56.
    Choyke PL, Glenn GM, Walther MM et al (2003) Hereditary renal cancers. Radiology 226:33–46PubMedCrossRefGoogle Scholar
  57. 57.
    Pavlovich CP, Walther MM, Eyler RA et al (2002) Renal tumors in the Birt-Hogg-Dube syndrome. Am J Surg Pathol 26:1542–1552PubMedCrossRefGoogle Scholar
  58. 58.
    Polascik TJ, Bostwick DG, Cairns P (2002) Molecular genetics and histopathologic features of adult distal nephron tumors. Urology 60:941–946PubMedCrossRefGoogle Scholar
  59. 59.
    Birt AR, Hogg GR, Dube WJ (1977) Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol 113:1674–1677PubMedCrossRefGoogle Scholar
  60. 60.
    Pan CC, Chen PC, Chiang H (2004) Overexpression of KIT (CD117) in chromophobe renal cell carcinoma and renal oncocytoma. Am J Clin Pathol 121:878–883PubMedCrossRefGoogle Scholar
  61. 61.
    Petit A, Castillo M, Santos M et al (2004) KIT expression in chromophobe renal cell carcinoma: comparative immunohistochemical analysis of KIT expression in different renal cell neoplasms. Am J Surg Pathol 28:676–678PubMedGoogle Scholar
  62. 62.
    Antonelli A, Portesi E, Cozzot A et al (2003) The collecting duct carcinoma of the kidney: a cytogenetical study. Eur Urol 43:680–685PubMedGoogle Scholar
  63. 63.
    Foster K, Crossey PA, Cairns P et al (1994) Molecular genetic investigation of sporadic renal cell carcinoma: analysis of allele loss on chromosomes 3p,5q,11p,17 and 22. Br J Cancer 69:230–234PubMedGoogle Scholar
  64. 64.
    Lubinski J, Hadaczek P, Podolski J et al (1994) Common regions of deletion in chromosome regions 3p12 and 3p14.2 in primary clear cell renal carcinomas. Cancer Res 54:3710–3713PubMedGoogle Scholar
  65. 65.
    Knebelmann B, Ananth S, Cohen HT, Sukhatme VP (1998) Transforming growth factor alpha is a target for the von Hippel-Lindau tumor suppressor gene. Cancer Res 58:226–231PubMedGoogle Scholar
  66. 66.
    Gomella LG, Sargent ER, Wade TP et al (1989) Expression of transforming growth factor alpha in normal human adult kidney and enhanced expression of transforming growth factors alpha and beta 1 in renal cell carcinoma. Cancer Res 49:6972–6975PubMedGoogle Scholar
  67. 67.
    Kinouchi T, Saiki S, Naoe T et al (1989) Correlation of c-myc expression with nuclear pleomorphism in human renal cell carcinoma. Cancer Res 9:3627–3630Google Scholar
  68. 68.
    Kenck C, Bugert P, Wilhelm M, Kovacs G (1997) Duplication of an approximately 1.5 Mb DNA segment at chromosome 5q22 indicates the locus of a new tumour gene in nonpapillary renal cell carcinomas. Oncogene 14:1093–1098PubMedCrossRefGoogle Scholar
  69. 69.
    Kovacs G (1993) Molecular cytogenetics of renal tumors. Adv Cancer Res 62:89–124PubMedCrossRefGoogle Scholar
  70. 70.
    Presti JC, Moch H, Reuter VE et al (1996) Renal cell carcinoma genetic analysis by comparative ge nomic hybridation and restriction fragment length polymorphism analysis. J Urol 156:281–285PubMedCrossRefGoogle Scholar
  71. 71.
    Gannon JV, Greaves R, Iggo R, Lane DP (1990) Activating mutations in p53 produce a common conformational effect. A monoclonal antibody specific for the mutant form. EMBO J 9:1595–1602PubMedGoogle Scholar
  72. 72.
    Levine AJ, Momand J, Finlay CA (1991) The p53 tumour suppressor gene. Nature 351:453–456PubMedCrossRefGoogle Scholar
  73. 73.
    Oda H, Nakatsuru Y, Ishikawa T (1995) Mutations of the p53 gene and p53 protein overexpression are associated with sarcomatoid transformation in renal cell carcinomas. Cancer Res 55:658–662PubMedGoogle Scholar
  74. 74.
    Hofmockel G, Wittmann A, Dammrich J, Basukas ID (1996) Expression of p53 and bcl-2 in primary locally confined renal cell carcinomas: no evidence for prognostic significance. Anticancer Res 16:3807–3811PubMedGoogle Scholar
  75. 75.
    Dijkhuizen T, Van Den Berg E, Van Den Berg A et al (1997) Genetics as a diagnostic tool in sarcomatoid renal cell cancer. Int J Cancer 72:265–269PubMedCrossRefGoogle Scholar
  76. 76.
    Teysier JR, Ferre D (1990) Chromosomal changes in renal cell carcinoma. No evidence for correlation with clinical stage. Cancer Genet Cytogenet 45:197–205CrossRefGoogle Scholar
  77. 77.
    Presti JC, Reuter VE, Cordon-Cardo C et al (1993) Allelic deletions in renal tumors: his to patho logical correlations. Cancer Res 53:5780–5783PubMedGoogle Scholar
