Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

Kidney: Clear cell renal cell carcinoma

Written2004-07Eva van den Berg, Stephan Stârkel
Clinical cytogeneticist, Department of Clinical Genetics, Academic Hospital Groningen, Ant. Deusinglaan 4, 9713 AW Groningen, the Netherlands

(Note : for Links provided by Atlas : click)


ICD-Morpho 8310/3 Clear cell adenocarcinoma, NOS
Atlas_Id 5020
Phylum Urinary system: Kidney::Common renal cell carcinoma (clear cell, nonpapillary carcinoma)
WHO/OMS Classification Urinary system
Other namesCommon renal cell carcinoma
Conventional renal cell carcinoma
Non papillary renal cell carcinoma


    Clear cell renal cell carcinoma (cRCC) is a distinct subtype of renal cell carcinoma, possibly originating from mature renal tubular cells in the proximal tubule of the nehpron.

Clinics and Pathology

Epidemiology It comprises 70-75% of cases.They show a male preponderance of 2:1.
Pathology The tumor mass of cRCC is multicolored, with a predominantly yellow surface with white or gray foci. It usually shows a solid growth pattern, but in some cases cystic or alveolar appearance is seen. The cytoplasm is clear, due to an intensive intracytoplasmatic accumulation of glycogen and lipids. The nuclei are condensed and hyperchromatic. Electronmicroscopical features resembling the proximale tubule can be found i.e. brush border formation and basal infoldings. Tumor cells express antigens of the proximal tubule.

Variants can be assigned which are characterized by augmentation of mitochondria leading to a stronger eosinophilia or granularity, respectively, of the cytoplasm. Spindle-shaped/pleomorphic variants as a result of sarcomatoid transformation can also be found.


cRCC is characterized by loss of (part of) the short arm of chromosome 3 due to (a) deletion(s) or unbalanced translocation(s) and restricted to this type. Regions frequently lost are 3p12-14, 3p21 and 3p25. Loss of at least two of these regions is necessary for kidney cells to develop into clear cell renal cell carcinoma, and loss of 3p21 is obligatory. Therefore, if a tumor shows only one deletion at 3p, either 3p14 or 3p25, it should be designated common type renal cell adenomas.

Other aberrations frequently found in common RCC are (partial) trisomy of chromosome 5, especially the 5q22-qter segment. Trisomy 12, and 20, and loss of chromosomes 8, 9, 13q, 14q, and structural abnormalities of the long arm of chromosomes 6 and 10 are also found and correlated with progression.

In general, cRCCs are sporadic tumors but also syndromic in patients with the von Hippel-Lindau (VHL) disease (germ line mutations in the VHL tumor suppressor gene assigned to 3p25). Also familial cRCC familial cRCC has been reported. All have in common the presence of abnormalities involving chromosome 3.

Genes involved and Proteins

Note Based on allele-segregation, LOH and mutation analyses, a step-wise model for cRCC tumorigenesis was put forward in which the loss of the translocation derivative chromosome 3 may lead to chromosomal mosaicism. Subsequently, cells lacking this chromosome may suffer a second hit resulting in full blown tumor development.

Loss of heterozygosity (LOH) and comparative genetic hybridization (CGH) analyses of cRCCs revealed that allelic (interstitial) losses predominantly occur in the chromosome 3p21 region in combination with either 3p25 or 3p13-14, or with both, and these allelic losses were restricted to the cRCC. These results suggest that loss of the 3p21 region is a prerequisite for malignant development of cRCC and indicate that several regions (and thus several genes) on human chromosome 3 contribute to cRCC tumor development.

Until today no tumor suppressor gene responsible for, or at least contributing to, cRCC has been identified -except for VHL-, in the different regions, although many candidate genes have been suggested such as FHIT (fragile histidine triad); TTRC1 (two-three-renal-cancer-1; DUTT1 (deleted in U-twenty twenty); locus NCR-1 (nonpapillary renal cell carcinoma 1) and RASSF1A (RAS association family 1).

