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Atlas Genet Cytogenet Oncol Haematol. 2002; 6(2)

Atlas of Genetics and Cytogenetics in Oncology and Haematology

OPEN ACCESS JOURNAL AT INIST-CNRS

Scope

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases. It presents structured review articles (“cards”) on genes, leukaemias, solid tumours, cancer-prone diseases, and also more traditional review articles (“deep insights”) on the above subjects and on surrounding topics. It also present case reports in hematology and educational items in the various related topics for students in Medicine and in Sciences.

Editorial correspondance

Jean-Loup Huret Genetics, Department of Medical Information, University Hospital F-86021 Poitiers, France tel +33 5 49 44 45 46 or +33 5 49 45 47 67 [email protected] or [email protected]

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 4 times a year by ARMGHM, a non profit organisation. Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy Institute – Villejuif – France).

http://AtlasGeneticsOncology.org

© ATLAS - ISSN 1768-3262

The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with the Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific Research (CNRS) on its electronic publishing platform I-Revues. Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS.



Scope

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases. It presents structured review articles (“cards”) on genes, leukaemias, solid tumours, cancer-prone diseases, and also more traditional review articles (“deep insights”) on the above subjects and on surrounding topics. It also present case reports in hematology and educational items in the various related topics for students in Medicine and in Sciences.

Editorial correspondance

Jean-Loup Huret Genetics, Department of Medical Information, University Hospital F-86021 Poitiers, France tel +33 5 49 44 45 46 or +33 5 49 45 47 67 [email protected] or [email protected]

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 4 times a year by ARMGHM, a non profit organisation. Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy Institute – Villejuif – France).

http://AtlasGeneticsOncology.org

© ATLAS - ISSN 1768-3262




Editor

Jean-Loup Huret (Poitiers, France)

Volume 6, Number 2, April - June 2002

Table of contents

Gene Section

FANCA (Fanconi anaemia A) 82 Hans Joenje

NQO1 (NAD(P)H dehydrogenase, quinone 1) 85 David Ross

P53 (Protein 53 kDa) 88 Thierry Soussi

RASSF1 (Ras association (RalGDS/AF-6) domain family member 1) 91 Debora Angeloni, Michael I Lerman

NFKB1 (nuclear factor of kappa light polypeptide ge ne enhancer in B-cells 1) 94 Fei Chen

NFKB2 (nuclear factor of kappa light polypeptide ge ne enhancer in B-cells 2 (p49/p100)) 96 Fei Chen

REL (v-rel reticuloendotheliosis viral oncogene hom olog (avian)) 98 Fei Chen

RELA (v-rel reticuloendotheliosis viral oncogene ho molog A) 100 Fei Chen

RELB (v-rel reticuloendotheliosis viral oncogene ho molog B) 102 Fei Chen

VHL (von Hippel-Lindau tumor suppressor) 104 Stéphane Richard

CHIC2 (cystein-rich hydrophobic domain 2) 109 Jean-Loup Huret

FCGR2B (Fc fragment of IgG, low affinity IIb, recep tor (CD32)) 110 Mary Callanan, Dominique Leroux

SDHD (succinate dehydrogenase complex II, subunit D , integral membrane protein) 112 Anne-Paule Gimenez-Roqueplo

SHH (Sonic hedgehog) 114 Thierry Magnaldo

STK11 (serine/threonine kinase 11) 119 Jean-Loup Huret

t(11;14)(q13;q32) in multiple myeloma Huret JL, Laï JL




SYK (spleen tyrosine kinase) 121 Jean-Loup Huret

Leukaemia Section

t(11;14)(p11;q32) 122 Antonio Cuneo

t(8;22)(p11;q11) 124 Nicholas CP Cross

Waldenstrom's macroglobulinemia (WM) 126 Antonio Cuneo, Gianluigi Castoldi

t(4;12)(q11-q21;p13) 128 Jean-Loup Huret

t(5;14)(q35;q32) 130 Jean-Loup Huret

t(5;17)(q13;q21) 132 Jean-Loup Huret

t(9;12)(q22;p12) 133 Jean-Loup Huret

Solid Tumour Section

Bone: Aneurysmal bone cysts 134 Paola Dal Cin

Uterus: leiomyoma 136 Roberta Vanni

Cancer Prone Disease Section

Hereditary paraganglioma (PGL) 140 Anne-Paule Gimenez-Roqueplo

Peutz-Jeghers syndrome 142 Jean-Loup Huret

Deep Insight Section

Deregulation of genetic pathways in neuroendocrine tumors 144 Alain Calender

Upstream Signal Transduction of NF-kB Activation 156 Fei Chen, Jacquelyn Bower, Laurence M. Demers, Xianglin Shi

The Fas - Fas Ligand apoptotic pathway 171 Pierre Bobé

Gene Section Mini Review


82



FANCA (Fanconi anaemia A) Hans Joenje

Department of Clinical Genetics and Human Genetics VU University Medical Center Van der Boechorststraat 7, NL-1081 BT Amsterdam, The Netherlands (HJ)

Published in Atlas Database: December 2001

Online updated version: http://AtlasGeneticsOncology.org/Genes/FA1ID102.html DOI: 10.4267/2042/37829

This article is an update of: Huret JL. FA1 (Fanconi anaemia 1). Atlas Genet Cytogenet Oncol Haematol.1998;2(3):81-82. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Other names: FACA; FAA; FA1

HGNC (Hugo): FANCA

Location: 16q24.3

DNA/RNA Description 43 exons spanning 80 kb.

Transcription 5.5 kb mRNA.

Protein Description 1455 amino acids; 163 kDa; 2 nuclear localisation signals (NLS) consensus sequences in N-terminus and a potential leucine zipper near C-term, none proven to functional as such.

Expression Wide: brain, placenta, testis, tonsils (mRNA); in mice: protein expression predominant in lymphoid organs, testis, ovary.

Localisation Mainly nuclear.

Function Binds to the protein encoded by FANCC (Fanconi anaemia complementation group C), as well as some of the other FA proteins (FANCE, FANCF, FANCG).

Homology No known homology or functional motifs.

Mutations Germinal Various nucleotide substitutions, deletions, or insertions have been described. Over 90% of the mutations are private, with about 30% being relatively large deletions. Founder mutations have been described in South Africa.

Implicated in Fanconi anaemia Note FANCA is implicated in the FA complementation group A.

Disease Fanconi anaemia is a chromosome instability syndrome/cancer prone disease (at risk of leukaemia and squamous cell carcinoma).

Prognosis Poor; mean survival is 20 years: patients die of bone marrow failure (infections, haemorrhages), leukaemia, or solid cancer.

Cytogenetics Spontaneously enhanced chromatid-type aberrations (breaks, gaps, interchanges; increased rate of breaks compared to control, when induced by specific clastogens known as DNA cross-linking agents (e.g. mitomycin C, diepoxybutane).

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References The Fanconi anaemia/breast cancer consortium. Positional cloning of the Fanconi anaemia group A gene. Nat Genet. 1996 Nov;14(3):324-8

Lo Ten Foe JR, Rooimans MA, Bosnoyan-Collins L, Alon N, Wijker M, Parker L, Lightfoot J, Carreau M, Callen DF, Savoia A, Cheng NC, van Berkel CG, Strunk MH, Gille JJ, Pals G, Kruyt FA, Pronk JC, Arwert F, Buchwald M, Joenje H. Expression cloning of a cDNA for the major Fanconi anaemia gene, FAA. Nat Genet. 1996 Nov;14(3):320-3

D'Andrea AD, Grompe M. Molecular biology of Fanconi anemia: implications for diagnosis and therapy. Blood. 1997 Sep 1;90(5):1725-36

Kruyt FA, Waisfisz Q, Dijkmans LM, Hermsen MA, Youssoufian H, Arwert F, Joenje H. Cytoplasmic localization of a functionally active Fanconi anemia group A-green fluorescent protein chimera in human 293 cells. Blood. 1997 Nov 1;90(9):3288-95

Kupfer GM, Näf D, Suliman A, Pulsipher M, D'Andrea AD. The Fanconi anaemia proteins, FAA and FAC, interact to form a nuclear complex. Nat Genet. 1997 Dec;17(4):487-90

Levran O, Erlich T, Magdalena N, Gregory JJ, Batish SD, Verlander PC, Auerbach AD. Sequence variation in the Fanconi anemia gene FAA. Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13051-6

Abu-Issa R, Eichele G, Youssoufian H. Expression of the Fanconi anemia group A gene (Fanca) during mouse embryogenesis. Blood. 1999 Jul 15;94(2):818-24

Garcia-Higuera I, Kuang Y, Näf D, Wasik J, D'Andrea AD. Fanconi anemia proteins FANCA, FANCC, and FANCG/XRCC9 interact in a functional nuclear complex. Mol Cell Biol. 1999 Jul;19(7):4866-73

Kruyt FA, Abou-Zahr F, Mok H, Youssoufian H. Resistance to mitomycin C requires direct interaction between the Fanconi anemia proteins FANCA and FANCG in the nucleus through an arginine-rich domain. J Biol Chem. 1999 Nov 26;274(48):34212-8

Kupfer G, Naf D, Garcia-Higuera I, Wasik J, Cheng A, Yamashita T, Tipping A, Morgan N, Mathew CG, D'Andrea AD. A patient-derived mutant form of the Fanconi anemia protein, FANCA, is defective in nuclear accumulation. Exp Hematol. 1999 Apr;27(4):587-93

Lightfoot J, Alon N, Bosnoyan-Collins L, Buchwald M. Characterization of regions functional in the nuclear localization of the Fanconi anemia group A protein. Hum Mol Genet. 1999 Jun;8(6):1007-15

McMahon LW, Walsh CE, Lambert MW. Human alpha spectrin II and the Fanconi anemia proteins FANCA and FANCC interact to form a nuclear complex. J Biol Chem. 1999 Nov 12;274(46):32904-8