  78. 78.
    Wu SQ, Hafez GR, Xing W et al (1996) The correlation between the loss of chromosome 14q with histologic tumor grade, pathologic stage, and outcome of patients with non-papillary renal cell carcinoma. Cancer 77:1154–1160PubMedCrossRefGoogle Scholar
  79. 79.
    Schullerus D, Herbers J, Chudek J et al (1997) Loss of heterozygosity at chromosomes 8p, 9p, and 14q is associated with stage and grade of nonpapillary renal cell carcinomas. J Pathol 183:151–155PubMedCrossRefGoogle Scholar
  80. 80.
    Pisters LL, el-Naggar AK, Luo W et al (1997) C-met proto-oncogen expression in benign and malignant human renal tissues. J Urol 158:724–728PubMedCrossRefGoogle Scholar
  81. 81.
    Nakopoulou L, Vouriakou C, Papaliodi E et al (1997) Immunodetection of c-met-oncogene’s protein product in renal cell neoplasia. Path Res Pract 193:299–304PubMedGoogle Scholar
  82. 82.
    Natali PG, Prat M, Nicotra MR et al (1996) Over-expression of the met-HGF receptor in renal cell carcinomas. Int J Cancer 69:212–217PubMedCrossRefGoogle Scholar
  83. 83.
    Sargent ER, Gomella LG, Belldegrun A et al (1989) Epidermal growth factor receptor gene expression in normal human kidney and renal cell carcinoma. J Urol 142:1364–1368PubMedGoogle Scholar
  84. 84.
    Weidner U, Peter S, Strohmeyer T et al (1990) Inverse relationship of epidermal growth factor receptor and HER2/neu gene expression in human renal cell carcinoma. Cancer Res 50:4504–4509PubMedGoogle Scholar
  85. 85.
    Bander NH, Cordon-Cardo C, Finstad CL et al (1985) Immunohistologic dissection of the human kidney using monoclonal antibodies. J Urol 133: 502–505PubMedGoogle Scholar
  86. 86.
    Cohen C, McCue PA, Derose PB (1988). Histogenesis of renal cell carcinoma and oncocytoma. An immunohistochemical study. Cancer 62:1946–1951PubMedCrossRefGoogle Scholar
  87. 87.
    Hennigar RA, Spicer SA, Sens DA et al (1986) Histochemical evidence for tubule segmentations in a case of Wilms’ tumor. Am J Clin Pathol 85: 724–731PubMedGoogle Scholar
  88. 88.
    Medeiros LJ, Michie SA, Johnson DE et al (1988) An immunoperoxidase study of renal cell carcinomas: correlations with nuclear grade, cell type and histologic pattern. Hum Pathol 19:980–987PubMedCrossRefGoogle Scholar
  89. 89.
    Wick MR, Cherwitz DL, Manivel JC, Sibley R (1999) Immunohistochemical findings in tumors of the kidney. In Eble JN (ed.) Tumors and tumor-like conditions of the kidneys and ureters. Churchill Livingstone, New York, pp 207–247Google Scholar
  90. 90.
    Yoshida SO, Iman A, Olson CA, Taylar CR (1986) Proximal renal tubular surface membrane antigens identified in primary and metastatic renal cell carcinomas. Arch Pathol Lab Med 110:825–832PubMedGoogle Scholar
  91. 91.
    Fleming S, Symes CE (1987) The distribution of cytokeratin antigens in the kidney and in renal tumors. Histopathology 11:157–170PubMedCrossRefGoogle Scholar
  92. 92.
    Mc Gregor DK, Khurana KH, Cao C et al (2001) Diagnosing primary and metastatic renal cell carcinoma: the use of the monoclonal antibody. Renal Cell Carcinoma Marker. Am J Surg Pathol 25: 1485–1492CrossRefGoogle Scholar
  93. 93.
    Pitz S, Moll R, Storkel S, Thoenes W (1987) Expression of intermediate filament proteins in subtypes of renal cell carcinomas and in renal oncocytoma. Distinction of two classes of renal cell tumors. Lab Invest 56:642–653PubMedGoogle Scholar
  94. 94.
    Chu PG, Weiss LM (2001) Cytokeratin 14 immunoreactivity distinguishes oncocytic tumour from its renal mimics: an immunohistochemical study of 63 cases. Histopathology 39:455–462PubMedCrossRefGoogle Scholar

Copyright information

© Feseo 2008

Authors and Affiliations

  • Manuel Valladares Ayerbes
    • 1
  • Guadalupe Aparicio Gallego
    • 2
  • Silvia Díaz Prado
    • 2
    • 3
  • Paula Jiménez Fonseca
    • 4
  • Rosario García Campelo
    • 1
  • Luis Miguel Antón Aparicio
    • 1
    • 3
  1. 1.Medical Oncology ServiceCHU Juan Canalejo Materno Infantil HospitalA CoruñaSpain
  2. 2.Investigation & Oncology Research UnitCHU Juan CanalejoLa CoruñaSpain
  3. 3.Department of MedicineUniversity of La CoruñaLa CoruñaSpain
  4. 4.Medical Oncology ServiceCentral HospitalAsturiasSpain

Personalised recommendations