The gene in the 3p25 region involved in cRCC development is the von Hippel Lindau (VHL) tumor suppressor gene. Somatic mutations and LOH of the VHL gene were also found in primary sporadic cRCCs. Occurrence of mutations in this gene in both sporadic as well as hereditary forms of cRCC suggests a key role of the VHL gene in oncogenesis. However, VHL is inactivated in only 30-50% of sporadic cRCC, suggesting involvement of another tumor suppressor gene located on 3p.

Loss of heterozygosity on chromosomes 8p or 9p provide prognostic significance in patients with locally advanced cRCC and PTEN/MMAC1 (chromosome 10) inactivation may play a role in the progression of cRCC.

To be noted

Some first array studies on RCC have recently been published showing that specific gene expression patterns could be associated with various tumors (types) including cRCC and other disease states.


Combined LOH/CGH analysis proves the existence of interstitial 3p deletions in renal cell carcinoma.
Alimov A, Kost-Alimova M, Liu J, Li C, Bergerheim U, Imreh S, Klein G, Zabarovsky ER
Oncogene. 2000 ; 19 (11) : 1392-1399.
PMID 10723130
Clear cell hidradenoma of the skin-a third tumor type with a t(11;19)--associated TORC1-MAML2 gene fusion.
Behboudi A, Winnes M, Gorunova L, van den Oord JJ, Mertens F, Enlund F, Stenman G
Genes, chromosomes & cancer. 2005 ; 43 (2) : 202-205.
PMID 15729701
Disruption of a novel gene, DIRC3, and expression of DIRC3-HSPBAP1 fusion transcripts in a case of familial renal cell cancer and t(2;3)(q35;q21).
Bodmer D, Schepens M, Eleveld MJ, Schoenmakers EF, Geurts van Kessel A
Genes, chromosomes & cancer. 2003 ; 38 (2) : 107-116.
PMID 12939738
Duplication of two distinct regions on chromosome 5q in non-papillary renal-cell carcinomas.
Bugert P, Von Knobloch R, Kovacs G
International journal of cancer. Journal international du cancer. 1998 ; 76 (3) : 337-340.
PMID 9579569
Hereditary renal cancers.
Choyke PL, Glenn GM, Walther MM, Zbar B, Linehan WM
Radiology. 2003 ; 226 (1) : 33-46.
PMID 12511666
Genetics in renal cell carcinoma.
Dal Cin P
Current opinion in urology. 2003 ; 13 (6) : 463-466.
PMID 14560139
The candidate tumor suppressor gene, RASSF1A, from human chromosome 3p21.3 is involved in kidney tumorigenesis.
Dreijerink K, Braga E, Kuzmin I, Geil L, Duh FM, Angeloni D, Zbar B, Lerman MI, Stanbridge EJ, Minna JD, Protopopov A, Li J, Kashuba V, Klein G, Zabarovsky ER
Proceedings of the National Academy of Sciences of the United States of America. 2001 ; 98 (13) : 7504-7509.
PMID 11390984
World Health Organization Classification of Tumours. Pathology and genetics of tumours of the urinary system and male genital organs.
Eble JN, Suter G, Epstein JI, Sesterhen IA Eds
IARC Press. : page L.
Somatic mutations of the von Hippel-Lindau disease tumour suppressor gene in non-familial clear cell renal carcinoma.
Foster K, Prowse A, van den Berg A, Fleming S, Hulsbeek MM, Crossey PA, Richards FM, Cairns P, Affara NA, Ferguson-Smith MA
Human molecular genetics. 1994 ; 3 (12) : 2169-2173.
PMID 7881415
Molecular cloning of the von Hippel-Lindau tumor suppressor gene and its role in renal carcinoma.
Gnarra JR, Duan DR, Weng Y, Humphrey JS, Chen DY, Lee S, Pause A, Dudley CF, Latif F, Kuzmin I, Schmidt L, Duh FM, Stackhouse T, Chen F, Kishida T, Wei MH, Lerman MI, Zbar B, Klausner RD, Linehan WM
Biochimica et biophysica acta. 1996 ; 1242 (3) : 201-210.
PMID 8603073
Gene expression patterns in renal cell carcinoma assessed by complementary DNA microarray.
Higgins JP, Shinghal R, Gill H, Reese JH, Terris M, Cohen RJ, Fero M, Pollack JR, van de Rijn M, Brooks JD
The American journal of pathology. 2003 ; 162 (3) : 925-932.
PMID 12598325
Genetic subtyping of renal cell carcinoma by comparative genomic hybridization.
Junker K, Weirich G, Amin MB, Moravek P, Hindermann W, Schubert J
Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer. 2003 ; 162 : 169-175.
PMID 12790331
Prognostic factors in renal cell carcinoma.
Kontak JA, Campbell SC
The Urologic clinics of North America. 2003 ; 30 (3) : 467-480.
PMID 12953749
Nonhomologous chromatid exchange in hereditary and sporadic renal cell carcinomas.