Morgan NV, Tipping AJ, Joenje H, Mathew CG. High frequency of large intragenic deletions in the Fanconi anemia group A gene. Am J Hum Genet. 1999 Nov;65(5):1330-41

Waisfisz Q, de Winter JP, Kruyt FA, de Groot J, van der Weel L, Dijkmans LM, Zhi Y, Arwert F, Scheper RJ, Youssoufian H, Hoatlin ME, Joenje H. A physical complex of the Fanconi anemia proteins FANCG/XRCC9 and FANCA. Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):10320-5

Waisfisz Q, Morgan NV, Savino M, de Winter JP, van Berkel CG, Hoatlin ME, Ianzano L, Gibson RA, Arwert F, Savoia A, Mathew CG, Pronk JC, Joenje H. Spontaneous functional

correction of homozygous fanconi anaemia alleles reveals novel mechanistic basis for reverse mosaicism. Nat Genet. 1999 Aug;22(4):379-83

Walsh CE, Yountz MR, Simpson DA. Intracellular localization of the Fanconi anemia complementation group A protein. Biochem Biophys Res Commun. 1999 Jun 16;259(3):594-9

Balta G, de Winter JP, Kayserili H, Pronk JC, Joenje H. Fanconi anemia A due to a novel frameshift mutation in hotspot motifs: lack of FANCA protein. Hum Mutat. 2000 Jun;15(6):578

Cheng NC, van de Vrugt HJ, van der Valk MA, Oostra AB, Krimpenfort P, de Vries Y, Joenje H, Berns A, Arwert F. Mice with a targeted disruption of the Fanconi anemia homolog Fanca. Hum Mol Genet. 2000 Jul 22;9(12):1805-11

de Winter JP, van der Weel L, de Groot J, Stone S, Waisfisz Q, Arwert F, Scheper RJ, Kruyt FA, Hoatlin ME, Joenje H. The Fanconi anemia protein FANCF forms a nuclear complex with FANCA, FANCC and FANCG. Hum Mol Genet. 2000 Nov 1;9(18):2665-74

Faivre L, Guardiola P, Lewis C, Dokal I, Ebell W, Zatterale A, Altay C, Poole J, Stones D, Kwee ML, van Weel-Sipman M, Havenga C, Morgan N, de Winter J, Digweed M, Savoia A, Pronk J, de Ravel T, Jansen S, Joenje H, Gluckman E, Mathew CG. Association of complementation group and mutation type with clinical outcome in fanconi anemia. European Fanconi Anemia Research Group. Blood. 2000 Dec 15;96(13):4064-70

Garcia-Higuera I, Kuang Y, Denham J, D'Andrea AD. The fanconi anemia proteins FANCA and FANCG stabilize each other and promote the nuclear accumulation of the Fanconi anemia complex. Blood. 2000 Nov 1;96(9):3224-30

Huber PA, Medhurst AL, Youssoufian H, Mathew CG. Investigation of Fanconi anemia protein interactions by yeast two-hybrid analysis. Biochem Biophys Res Commun. 2000 Feb 5;268(1):73-7

van de Vrugt HJ, Cheng NC, de Vries Y, Rooimans MA, de Groot J, Scheper RJ, Zhi Y, Hoatlin ME, Joenje H, Arwert F. Cloning and characterization of murine fanconi anemia group A gene: Fanca protein is expressed in lymphoid tissues, testis, and ovary. Mamm Genome. 2000 Apr;11(4):326-31

Wong JC, Alon N, Norga K, Kruyt FA, Youssoufian H, Buchwald M. Cloning and analysis of the mouse Fanconi anemia group A cDNA and an overlapping penta zinc finger cDNA. Genomics. 2000 Aug 1;67(3):273-83

Futaki M, Watanabe S, Kajigaya S, Liu JM. Fanconi anemia protein, FANCG, is a phosphoprotein and is upregulated with FANCA after TNF-alpha treatment. Biochem Biophys Res Commun. 2001 Feb 23;281(2):347-51

Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn MS, Timmers C, Hejna J, Grompe M, D'Andrea AD. Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Mol Cell. 2001 Feb;7(2):249-62

Gregory JJ Jr, Wagner JE, Verlander PC, Levran O, Batish SD, Eide CR, Steffenhagen A, Hirsch B, Auerbach AD. Somatic mosaicism in Fanconi anemia: evidence of genotypic reversion in lymphohematopoietic stem cells. Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2532-7

Grompe M, D'Andrea A. Fanconi anemia and DNA repair. Hum Mol Genet. 2001 Oct 1;10(20):2253-9

McMahon LW, Sangerman J, Goodman SR, Kumaresan K, Lambert MW. Human alpha spectrin II and the FANCA, FANCC, and FANCG proteins bind to DNA containing psoralen

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interstrand cross-links. Biochemistry. 2001 Jun 19;40(24):7025-34

Medhurst AL, Huber PA, Waisfisz Q, de Winter JP, Mathew CG. Direct interactions of the five known Fanconi anaemia proteins suggest a common functional pathway. Hum Mol Genet. 2001 Feb 15;10(4):423-9

Otsuki T, Furukawa Y, Ikeda K, Endo H, Yamashita T, Shinohara A, Iwamatsu A, Ozawa K, Liu JM. Fanconi anemia protein, FANCA, associates with BRG1, a component of the human SWI/SNF complex. Hum Mol Genet. 2001 Nov 1;10(23):2651-60

Qiao F, Moss A, Kupfer GM. Fanconi anemia proteins localize to chromatin and the nuclear matrix in a DNA damage- and cell cycle-regulated manner. J Biol Chem. 2001 Jun 29;276(26):23391-6

Ren J, Youssoufian H. Functional analysis of the putative peroxidase domain of FANCA, the Fanconi anemia complementation group A protein. Mol Genet Metab. 2001 Jan;72(1):54-60

Yagasaki H, Adachi D, Oda T, Garcia-Higuera I, Tetteh N, D'Andrea AD, Futaki M, Asano S, Yamashita T. A cytoplasmic serine protein kinase binds and may regulate the Fanconi anemia protein FANCA. Blood. 2001 Dec 15;98(13):3650-7

This article should be referenced as such:

Joenje H. FANCA (Fanconi anaemia A). Atlas Genet Cytogenet Oncol Haematol. 2002; 6(2):82-84.



85



NQO1 (NAD(P)H dehydrogenase, quinone 1) David Ross

School of Pharmacy, University of Colorado Health Sciences Center, Denver 80262, USA (DR)


Online updated version: http://AtlasGeneticsOncology.org/Genes/NQO1ID375.html DOI: 10.4267/2042/37830

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Other names: DIA4; DT-Diaphorase; NMO1

HGNC (Hugo): DIA4

Location: 16q22.1

NQO1 (16q22) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.

DNA/RNA Description Spans approximately 20 kb consisting of 6 exons and 5 introns. Highly inducible protein and the 5' flanking region contains an AP2, ARE or EpRE (antioxidant or electrophile responsive element) and an XRE (xenobiotic responsive element).

Transcription Three mRNA sizes (1.2, 1.7 and 2.7 kb) have been observed due to multiple polyadenylation sites. An alternatively spliced form of NQO1 mRNA lacking exon 4 is also possible although the corresponding truncated protein has not been detected.

Protein Description NQO1 is a flavoprotein which functions as a homodimer. The physiological dimer has one catalytic

site per monomer. Each monomer consists of 273 amino acids.

Expression NQO1 is expressed in human epithelial and endothelial tissues and at high levels throughout many human solid tumors.

Localisation NQO1 is a mainly cytosolic enzyme (approx. 90%) although it has also been localized in smaller amounts to mitochondria, endoplasmic reticulum and nucleus.

Function NQO1 catalyzes obligate two electron reduction of a wide variety of substrates. The most efficient substrates are quinones but the enzyme will also reduce quinone-imines, nitro and azo compounds. The enzyme functions via a hydride transfer mechanism and requires a pyridine nucleotide cofactor. Reduction proceeds with equal facility with both NADH and NADPH. NQO1 can generate antioxidant forms of both vitamin E and ubiquinone after free radical attack. The capability to protect cells from oxidative challenge and the ability to reduce quinones via an obligate two electron mechanism, which precludes generation of reactive oxygen radicals, demonstrates that NQO1 is a chemoprotective enzyme. Certain compounds such as antitumor quinones, however, can be bioactivated by two electron reduction and in these cases NQO1 serves as an activating enzyme. Because of the high levels of NQO1 in certain tumors, this has led to an interest in designing compounds which can be efficiently bioactivated by NQO1 as antitumor agents.

Homology Amino acid homology across species is high (mouse/human 86%, mouse/rat -94%, human/rat 86%). NQO2 is a separate gene product demonstrating 49%

NQO1 (NAD(P)H dehydrogenase, quinone 1) Ross D


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and 54% similarity at the amino acid and nucleotide levels respectively.

Mutations Germinal Two polymorphisms have been characterized. The NQO1 *2 allele represents a C609T change in the cDNA coding for a Pro187Ser change in the enzyme. The NQO1 *3 allele is a C465T change in the cDNA coding for an Arg139Trp change. The NQO1 * 2 allele is much more frequent than the *3 allele and has profound consequences for phenotype. The NQO1 *2 protein has diminished catalytic activity and the protein is rapidly degraded by the ubiquitin-proteasomal system. As a result, cells and tissues carrying the homozygous NQO1 *2 allele have no detectable NQO1 activity and at best, trace levels of NQO1 protein. The NQO1 *2/*2 genotype is effectively a null polymorphism. NQO1 is highly inducible and although NQO1 levels can vary considerably among individuals with the same genotype, the NQO1 *2 allele has been reported to show a gene dose effect since heterozygotes (NQO1 *1/*2) contained significantly less NQO1 protein than wild type (NQO1 *1/*1) samples.