Kovacs G, Kung HF
Proceedings of the National Academy of Sciences of the United States of America. 1991 ; 88 (1) : 194-198.
PMID 1986366
Identification of the von Hippel-Lindau disease tumor suppressor gene.
Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L
Science (New York, N.Y.). 1993 ; 260 (5112) : 1317-1320.
PMID 8493574
Physical and functional mapping of a tumor suppressor locus for renal cell carcinoma within chromosome 3p12.
Lott ST, Lovell M, Naylor SL, Killary AM
Cancer research. 1998 ; 58 (16) : 3533-3537.
PMID 9721855
Renal cancer: cytogenetic and molecular genetic aspects.
Meloni-Ehrig AM
American journal of medical genetics. 2002 ; 115 (3) : 164-172.
PMID 12407697
Genetic progression of renal cell carcinoma.
Moch H, Mihatsch MJ
Virchows Archiv : an international journal of pathology. 2002 ; 441 (4) : 320-327.
PMID 12404056
Epigenetic inactivation of the RASSF1A 3p21.3 tumor suppressor gene in both clear cell and papillary renal cell carcinoma.
Morrissey C, Martinez A, Zatyka M, Agathanggelou A, Honorio S, Astuti D, Morgan NV, Moch H, Richards FM, Kishida T, Yao M, Schraml P, Latif F, Maher ER
Cancer research. 2001 ; 61 (19) : 7277-7281.
PMID 11585766
The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers.
Ohta M, Inoue H, Cotticelli MG, Kastury K, Baffa R, Palazzo J, Siprashvili Z, Mori M, McCue P, Druck T, Croce CM, Huebner K
Cell. 1996 ; 84 (4) : 587-597.
PMID 8598045
The genetic basis of renal cell carcinoma.
Pavlovich CP, Schmidt LS, Phillips JL
The Urologic clinics of North America. 2003 ; 30 (3) : 437-454.
PMID 12953747
Allelic loss on chromosomes 8 and 9 correlates with clinical outcome in locally advanced clear cell carcinoma of the kidney.
Presti JC Jr, Wilhelm M, Reuter V, Russo P, Motzer R, Waldman F
The Journal of urology. 2002 ; 167 (3) : 1464-1468.
PMID 11832771
Deletion of chromosome 3p14.2-p25 involving the VHL and FHIT genes in conventional renal cell carcinoma.
Sükösd F, Kuroda N, Beothe T, Kaur AP, Kovacs G
Cancer research. 2003 ; 63 (2) : 455-457.
PMID 12543802
Frequent somatic mutations and loss of heterozygosity of the von Hippel-Lindau tumor suppressor gene in primary human renal cell carcinomas.
Shuin T, Kondo K, Torigoe S, Kishida T, Kubota Y, Hosaka M, Nagashima Y, Kitamura H, Latif F, Zbar B
Cancer research. 1994 ; 54 (11) : 2852-2855.
PMID 8187067
The DUTT1 gene, a novel NCAM family member is expressed in developing murine neural tissues and has an unusually broad pattern of expression.
Sundaresan V, Roberts I, Bateman A, Bankier A, Sheppard M, Hobbs C, Xiong J, Minna J, Latif F, Lerman M, Rabbitts P
Molecular and cellular neurosciences. 1998 ; 11 (1-2) : 29-35.
PMID 9608531
Molecular subclassification of kidney tumors and the discovery of new diagnostic markers.
Takahashi M, Yang XJ, Sugimura J, Backdahl J, Tretiakova M, Qian CN, Gray SG, Knapp R, Anema J, Kahnoski R, Nicol D, Vogelzang NJ, Furge KA, Kanayama H, Kagawa S, Teh BT
Oncogene. 2003 ; 22 (43) : 6810-6818.
PMID 14555994
Chromosome 3 translocations and the risk to develop renal cell cancer: a Dutch intergroup study.
Van Erp F, Van Ravenswaaij C, Bodmer D, Eleveld M, Hoogerbrugge N, Mulders P, Geurts van Kessel A
Genetic counseling (Geneva, Switzerland). 2003 ; 14 (2) : 149-154.
PMID 12872808
Intragenic PTEN/MMAC1 loss of heterozygosity in conventional (clear-cell) renal cell carcinoma is associated with poor patient prognosis.
Velickovic M, Delahunt B, McIver B, Grebe SK
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2002 ; 15 (5) : 479-485.
PMID 12011252
The allelic loss of chromosome 3p25 with c-myc gain is related to the development of clear-cell renal cell carcinoma.
Yamaguchi S, Yoshihiro S, Matsuyama H, Nagao K, Fukunaga K, Matsumoto H, Matsuda K, Oba K, Naito K
Clinical genetics. 2003 ; 63 (3) : 184-191.
PMID 12694227
Molecular genetics of kidney cancer.
Zimmer M, Iliopoulos O
Cancer treatment and research. 2003 ; 116 : 3-27.
PMID 14650823
Classification of renal cell cancer based on (cyto)genetic analysis.
van den Berg E, Dijkhuizen T
Contributions to nephrology. 1999 ; 128 : 51-61.
PMID 10597377