Implicated in Leukemia Note Increased risk of leukemia has been associated with the NQO1 *2 allele and diminished NQO1 activity. Childhood leukemia (particularly with MLL fusions), adult leukemia (ALL, AML particularly with translocations or inversions) and secondary leukemias and myelodysplasias as a result of chemotherapy have been associated with the NQO1 *2 polymorphism. Increased benzene induced myelotoxicity in occupationally exposed individuals has also been linked to the NQO1 *2 polymorphism.

Solid tumors Note Increased risk of renal and urothelial cell carcinomas and cutaneous basal cell carcinomas have also been associated with the NQO1 *2 polymorphism but conflicting results have been obtained in colon cancer and lung cancer.

References Jaiswal AK, McBride OW, Adesnik M, Nebert DW. Human dioxin-inducible cytosolic NAD(P)H:menadione oxidoreductase. cDNA sequence and localization of gene to chromosome 16. J Biol Chem. 1988 Sep 25;263(27):13572-8

Lind C, Cadenas E, Hochstein P, Ernster L. DT-diaphorase: purification, properties, and function. Methods Enzymol. 1990;186:287-301

Jaiswal AK. Human NAD(P)H:quinone oxidoreductase (NQO1) gene structure and induction by dioxin. Biochemistry. 1991 Nov 5;30(44):10647-53

Traver RD, Horikoshi T, Danenberg KD, Stadlbauer TH, Danenberg PV, Ross D, Gibson NW. NAD(P)H:quinone oxidoreductase gene expression in human colon carcinoma cells: characterization of a mutation which modulates DT-diaphorase activity and mitomycin sensitivity. Cancer Res. 1992 Feb 15;52(4):797-802

Ross D, Siegel D, Beall H, Prakash AS, Mulcahy RT, Gibson NW. DT-diaphorase in activation and detoxification of quinones. Bioreductive activation of mitomycin C. Cancer Metastasis Rev. 1993 Jun;12(2):83-101

Ross D, Beall H, Traver RD, Siegel D, Phillips RM, Gibson NW. Bioactivation of quinones by DT-diaphorase, molecular, biochemical, and chemical studies. Oncol Res. 1994;6(10-11):493-500

Beall HD, Murphy AM, Siegel D, Hargreaves RH, Butler J, Ross D. Nicotinamide adenine dinucleotide (phosphate): quinone oxidoreductase (DT-diaphorase) as a target for bioreductive antitumor quinones: quinone cytotoxicity and selectivity in human lung and breast cancer cell lines. Mol Pharmacol. 1995 Sep;48(3):499-504

Gasdaska PY, Fisher H, Powis G. An alternatively spliced form of NQO1 (DT-diaphorase) messenger RNA lacking the putative quinone substrate binding site is present in human normal and tumor tissues. Cancer Res. 1995 Jun 15;55(12):2542-7

Li R, Bianchet MA, Talalay P, Amzel LM. The three-dimensional structure of NAD(P)H:quinone reductase, a flavoprotein involved in cancer chemoprotection and chemotherapy: mechanism of the two-electron reduction. Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8846-50

Pan SS, Forrest GL, Akman SA, Hu LT. NAD(P)H:quinone oxidoreductase expression and mitomycin C resistance developed by human colon cancer HCT 116 cells. Cancer Res. 1995 Jan 15;55(2):330-5

Beyer RE, Segura-Aguilar J, Di Bernardo S, Cavazzoni M, Fato R, Fiorentini D, Galli MC, Setti M, Landi L, Lenaz G. The role of DT-diaphorase in the maintenance of the reduced antioxidant form of coenzyme Q in membrane systems. Proc Natl Acad Sci U S A. 1996 Mar 19;93(6):2528-32

Hu LT, Stamberg J, Pan S. The NAD(P)H:quinone oxidoreductase locus in human colon carcinoma HCT 116 cells resistant to mitomycin C. Cancer Res. 1996 Nov 15;56(22):5253-9

Kelsey KT, Ross D, Traver RD, Christiani DC, Zuo ZF, Spitz MR, Wang M, Xu X, Lee BK, Schwartz BS, Wiencke JK. Ethnic variation in the prevalence of a common NAD(P)H quinone oxidoreductase polymorphism and its implications for anti-cancer chemotherapy. Br J Cancer. 1997;76(7):852-4

Siegel D, Bolton EM, Burr JA, Liebler DC, Ross D. The reduction of alpha-tocopherolquinone by human NAD(P)H: quinone oxidoreductase: the role of alpha-tocopherolhydroquinone as a cellular antioxidant. Mol Pharmacol. 1997 Aug;52(2):300-5

Traver RD, Siegel D, Beall HD, Phillips RM, Gibson NW, Franklin WA, Ross D. Characterization of a polymorphism in NAD(P)H: quinone oxidoreductase (DT-diaphorase). Br J Cancer. 1997;75(1):69-75

Gaedigk A, Tyndale RF, Jurima-Romet M, Sellers EM, Grant DM, Leeder JS. NAD(P)H:quinone oxidoreductase: polymorphisms and allele frequencies in Caucasian, Chinese and Canadian Native Indian and Inuit populations. Pharmacogenetics. 1998 Aug;8(4):305-13

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Radjendirane V, Joseph P, Lee YH, Kimura S, Klein-Szanto AJ, Gonzalez FJ, Jaiswal AK. Disruption of the DT diaphorase (NQO1) gene in mice leads to increased menadione toxicity. J Biol Chem. 1998 Mar 27;273(13):7382-9

Winski SL, Hargreaves RH, Butler J, Ross D. A new screening system for NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumor quinones: identification of a new aziridinylbenzoquinone, RH1, as a NQO1-directed antitumor agent. Clin Cancer Res. 1998 Dec;4(12):3083-8

Larson RA, Wang Y, Banerjee M, Wiemels J, Hartford C, Le Beau MM, Smith MT. Prevalence of the inactivating 609C-->T polymorphism in the NAD(P)H:quinone oxidoreductase (NQO1) gene in patients with primary and therapy-related myeloid leukemia. Blood. 1999 Jul 15;94(2):803-7

Moran JL, Siegel D, Ross D. A potential mechanism underlying the increased susceptibility of individuals with a polymorphism in NAD(P)H:quinone oxidoreductase 1 (NQO1) to benzene toxicity. Proc Natl Acad Sci U S A. 1999 Jul 6;96(14):8150-5

Siegel D, McGuinness SM, Winski SL, Ross D. Genotype-phenotype relationships in studies of a polymorphism in NAD(P)H:quinone oxidoreductase 1. Pharmacogenetics. 1999 Feb;9(1):113-21

Wiemels JL, Pagnamenta A, Taylor GM, Eden OB, Alexander FE, Greaves MF. A lack of a functional NAD(P)H:quinone oxidoreductase allele is selectively associated with pediatric leukemias that have MLL fusions. United Kingdom Childhood Cancer Study Investigators. Cancer Res. 1999 Aug 15;59(16):4095-9

Faig M, Bianchet MA, Talalay P, Chen S, Winski S, Ross D, Amzel LM. Structures of recombinant human and mouse NAD(P)H:quinone oxidoreductases: species comparison and structural changes with substrate binding and release. Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3177-82

Long DJ 2nd, Waikel RL, Wang XJ, Perlaky L, Roop DR, Jaiswal AK. NAD(P)H:quinone oxidoreductase 1 deficiency increases susceptibility to benzo(a)pyrene-induced mouse skin carcinogenesis. Cancer Res. 2000 Nov 1;60(21):5913-5

Naoe T, Takeyama K, Yokozawa T, Kiyoi H, Seto M, Uike N, Ino T, Utsunomiya A, Maruta A, Jin-nai I, Kamada N, Kubota Y, Nakamura H, Shimazaki C, Horiike S, Kodera Y, Saito H, Ueda

R, Wiemels J, Ohno R. Analysis of genetic polymorphism in NQO1, GST-M1, GST-T1, and CYP3A4 in 469 Japanese patients with therapy-related leukemia/ myelodysplastic syndrome and de novo acute myeloid leukemia. Clin Cancer Res. 2000 Oct;6(10):4091-5

Ross D, Kepa JK, Winski SL, Beall HD, Anwar A, Siegel D. NAD(P)H:quinone oxidoreductase 1 (NQO1): chemoprotection, bioactivation, gene regulation and genetic polymorphisms. Chem Biol Interact. 2000 Dec 1;129(1-2):77-97

Siegel D, Ross D. Immunodetection of NAD(P)H:quinone oxidoreductase 1 (NQO1) in human tissues. Free Radic Biol Med. 2000 Aug;29(3-4):246-53

Asher G, Lotem J, Cohen B, Sachs L, Shaul Y. Regulation of p53 stability and p53-dependent apoptosis by NADH quinone oxidoreductase 1. Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):1188-93

Faig M, Bianchet MA, Winski S, Hargreaves R, Moody CJ, Hudnott AR, Ross D, Amzel LM. Structure-based development of anticancer drugs: complexes of NAD(P)H:quinone oxidoreductase 1 with chemotherapeutic quinones. Structure. 2001 Aug;9(8):659-67

Long DJ 2nd, Waikel RL, Wang XJ, Roop DR, Jaiswal AK. NAD(P)H:quinone oxidoreductase 1 deficiency and increased susceptibility to 7,12-dimethylbenz[a]-anthracene-induced carcinogenesis in mouse skin. J Natl Cancer Inst. 2001 Aug 1;93(15):1166-70

Siegel D, Anwar A, Winski SL, Kepa JK, Zolman KL, Ross D. Rapid polyubiquitination and proteasomal degradation of a mutant form of NAD(P)H:quinone oxidoreductase 1. Mol Pharmacol. 2001 Feb;59(2):263-8

Smith MT, Wang Y, Kane E, Rollinson S, Wiemels JL, Roman E, Roddam P, Cartwright R, Morgan G. Low NAD(P)H:quinone oxidoreductase 1 activity is associated with increased risk of acute leukemia in adults. Blood. 2001 Mar 1;97(5):1422-6


Ross D. NQO1 (NAD(P)H dehydrogenase, quinone 1). Atlas Genet Cytogenet Oncol Haematol. 2002; 6(2):85-87.