This paper should be referenced as such :
van den Berg, E ; Störkel, S
Kidney: Clear cell renal cell carcinoma
Atlas Genet Cytogenet Oncol Haematol. 2004;8(3):260-262.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other genes implicated (Data extracted from papers in the Atlas) [ 58 ]


External links

arrayMap Topo ( C64) arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
Other databaseTumor Portal - Broad Institute
Other databaseICGC Data Portal - [KIRC-US] Kidney Renal Clear Cell Carcinoma - TCGA, US
Other databasecBioPortal: Kidney Renal Clear Cell Carcinoma (BGI, Nature Genetics 2012)
Other databasecBioPortal: Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013)
Other databasecBioPortal: Kidney Renal Clear Cell Carcinoma (TCGA, Provisional)
Other databasecBioPortal: Kidney Renal Papillary Cell Carcinoma (TCGA, Provisional)
Other databaseKidney renal clear cell carcinoma (KIRC) TCGA Copy Number Portal
Other databaseRenal clear cell carcinoma ( intOGen )
Other databaseSerous ovarian adenocarcinoma ( intOGen )
Other databaseKidney Clear Cell Carcinoma (TCGA)(OASIS Portal)
Other databaseKidney Renal Clear Cell Carcinoma [ Genomic Data Commons - NCI TCGA-KIRC]
Disease databaseKidney: Clear cell renal cell carcinoma
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Tue Oct 12 14:40:14 CEST 2021

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us