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P53 (Protein 53 kDa) Thierry Soussi

Laboratoire de Genotoxicologie des tumeurs, Institut Curie, Universite Pierre et Marie Curie, 26 rue d'Ulm, 75005 Paris, France (TS)


Online updated version: http://AtlasGeneticsOncology.org/Genes/P53ID88.html DOI: 10.4267/2042/37831

This article is an update of: Hamelin R, Huret JL. P53 (protein 53 kDa). Atlas Genet Cytogenet Oncol Haematol.1999;3(1):8-10. Hamelin R, Huret JL. P53 (protein 53 kDa). Atlas Genet Cytogenet Oncol Haematol.1998;2(4):119. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Other names: TP53 (Tumour Protein 53)

HGNC (Hugo): TP53

Location: 17p13

Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.

DNA/RNA Description The gene encompasses 20 kb of DNA; 11 exons (the first is non-coding).

Transcription 3.0 kb mRNA; 1179 bp open reading frame.

Protein Description 393 amino acids; 53 kDa protein; numerous post translational modifications, phosphorylation,

acetylation, ubiquitination; contains from N-term to C-term, a transactivation domain (1-42), a Proline rich domain (63-97), a specific DNA binding domain (102-292), 3 nuclear localization signals (305-322), a tetramerization domain that include a nuclear export signal (325-355) and a negative regulatory domain (360-393).

Expression Widely expressed.

Localisation Nucleus.

Function Tumour suppressor gene. P53 is a transcription factor present at minute level in any normal cells. Upon various types of stress (DNA damage, hypoxia, nucleotide pool depletion, viral infection, oncogene activation), postranslational modification lead to p53 stabilisation and activation. Although the number of genes activated by p53 is rather large, the outcome of p53 activation is either cell cycle arrest in G1 (by p21), in G2 (by 14-3-3 g) or apoptosis (by BAX, PUMA or NOXA). The cell growth arrest activity of p53 allows the activation of the DNA repair system of the cell.

Homology The five domains are highly-conserved regions between species (from human to fly). Two new genes homologous to p53 have been discovered, p73 localized at 1p36 and p63 localized at 3q27.

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Mutations Germinal In Li-Fraumeni syndrome, a dominantly inherited disease in which affected individuals are predisposed to develop sarcomas, osteosarcomas, leukemias and breast cancers at unusually early ages.

Somatic P53 is mutated in about 50% of human cancers, and the non-mutated allele is generally lost; the frequency and the type of mutation may vary from one tumour type to another; these mutations are missense (80%), non-sense (7.5%), deletions, insertions or splicing mutations (12.5%); there are some hot-spots for mutations at CpG dinucleotides at positions 175, 248, 273 and 282; P53 mutation is an adverse prognostic feature in a number of cancer, but not in all. Mutational events are related to carcinogen exposure in lung, liver and skin cancer.

Implicated in Li-Fraumeni syndrome Disease Autosomal dominant condition; cancer prone disease; Li-Fraumeni syndrome is defined by the existence of both a proband with a sarcoma and two other first-degree relatives with a cancer by age 45 years; a germline mutation of P53 is found in at least 50% of cases; germline mutation of the kinase CHK2, an activator of p53, has been discovered in several Li-Fraumeni families free of p53 mutation.

Prognosis Most common cancer in Li-Fraumeni children are: soft tissues sarcoma before the age of 5 yrs and osteosarcoma afterwards, and breast cancer in young adults; other frequent cancers: brain tumours, leukaemias, adrenocortical carcinoma; 1/3 of patients have developped more than one primary cancer, which is quite characteristic of Li-Fraumeni syndrome but may also be representative of Bloom's syndrome; cancers in this disease, as in other cancer-prone diseases, often occur early in life: 50% of patients aged 30 yrs have had a cancer (i.e. penetrance is 50%, according to this disease definition); and penetrance is 90% at age 60 yrs.

Oncogenesis Known germinal mutation are variable, but are mostly missense mutations located in exons 4 to 9 in tumours occurring in these patients, the other (wildtype) allele is lost, in accordance with the two-hit model for neoplasia, as is found in retinoblastoma.

Haematological malignancies Oncogenesis P53 gene alterations have been found in: 20-30% of blast crisis CML (mostly in the myeloid type), often

associated with i(17q); in 5% of MDS cases and 15% of ANLL often with a visible del(17p); in 2% of ALL (but with high variations according to the ALL type, reaching 50% of L3 ALL (and Burkitt lymphomas); in 15% of CLL (and 40% in the aggressive CLL transformation into the Richter's syndrome) and 30% of adult T-cell leukaemia (only found in the aggressive form), in 5-10% of multiple myelomas; in 60-80% of Hodgkin disease; in 30% of high grade B-cell NHL (rare in low grade NHL), and 50% of HIV-related NHL; P53 gene alterations in haematological malignancies are associated with a poor prognosis.

Lung cancers Disease Lung cancers are neuroendocrine lung tumours (small cell lung carcinomas, carcinoids, large cell neuroendocrine carcinomas) or non neuroendocrine lung tumours (squamous carcinomas, adenocarcinomas, large cell carcinomas).

Oncogenesis Is multistep, through C-MYC or N-MYC activation, H-RAS1 or K-RAS2 mutation, P53, RB1, and P16 inactivation, loss of heterozygosity (LOH) at 3p, 13q, 17p; P 53 mutations, in this particular case, does not seem to have prognostic implication; P53 is mutated in 30% of lung adenocarcinomas to 80% of small cell lung carcinomas; hotspots at codons 157, 158, 179, 245, 248 and 273. p53 mutations in lung cancer from smoker have a very specific pattern related to carcinogen exposure (high frequency to GC->TA transversion and hot spot at codon 157 and 158).

Colorectal cancers Disease There are two types of colorectal cancers, according to the ploidy: - the diploid form, RER+ (Replication Error+), sporadic, without loss of heterozygosity (LOH), with few mutations of p53 and APC, and right-sided; - the polyploid form, RER-, with LOH (5q, 17p, 18q), mutations in p53, and more often left-sided, they have a worse prognosis.

Prognosis Survival, although improving, is not much more than 50% after 5 years.

Cytogenetics Diploid tumours without frequent allelic losses; aneuploid tumours with numerous allelic losses; LOH on chromosomes 17 and 18 in more than 75% of cases; other chromosome arms losses in about 50% of cases.

Oncogenesis A number of genes are known to be implicated in tumour progression in colorectal cancers: APC, P53, KRAS2, mismatch repair genes (MMR genes); P53 is mutated in 60-65% of colorectal cancer cases;

P53 (Protein 53 kDa) Soussi T


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mutations of P53 are mostly located in exons 4 to 8 with hotspots at codons 175, 245, 248, 273 and 282.

Bladder cancer Prognosis Highly variable, according to the stage and the grade.

Cytogenetics -9, -11 or del(11p), del(17p) and LOH at 17p, del(13q), frequent other LOH, aneuploidy, polyploidy, complex karyotypes.

Oncogenesis Multi-step and largely unknown process; loss of 9q and P53 mutations would be early events; RB1, and P16 inactivation, EGFR overexpression, LOH at 3p, 8p, 11p, 13q, 17p, 18q; P53 is mutated in 40-60% of bladder cancer cases; P53 mutations bear a prognostic implication.

Breast cancer Prognosis P53 mutation bears a prognostic implication in N+ patients and is related to poor response to doxorubicin therapy.

Oncogenesis P53 is mutated in 30% of breast cancers; preferentially observed in advanced and aggressive forms; probably a late event; hotspots at codons 175, 248, and 273. The frequency and pattern of p53 mutation in breast cancer is subject to important geographical variations.

Skin cancers Disease Skin cancers include basal cell carcinomas, squamous cell cercinomas, and melanomas.

Prognosis Highly different according to the pathological group.

Oncogenesis P53 is mutated in 40-60% of skin cancers; hotspots at codons 196, 248, 278. The pattern of p53 mutation in skin cancer is highly related to UV exposure.

Oesophagus cancers Disease Two main forms: squamous cell carcinoma and adenocarcinoma.

Oncogenesis P53 is mutated in 50% of oesophagus cancers (70% in squamous cell carcinoma and 45% of adenocarcinoma); probably an early event; hotspots at codons 175, 248 and 273. The pattern of p53 mutation is different in squamous cell carcinoma and adenocarcinoma.

Liver cancer Cytogenetics Losses of 1p, 4q, 5p, 5q, 8q, 13q, 16p, 16q, and 17p in 20 to 50% of cases.

Oncogenesis Specific mutation at codon 249 related to aflatoxin B1 dietary exposure in exposed area (China, Africa); low frequency of mutation in developed countries.

Prostate cancer and other cancers

To be noted Note Germinal mutations of P53 have also been found in families where the criteria for the Li-Fraumeni syndrome were not reached.

References Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997 Feb 7;88(3):323-31

Varley JM, Evans DG, Birch JM. Li-Fraumeni syndrome--a molecular and clinical review. Br J Cancer. 1997;76(1):1-14

Prives C, Hall PA. The p53 pathway. J Pathol. 1999 Jan;187(1):112-26

Ljungman M. Dial 9-1-1 for p53: mechanisms of p53 activation by cellular stress. Neoplasia. 2000 May-Jun;2(3):208-25

Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature. 2000 Nov 16;408(6810):307-10

Vousden KH. p53: death star. Cell. 2000 Nov 22;103(5):691-4

Yang A, McKeon F. P63 and P73: P53 mimics, menaces and more. Nat Rev Mol Cell Biol. 2000 Dec;1(3):199-207

Soussi T, Béroud C. Assessing TP53 status in human tumours to evaluate clinical outcome. Nat Rev Cancer. 2001 Dec;1(3):233-40

Wahl GM, Carr AM. The evolution of diverse biological responses to DNA damage: insights from yeast and p53. Nat Cell Biol. 2001 Dec;3(12):E277-86


Soussi T. P53 (Protein 53 kDa). Atlas Genet Cytogenet Oncol Haematol. 2002; 6(2):88-90.



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RASSF1 (Ras association (RalGDS/AF-6) domain family member 1) Debora Angeloni, Michael I Lerman

Laboratory of Immunobiology, National Cancer Institute, Frederick Cancer Research Facility Bldg. 560 Rm. 13 34 Frederick, MD 21702, USA (DA, MIL)


Online updated version: http://AtlasGeneticsOncology.org/Genes/RASSF1ID377.html DOI: 10.4267/2042/37832


Identity Other names: 123F2; RDA32; REH3P21

HGNC (Hugo): RASSF1

Location: 3p21.3

Local order: telomeric to BLU and centromeric to FUS1


Note RASSF1 is also known as NORE2A. More correctly, NORE must be considered a paralog of RASSF1, a human ortholog of mouse NoreA. Genomic clones: cosmid LUCA 12 and LUCA 13.

DNA/RNA Description The genomic size of the gene is about 7.6 kb.

Transcription At least three alternative transcripts were identified (A, B and C) that originate from alternative splicing and promoter usage. Exons 3 to 6 are common to all forms. Transcript A has two 5' exons (designated 1a and 2ab), this cDNA is 1,873 bp (ORF: 340 amino acids). RASSF1B first exon is designated 1b and is different from RASSF1A. Exon two is 2ab as in transcript A. cDNA size: 1,664 bp. Transcript RASSF1C first exon is designated 2g, cDNA size 1700 bp (ORF 270 amino acids).

Pseudogene No known pseudogenes.

Grey: exon 1a, green: exon 1b; blue: exon 2ab; yellow : exon 2g; brown: exons 3,4, 5, 6. Arrows: transcription start sites. CpG: location of CpG islands. RASSF1A and RASSF1B start with exon 1a and 1b respectively. The second exon (2ab) is common to both forms. Exon 2g is the first exon of RASSF1C and is present in this transcript only.

RASSF1 (Ras association (RalGDS/AF-6) domain family member 1) Angeloni D, Lerman MI


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Protein

Schematic representation of RASSF1 protein variants, as deduced from the transcripts.

Description The carboxy terminus of RASSF1A shows about 55% identity to the mouse protein Nore1 and the rat protein Maxp1, both are Ras effector proteins (Nore1 was shown to interact in vivo with Ras upon receptor activation in a GTP-dependent manner). RASSF1A N terminus has high homology with a domain known as protein kinase C conserved region 1 domain (a cysteine-rich diacylglycerol/ phorbol ester binding domain). RASSF1B most likely is constituted only of the Ras association domain.

Expression RASSF1A and RASSF1C are expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, small intestine, colon, peripheral blood leukocytes. RASSF1B is expressed predominantly in cells of hematopoietic origin.

Localisation Not determined.

Function RASSF1 binds Ras in a GTP-dependent manner and may serve as the effector that mediates Ras apoptotic effects. Alternatively, it may sequester RAS proteins thereby regulating the availability of these proteins for signaling.

Mutations Note Single nucleotide polymorphism (SNP) in exon 1a: AAG (Lys21)/CAG (Gln21).

Somatic Mutations were rarely found. In non small cell lung cancer four were found: GAC (Asp129) to GAG

(Glu129); ATT (Ile135) to ACT (Thr135); CGG (Arg257) to CAG (Gln257); GCC (Ala336) to ACC (Thr336).

Implicated in Cear cell renal carcinoma and papillary renal carcinoma; lung cancer; ovarian cancer; prostate cancer; gastric adenocarcinoma; bladder carcinoma; nasopharingeal carcinoma; breast cancer Note The mechanism of inactivation of this tumor suppressor consists in promoter hypermethylation. The gene promoter was found hypermetylated in 90 % of primary kidney tumors and 40 % of lung tumors. Hypermethylation and loss of transcription were causally related. Hypermethylation occurs in variable percentage in other tumors and indicate a role for this gene in malignant progression (62 % of bladder carcinoma; 49 % of breast tumors; 40 % of ovarian tumors; 12 % of colon cancer).

References Dammann R, Li C, Yoon JH, Chin PL, Bates S, Pfeifer GP. Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3. Nat Genet. 2000 Jul;25(3):315-9

Lerman MI, Minna JD. The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes. The International Lung Cancer Chromosome 3p21.3 Tumor Suppressor Gene Consortium. Cancer Res. 2000 Nov 1;60(21):6116-33

Vos MD, Ellis CA, Bell A, Birrer MJ, Clark GJ. Ras uses the novel tumor suppressor RASSF1 as an effector to mediate apoptosis. J Biol Chem. 2000 Nov 17;275(46):35669-72

Agathanggelou A, Honorio S, Macartney DP, Martinez A, Dallol A, Rader J, Fullwood P, Chauhan A, Walker R, Shaw JA, Hosoe S, Lerman MI, Minna JD, Maher ER, Latif F. Methylation associated inactivation of RASSF1A from region 3p21.3 in lung, breast and ovarian tumours. Oncogene. 2001 Mar 22;20(12):1509-18

Burbee DG, Forgacs E, Zöchbauer-Müller S, Shivakumar L, Fong K, Gao B, Randle D, Kondo M, Virmani A, Bader S, Sekido Y, Latif F, Milchgrub S, Toyooka S, Gazdar AF, Lerman MI, Zabarovsky E, White M, Minna JD. Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression. J Natl Cancer Inst. 2001 May 2;93(9):691-9

Byun DS, Lee MG, Chae KS, Ryu BG, Chi SG. Frequent epigenetic inactivation of RASSF1A by aberrant promoter hypermethylation in human gastric adenocarcinoma. Cancer Res. 2001 Oct 1;61(19):7034-8

Dammann R, Takahashi T, Pfeifer GP. The CpG island of the novel tumor suppressor gene RASSF1A is intensely methylated in primary small cell lung carcinomas. Oncogene. 2001 Jun 14;20(27):3563-7

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Dammann R, Yang G, Pfeifer GP. Hypermethylation of the cpG island of Ras association domain family 1A (RASSF1A), a putative tumor suppressor gene from the 3p21.3 locus, occurs in a large percentage of human breast cancers. Cancer Res. 2001 Apr 1;61(7):3105-9

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. The candidate tumor suppressor gene, RASSF1A, from human chromosome 3p21.3 is involved in kidney tumorigenesis. Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7504-9

Lee MG, Kim HY, Byun DS, Lee SJ, Lee CH, Kim JI, Chang SG, Chi SG. Frequent epigenetic inactivation of RASSF1A in human bladder carcinoma. Cancer Res. 2001 Sep 15;61(18):6688-92

Lo KW, Kwong J, Hui AB, Chan SY, To KF, Chan AS, Chow LS, Teo PM, Johnson PJ, Huang DP. High frequency of

promoter hypermethylation of RASSF1A in nasopharyngeal carcinoma. Cancer Res. 2001 May 15;61(10):3877-81

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. Epigenetic inactivation of the RASSF1A 3p21.3 tumor suppressor gene in both clear cell and papillary renal cell carcinoma. Cancer Res. 2001 Oct 1;61(19):7277-81

Yoon JH, Dammann R, Pfeifer GP. Hypermethylation of the CpG island of the RASSF1A gene in ovarian and renal cell carcinomas. Int J Cancer. 2001 Oct 15;94(2):212-7


Angeloni D, Lerman MI. RASSF1 (Ras association (RalGDS/AF-6) domain family member 1). Atlas Genet Cytogenet Oncol Haematol. 2002; 6(2):91-93.



94



NFKB1 (nuclear factor of kappa light polypeptide gene enhancer in B-cells 1) Fei Chen

Health Effects Laboratory Division, NIOSH, 1095 Willowdale Rd, Morgantown, WV 26505, USA (FC)

Published in Atlas Database: January 2002

Online updated version: http://AtlasGeneticsOncology.org/Genes/NFKB1ID323.html DOI: 10.4267/2042/37833


Identity Other names: NF-kB p105; NF-kB p50

HGNC (Hugo): NFKB1

Location: 4q23-q24

Note See also, in the Deep Insight section: Upstream Signal Transduction of NF-kB Activation.

DNA/RNA Description The gene encoding human nfkb1 has 24 exons spanning 156 kb. The expression of nfkb1 can be positively regulated by NF-kB itself and possibly Ets family transcription factors.

Protein Description The nfkb1 gene encodes a protein composed 968 amino acids with an approximately molecular weight of 105 kDa, which was considered as a precursor of p50 subunit of NF-kB complexes. In the N-terminal region of NF-kB1, there is a Rel homology domain (RHD)

composed of ~300 amino acids that are responsible for DNA binding, dimerization with other Rel family members, and interaction with IkB proteins. The C-terminal region of NF-kB1 contains multiple copies of the so-called ankyrin repeats which is found in IkB family members, including IkBa, IkBb, IkBe, Bcl3, and Drosophila cactus. The earlier studies by several groups demonstrated that NF-kB1 was posttranslationally cleaved to produce the p50 molecule through the ubiquitin-proteasome dependent degradation of the C-terminal portion of NF-kB1. Further studies by Lin and Ghosh suggested that a glycine-rich region (GRR) within the region of 375 to 400 of NF-kB1 is necessary and sufficient for directing the cleavage of NF-kB1. However, recent studies challenged this model and revealed a novel mechanism in which p50 is generated by a unique cotranslational processing event involving the 26S proteasome. In other words, NF-kB1 is not the precursor of p50.

Expression Nfkb1 is widely expressed in virtually all type of cells in both adults and in the embryo.

Localisation Cytosol, nuclei after activation.

NFKB1 nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 Chen F


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Function Regulation of the genes involved in cell-to-cell interaction, intercellular communication, cell recruitment or transmigration, amplification or spreading of primary pathogenic signals, and initiation or acceleration of tumorigenesis. The full length of NF-kB1 can serve as an endogenous inhibitor for the NF-kB p50/p65(RelA) heterodimer. It has been proposed that the homodimer of NF-kB p50 was transcriptionally inactive in the absence of Bcl3. Furthermore, the NF-kB p50 homodimer may function to competitively inhibit B binding by transactivating NF- B dimers. The Bcl3 protein can form a complex with this homodimer at B sites and act as a transactivator of NF-kB p50 homodimer. Interaction with: members of IkB family and Rel family, LYL1, Bcl3, NCOA1a (V).

Implicated in Cancer (see below), autoimmune arthritis, glomerulonephritis, asthma, inflammatory bowel disease, septic shock, lung fibrosis, HTLV-1 infection, and AIDS Oncogenesis Overexpression of nfkb1 has been found in a number of human cancer including non-small cell lung carcinoma,

colon cancer, prostate cancer, breast cancer, bone cancer and brain cancer. The rearrangement of nfkb1 gene, however, only has been identified in certain acute lymphoblastic leukemias.

References Liptay S, Schmid RM, Perkins ND, Meltzer P, Altherr MR, McPherson JD, Wasmuth JJ, Nabel GJ. Related subunits of NF-kappa B map to two distinct loci associated with translocations in leukemia, NFKB1 and NFKB2. Genomics. 1992 Jun;13(2):287-92

Baldwin AS Jr. The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol. 1996;14:649-83

Ghosh S, May MJ, Kopp EB. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol. 1998;16:225-60

Lin L, DeMartino GN, Greene WC. Cotranslational biogenesis of NF-kappaB p50 by the 26S proteasome. Cell. 1998 Mar 20;92(6):819-28

Chen F, Castranova V, Shi X, Demers LM. New insights into the role of nuclear factor-kappaB, a ubiquitous transcription factor in the initiation of diseases. Clin Chem. 1999 Jan;45(1):7-17


Chen F. NFKB1 (nuclear factor of kappa light polypeptide gene enhancer in B-cells 1). Atlas Genet Cytogenet Oncol Haematol. 2002; 6(2):94-95.



96



NFKB2 (nuclear factor of kappa light polypeptide gene enhancer in B-cells 2 (p49/p100)) Fei Chen



Online updated version : http://AtlasGeneticsOncology.org/Genes/NFKB2ID362.html DOI: 10.4267/2042/37834


Identity Other names: NF-kB p100; NF-kB p52; Lyt10

HGNC (Hugo): NFKB2

Location: 10q24


DNA/RNA Description The gene encoding human nfkb2 has 24 exons spanning 8 kb. The expression of nfkb2 can be regulated by two distinct promoters, P1 and P2, in which a number of consensus binding sites for transcription factors, including SP1, AP1 and putative NF-kappa B (kappa B sites), were identified.

Protein Description The human nfkb2 gene encodes a protein composed 900 amino acids with an approximately molecular weight of 100 kDa, which was considered as a precursor of p52 subunit of NF-kB complexes. The structural characteristics of NF-kB2 are much similar with that of NF-kB1: A N-terminal RHD; two nuclear

localization sequences within the C-terminus of RHD, a putative GRR region that possibly contributes to the generation of NF-kB p52 from the precursor, NF-kB2. The C-terminal region of NF-kB2 also contains multiple copies of the so-called ankyrin repeats and one proline, glutamic acid, serine, and threonine (PEST) domain. Studies demonstrated that NF-kB2 was posttranslationally cleaved to produce the p52 molecule through the ubiquitin-proteasome dependent degradation of the C-terminal 406-900 portion of NF-kB2. However, other studies revealed that the mechanism for the generation of NF-kB p52 is through cotranslational processing. Recent studies demonstrated that the processing of NF-kB p52 required IKKa- and/or NIK-dependent C-terminal phosphorylation of NF-kB2.

Expression Nfkb2 is expressed mainly in lymphoid cells and mononuclear cells.


Function Regulation of the genes involved in cell-to-cell interaction, intercellular communication, cell recruitment or transmigration, amplification or spreading of primary pathogenic signals, and initiation or acceleration of tumorigenesis.

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Similar with NF-kB1, the full length of NF-kB2 can serve as an endogenous inhibitor for the NF-kB p50/ p65(RelA) or NF-kB p52/p65 heterodimer. The homodimer of NF-kB p52 was transcriptionally inactive in the absence of Bcl3. Furthermore, the NF-kB p52 homodimer may function to competitively inhibit B binding by transactivating NF- B dimers. The Bcl3 protein can form a complex with this homodimer at B sites and act as a transactivator of NF-kB p52 homodimer. Interaction with: members of IkB family and Rel family, Bcl3.

Implicated in Hematological malignancies (see below) and other diseases: autoimmune arthritis, glomerulonephritis, asthma, inflammatory bowel disease, septic shock, lung fibrosis, cancer, HTLV-1 infection, and AIDS Disease t(10;14)(q24;q11) or t(10;14)(q24;q32) in haemato-logical malignancies.

Cytogenetics Poor.

Oncogenesis Unlike its relative nfkb1, rearrangement of nfkb2 gene locus has been found in many forms of lymophomas. The chromosomal translocations by t(10;14)(q24;q11) and t(10;14)(q24;q32) cause deletions of sequences encoding the ankyrin repeat motif of NF-kB2. Consequently, this carboxyl terminal truncated NF-kB2 is constitutively located in the nucleus of cells, which was found in small percentage of B-cell non-Hodgkin's lymphoma, cutaneous lymphomas, T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemias, and multiple myelomas. Chromosomal

translocation generated a fusion NF-kB2- IGHA1 or NF-kB2- TCRa or TCRd transcriptional unit.

References Neri A, Chang CC, Lombardi L, Salina M, Corradini P, Maiolo AT, Chaganti RS, Dalla-Favera R. B cell lymphoma-associated chromosomal translocation involves candidate oncogene lyt-10, homologous to NF-kappa B p50. Cell. 1991 Dec 20;67(6):1075-87

Liptay S, Schmid RM, Perkins ND, Meltzer P, Altherr MR, McPherson JD, Wasmuth JJ, Nabel GJ. Related subunits of NF-kappa B map to two distinct loci associated with translocations in leukemia, NFKB1 and NFKB2. Genomics. 1992 Jun;13(2):287-92



Chen F, Castranova V, Shi X, Demers LM. New insights into the role of nuclear factor-kappaB, a ubiquitous transcription factor in the initiation of diseases. Clin Chem. 1999 Jan;45(1):7-17

Heusch M, Lin L, Geleziunas R, Greene WC. The generation of nfkb2 p52: mechanism and efficiency. Oncogene. 1999 Nov 4;18(46):6201-8

Senftleben U, Cao Y, Xiao G, Greten FR, Krähn G, Bonizzi G, Chen Y, Hu Y, Fong A, Sun SC, Karin M. Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. Science. 2001 Aug 24;293(5534):1495-9

Xiao G, Cvijic ME, Fong A, Harhaj EW, Uhlik MT, Waterfield M, Sun SC. Retroviral oncoprotein Tax induces processing of NF-kappaB2/p100 in T cells: evidence for the involvement of IKKalpha. EMBO J. 2001 Dec 3;20(23):6805-15


Chen F. NFKB2 (nuclear factor of kappa light polypeptide gene enhancer in B-cells 2 (p49/p100)). Atlas Genet Cytogenet Oncol Haematol. 2002; 6(2):96-97.



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REL (v-rel reticuloendotheliosis viral oncogene homolog (avian)) Fei Chen



Online updated version: http://AtlasGeneticsOncology.org/Genes/RELID322.html DOI: 10.4267/2042/37837


Identity Other names: c-rel

HGNC (Hugo): REL

Location: 2p13-p12


DNA/RNA Description The gene encoding human Rel has 11 exons spanning ~ 40 kb. The promoter region of rel gene contains five NF-kB binding sites and six Sp1 binding sites, and a number of AP2 sites. Thus, the expression of rel gene might be through auto- regulation along with certain stress signals.

Protein Description The human rel gene encodes a protein composed 619 amino acids with an approximately molecular weight of 68-70 kDa. The Rel protein is structurally similar with other Rel family members containing RHD, NLS and TA domain. However, analysis of X-ray crystal structure revealed that the Rel homodimer preferentially binds to the CD28RE with higher affinity as compared to other canonical kB sequences.

Expression Wide.


Function regulation of the genes involved in cell-to-cell interaction, intercellular communication, cell recruitment or transmigration, amplification or spreading of primary pathogenic signals, cell apoptosis, and initiation or acceleration of tumorigenesis. Interaction with: members of IkB family and Rel family; MKK4; c-Fos; c-Jun; UBE2; PPP4C.

Implicated in Cancer, autoimmune arthritis, glomerulonephritis, asthma, inflammatory bowel disease, septic shock, lung fibrosis, HTLV-1 infection, and AIDS Oncogenesis Amplification of rel locus was frequently noted in a number of lymphomas.

Note Only one report suggested the rearrangement of rel gene in certain type of lymphomas. This rearrangement of rel gene resulted in the deletion of the C-terminal domain of Rel and the fusion of the RHD of Rel with Nrg.

References Lu D, Thompson JD, Gorski GK, Rice NR, Mayer MG, Yunis JJ. Alterations at the rel locus in human lymphoma. Oncogene. 1991 Jul;6(7):1235-41

Deloukas P, van Loon AP. Genomic organization of the gene encoding the p65 subunit of NF-kappa B: multiple variants of the p65 protein may be generated by alternative splicing. Hum Mol Genet. 1993 Nov;2(11):1895-900

REL v-rel reticuloendotheliosis viral oncogene homolog (avian) Chen F

Atlas Genet Cytogenet Oncol Haematol. 2002; 6(2) 99



Zhong H, Voll RE, Ghosh S. Phosphorylation of NF-kappa B p65 by PKA stimulates transcriptional activity by promoting a novel bivalent interaction with the coactivator CBP/p300. Mol Cell. 1998 Apr;1(5):661-71

Rayet B, Gélinas C. Aberrant rel/nfkb genes and activity in human cancer. Oncogene. 1999 Nov 22;18(49):6938-47


Chen F. REL (v-rel reticuloendotheliosis viral oncogene homolog (avian)). Atlas Genet Cytogenet Oncol Haematol. 2002; 6(2):98-99.



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RELA (v-rel reticuloendotheliosis viral oncogene homolog A) Fei Chen



Online updated version: http://AtlasGeneticsOncology.org/Genes/RELAID325.html DOI: 10.4267/2042/37835


Identity Other names: NF-kB3; NF-kB p65

HGNC (Hugo): RELA

Location: 11q12-q13


Note See also, in the Deep Insight section: Upstream Signal Transduction of NF-kB Activation

DNA/RNA Description The gene encoding human RelA has 10 exons spanning 8.1 kb. The shorter variants of RelA (p65d) can be generated by alternative splicing of intron 1, 6, or 7. The p65d1 lacks codons for amino acids 222 to 231 and p65d2 lacks codons for amino acids 13 to 25 of the conserved Rel homology domain. An additional alternative splicing form of p65, p65d3 has been identified in a non-small-cell lung carcinoma cell line that lacks codons for amino acids 187 to 293 of the Rel homology domain.

Protein Description The relA gene encodes a protein composed 551 amino acids with an approximately molecular weight of 65 kDa. The N-terminal region of RelA contains a Rel homology domain (RHD) followed by a nuclear localization signal. The C-terminal region of RelA contains a putative leucine zipper domain and a transactivation domain that is important for the NF-kB-mediated gene transactivation. A number of protein kinases can phosphorylate RelA and consequently potentiate the transcriptional activity of NF-kB complexes. These kinases include IKKb, PKA, and possibly GSK3 and MAP kinase p38. The phosphorylation of the transactivation domain of RelA was considered as an important event for the recruitment and/or interaction with co-factors and general transcriptional machinery subunits such as p300 and TFIIB.

Expression Wide.


Function regulation of the genes involved in cell-to-cell interaction, intercellular communication, cell recruitment or transmigration, amplification or spreading of primary pathogenic signals,

RELA Chen F


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cell apoptosis, and initiation or acceleration of tumorigenesis. The p50/RelA complex is the most abundant NF-kB complex in all type tissues or cells. Interaction with: members of IkB family and Rel family; GR; HDAC3; CREB; p300; Sp1, Egr1; AES; TFIIB.

Implicated in Cancer, autoimmune arthritis, glomerulonephritis, asthma, inflammatory bowel disease, septic shock, lung fibrosis, HTLV-1 infection, and AIDS Oncogenesis Chromosomal rearrangement or point mutation of relA gene has been implicated infrequently in human lymphoid tumors. A t(11;14)(q14;q32?) chromosomal translocation was described in 4 cases of lymphoproliferative disorders (LPD), which possibly involved p65 gene rearrangement. Gene amplification or increased expression of relA has also been noted in some cases of squamous carcinomas of head and neck, and in adenocarcinomas of breast and stomach.

References Van Den Berghe H, Parloir C, David G, Michaux JL, Sokal G. A new characteristic karyotypic anomaly in lymphoproliferative disorders. Cancer. 1979 Jul;44(1):188-95

Deloukas P, van Loon AP. Genomic organization of the gene encoding the p65 subunit of NF-kappa B: multiple variants of the p65 protein may be generated by alternative splicing. Hum Mol Genet. 1993 Nov;2(11):1895-900



Zhong H, Voll RE, Ghosh S. Phosphorylation of NF-kappa B p65 by PKA stimulates transcriptional activity by promoting a novel bivalent interaction with the coactivator CBP/p300. Mol Cell. 1998 Apr;1(5):661-71

Rayet B, Gélinas C. Aberrant rel/nfkb genes and activity in human cancer. Oncogene. 1999 Nov 22;18(49):6938-47


Chen F. RELA (v-rel reticuloendotheliosis viral oncogene homolog A). Atlas Genet Cytogenet Oncol Haematol. 2002; 6(2):100-101.



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RELB (v-rel reticuloendotheliosis viral oncogene homolog B) Fei Chen



Online updated version: http://AtlasGeneticsOncology.org/Genes/RELBID324.html DOI: 10.4267/2042/37836


Identity Other names: I-Rel

HGNC (Hugo): RELB

Location: 19q13.32


DNA/RNA Description The gene encoding human RelB has 11 exons spanning ~37 kb. Analysis of the 5'-flanking region of human relb gene indicates that RelB transcription is dependent on a TATA-less promoter containing two kB sites. Thus, while relA is constitutively expressed, the expression of both rel and relb is in an inducible fashion and dependent on NF-kB.

Protein Description The human relb gene encodes a protein composed 579 amino acids with an approximately molecular weight of 66 kDa. Although structurally similar with other Rel family proteins containing RHD, NLS and TA domain, RelB contains an additional 121 amino acid region located at the N-terminus of RHD. Original study indicated that RelB failed to associate with RelA(p65) and to interact with DNA. That is the reason why it was named as inhibitive-Rel (I-Rel). In contrast, later studies demonstrated that RelB was able to form a heterodimer with NF-kB p50 or p52 and induce the transcription of target constructs or genes. No DNA

binding activity has been suggested for the homodimeric complex of RelB, which may be possibly due to the N-terminal 121 amino acid domain that interfered with the DNA binding of RHD.

Expression Wide.


Function regulation of the genes involved in cell-to-cell interaction, intercellular communication, cell recruitment or transmigration, amplification or spreading of primary pathogenic signals, cell apoptosis, and initiation or acceleration of tumorigenesis. Interaction with:members of IkB family and Rel family.

Implicated in Cancer, autoimmune arthritis, glomerulonephritis, asthma, inflammatory bowel disease, septic shock, lung fibrosis, HTLV-1 infection, and AIDS

References Ruben SM, Klement JF, Coleman TA, Maher M, Chen CH, Rosen CA. I-Rel: a novel rel-related protein that inhibits NF-kappa B transcriptional activity. Genes Dev. 1992 May;6(5):745-60

Bours V, Azarenko V, Dejardin E, Siebenlist U. Human RelB (I-Rel) functions as a kappa B site-dependent transactivating member of the family of Rel-related proteins. Oncogene. 1994 Jun;9(6):1699-702

RELB v-rel reticuloendotheliosis viral oncogene homolog B Chen F


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Chen F. RELB (v-rel reticuloendotheliosis viral oncogene homolog B). Atlas Genet Cytogenet Oncol Haematol. 2002; 6(2):102-103.

Gene Section Review


104



VHL (von Hippel-Lindau tumor suppressor) Stéphane Richard

Génétique Oncologique EPHE, Faculté de Médecine Paris-Sud, 63 av Gabriel Péri, 94276 LE KREMLIN BICETRE, France (SR)


Online updated version: http://AtlasGeneticsOncology.org/Genes/VHLID132.html DOI: 10.4267/2042/37838


Identity HGNC (Hugo): VHL

Location: 3p25-26

Note Tumour suppressor.

DNA/RNA Description The VHL gene spans 10 kb and is composed of three exons.

Transcription The VHL gene encodes a 4.7 kb mRNA which is widely expressed in both foetal and adult tissues. An alternatively spliced VHL transcript has been detected reflecting the absence of exon 2 (isoform II) but no endogenous associated protein has been reported.

VHL von Hippel-Lindau tumor suppressor Richard S


105

Protein Description The full-length VHL protein, pVHL, contains 213 amino-acids (28-30 kDa) ("pVHL30") A second major VHL-gene product arises by internal translation initiation from the codon 54 methionine, producing a 160 amino-acid protein (18-19 kDa) ("pVHL19").

Expression pVHL is widely expressed in both foetal and adult human tissues.

Localisation The pVHL is largely a cytoplasmic protein but appears to shuttle between the cytoplasm and nucleus.

Function pVHL interacts with three other proteins, elongin C and B and Cullin 2 (CUL2), in a complex referred to as VCB-CUL2. pVHL has two main structural domains: an N-terminal domain composed mainly of b-sheets (the b domain) and a smaller C-terminal domain between aminoacids 155-192 composed mainly of a helices (a-domain). The a domain consists of three a helices that combines with a fourth a helice donated by elongin C. The b-domain is on the opposite side of the a domain and is free to contact other protein. VHL and angiogenesis- A main function of the pVHL is to negatively regulate hypoxia-inducible mRNAs such as the mRNA encoding VEGF, EPO, PDGF and the glucose-transporter GLUT-1. pVHL plays a critical role in targeting the hypoxia-inducible transcription factor HIF-1a for degradation by the proteasome. HIF-

1a contributes to form the HIF-1 transcriptional complex responsible for activation of genes involved in metabolism, angiogenesis and apoptosis. The VCB-CUL2 complex has been demonstrated as a ubiquitin-ligase system presenting many similarities with the SCF system ("Skp1-CUL1-Fbox protein"). HIF is normally degraded under normoxic conditions and binding to VHL is dependent on hydroxylation of Pro 564 in HIF-1a (Figure 1). When the VHL gene is mutated, absence of HIF degradation is responsible for abnormal accumulation of VEGF and other hypoxia-inducible mRNA explaining the angiogenic phenotype of VHL tumours. pVHL may also downregulate VEGF production by direct binding and inhibiting to the transcriptional activator SP1. In homozygous VHL knock-out mice, embryos will die early because of a major disorder of placental vasculogenesis. Other functions pVHL plays a role in: ability of cells to exit the cell cycle and enter the quiescent state. assembly of extracellular fibronectin matrix. degradation of TGFa LYT10, TGFb, and carbonic anhydrases CA9 and CA12. regulation of the urokinase-type plasminogen activator system. inhibition of the hepatocyte growth factor-induced invasion in renal cell carcinoma. a direct interaction with atypical protein kinase C (PKC) z and l has also recently been demonstrated. Thus, VHL appears as a multifunctional gene and may play a gatekeeper role especially in kidney.



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Homology The primary sequence structure of pVHL shows minimal homology to any knows protein but evolutionary conservation of the pVHL is very strong except for the first 53 amino acids.

Mutations Germinal Germline mutations cause von Hippel-Lindau disease. VHL mutations are heterogeneous and distributed widely throughout the coding sequence except 5' for the translation initiation site for pVHL19. There is a few recurrent mutations and only one founder effect is known, originating from Germany (T292C resulting in a Tyr98His substitution). Point mutations occur in about 60% of cases (Figure 2) and large deletions in about 40%. VHL 1 (without pheochromocytoma) is mainly produced by mutations responsible for truncated protein (deletions, frameshift mutations and nonsense mutations). VHL type 2 (with high risk of pheochromocytoma) is mainly produced by missense mutations. Type 2B is the potentially "full" form of the disease (frequent mutations: Arg167Gln, Arg167Trp). Type 2A is associated with a very low risk of clear cell renal cell cancer (RCC) (common mutation: Tyr98His). Type 2C is characterized by the occurrence of pheochromo-cytoma only (example: Leu188Val). Between 10 and 15% of cryptic VHL cases could be explained by de novo mutations and there are some cases of germline mosaicism. There is some evidence that genetic modifiers may influence the phenotypic expression of the disease.

Somatic Mutations are encountered in 60 % of sporadic clear cell RCC. In addition, 15% of tumours show evidence of inactivation by methylation. VHL alterations have been associated with occupational exposure to trichlorethylene. Somatic mutations are also frequent in CNS sporadic hemangioblastoma but rarer in sporadic endolymphatic sac tumours, pancreatic serous cystadenomas and endocrine tumours, epididymal cystadenomas and pheochromocytomas.

Implicated in von Hippel-Lindau disease Disease Von Hippel-Lindau (VHL) disease is a hereditary devastating cancer syndrome, predisposing to the development of various benign and malignant tumours (Central nervous system hemangio-blastomas and Retinal hemangioblastomas, endolymphatic sac tumours, clear cell renal cell cancer and/or renal cysts,

pheochromocytoma, pancreatic cysts and neuroendocrine tumours, epididymal and broad ligament cystadenomas). VHL disease is the first cause of hereditary kidney cancer.

Sporadic renal cell carcinomas Sporadic hemangioblastomas

References Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993 May 28;260(5112):1317-20

Brauch H, Kishida T, Glavac D, Chen F, Pausch F, Höfler H, Latif F, Lerman MI, Zbar B, Neumann HP. Von Hippel-Lindau (VHL) disease with pheochromocytoma in the Black Forest region of Germany: evidence for a founder effect. Hum Genet. 1995 May;95(5):551-6

Neumann HP, Lips CJ, Hsia YE, Zbar B. Von Hippel-Lindau syndrome. Brain Pathol. 1995 Apr;5(2):181-93

Iliopoulos O, Levy AP, Jiang C, Kaelin WG Jr, Goldberg MA. Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10595-9

Los M, Jansen GH, Kaelin WG, Lips CJ, Blijham GH, Voest EE. Expression pattern of the von Hippel-Lindau protein in human tissues. Lab Invest. 1996 Aug;75(2):231-8

Zbar B, Kishida T, Chen F, Schmidt L, Maher ER, Richards FM, Crossey PA, Webster AR, Affara NA, Ferguson-Smith MA, Brauch H, Glavac D, Neumann HP, Tisherman S, Mulvihill JJ, Gross DJ, Shuin T, Whaley J, Seizinger B, Kley N, Olschwang S, Boisson C, Richard S, Lips CH, Lerman M. Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. Hum Mutat. 1996;8(4):348-57

Decker HJ, Weidt EJ, Brieger J. The von Hippel-Lindau tumor suppressor gene. A rare and intriguing disease opening new insight into basic mechanisms of carcinogenesis. Cancer Genet Cytogenet. 1997 Jan;93(1):74-83

Maher ER, Kaelin WG Jr. von Hippel-Lindau disease. Medicine (Baltimore). 1997 Nov;76(6):381-91

Prowse AH, Webster AR, Richards FM, Richard S, Olschwang S, Resche F, Affara NA, Maher ER. Somatic inactivation of the VHL gene in Von Hippel-Lindau disease tumors. Am J Hum Genet. 1997 Apr;60(4):765-71

Béroud C, Joly D, Gallou C, Staroz F, Orfanelli MT, Junien C. Software and database for the analysis of mutations in the VHL gene. Nucleic Acids Res. 1998 Jan 1;26(1):256-8

Ivanov SV, Kuzmin I, Wei MH, Pack S, Geil L, Johnson BE, Stanbridge EJ, Lerman MI. Down-regulation of transmembrane carbonic anhydrases in renal cell carcinoma cell lines by wild-type von Hippel-Lindau transgenes. Proc Natl Acad Sci U S A. 1998 Oct 13;95(21):12596-601

Kaelin WG Jr, Maher ER. The VHL tumour-suppressor gene paradigm. Trends Genet. 1998 Oct;14(10):423-6

Knebelmann B, Ananth S, Cohen HT, Sukhatme VP. Transforming growth factor alpha is a target for the von Hippel-Lindau tumor suppressor. Cancer Res. 1998 Jan 15;58(2):226-31

Neumann HP, Bender BU, Berger DP, Laubenberger J, Schultze-Seemann W, Wetterauer U, Ferstl FJ, Herbst EW,



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Schwarzkopf G, Hes FJ, Lips CJ, Lamiell JM, Masek O, Riegler P, Mueller B, Glavac D, Brauch H. Prevalence, morphology and biology of renal cell carcinoma in von Hippel-Lindau disease compared to sporadic renal cell carcinoma. J Urol. 1998 Oct;160(4):1248-54

Ohh M, Yauch RL, Lonergan KM, Whaley JM, Stemmer-Rachamimov AO, Louis DN, Gavin BJ, Kley N, Kaelin WG Jr, Iliopoulos O. The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. Mol Cell. 1998 Jun;1(7):959-68

Olschwang S, Richard S, Boisson C, Giraud S, Laurent-Puig P, Resche F, Thomas G. Germline mutation profile of the VHL gene in von Hippel-Lindau disease and in sporadic hemangioblastoma. Hum Mutat. 1998;12(6):424-30

Pause A, Lee S, Lonergan KM, Klausner RD. The von Hippel-Lindau tumor suppressor gene is required for cell cycle exit upon serum withdrawal. Proc Natl Acad Sci U S A. 1998 Feb 3;95(3):993-8

Stolle C, Glenn G, Zbar B, Humphrey JS, Choyke P, Walther M, Pack S, Hurley K, Andrey C, Klausner R, Linehan WM. Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. Hum Mutat. 1998;12(6):417-23

Webster AR, Richards FM, MacRonald FE, Moore AT, Maher ER. An analysis of phenotypic variation in the familial cancer syndrome von Hippel-Lindau disease: evidence for modifier effects. Am J Hum Genet. 1998 Oct;63(4):1025-35

Brauch H, Weirich G, Hornauer MA, Störkel S, Wöhl T, Brüning T. Trichloroethylene exposure and specific somatic mutations in patients with renal cell carcinoma. J Natl Cancer Inst. 1999 May 19;91(10):854-61

Cohen HT, Zhou M, Welsh AM, Zarghamee S, Scholz H, Mukhopadhyay D, Kishida T, Zbar B, Knebelmann B, Sukhatme VP. An important von Hippel-Lindau tumor suppressor domain mediates Sp1-binding and self-association. Biochem Biophys Res Commun. 1999 Dec 9;266(1):43-50

Gallou C, Joly D, Méjean A, Staroz F, Martin N, Tarlet G, Orfanelli MT, Bouvier R, Droz D, Chrétien Y, Maréchal JM, Richard S, Junien C, Béroud C. Mutations of the VHL gene in sporadic renal cell carcinoma: definition of a risk factor for VHL patients to develop an RCC. Hum Mutat. 1999;13(6):464-75

Iwai K, Yamanaka K, Kamura T, Minato N, Conaway RC, Conaway JW, Klausner RD, Pause A. Identification of the von Hippel-lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex. Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12436-41

Koochekpour S, Jeffers M, Wang PH, Gong C, Taylor GA, Roessler LM, Stearman R, Vasselli JR, Stetler-Stevenson WG, Kaelin WG Jr, Linehan WM, Klausner RD, Gnarra JR, Vande Woude GF. The von Hippel-Lindau tumor suppressor gene inhibits hepatocyte growth factor/scatter factor-induced invasion and branching morphogenesis in renal carcinoma cells. Mol Cell Biol. 1999 Sep;19(9):5902-12

Kroll SL, Paulding WR, Schnell PO, Barton MC, Conaway JW, Conaway RC, Czyzyk-Krzeska MF. von Hippel-Lindau protein induces hypoxia-regulated arrest of tyrosine hydroxylase transcript elongation in pheochromocytoma cells. J Biol Chem. 1999 Oct 15;274(42):30109-14

Los M, Zeamari S, Foekens JA, Gebbink MF, Voest EE. Regulation of the urokinase-type plasminogen activator system by the von Hippel-Lindau tumor suppressor gene. Cancer Res. 1999 Sep 1;59(17):4440-5

Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ.

The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999 May 20;399(6733):271-5

Ohh M, Kaelin WG Jr. The von Hippel-Lindau tumour suppressor protein: new perspectives. Mol Med Today. 1999 Jun;5(6):257-63

Ohh M, Takagi Y, Aso T, Stebbins CE, Pavletich NP, Zbar B, Conaway RC, Conaway JW, Kaelin WG Jr. Synthetic peptides define critical contacts between elongin C, elongin B, and the von Hippel-Lindau protein. J Clin Invest. 1999 Dec;104(11):1583-91

Okuda H, Hirai S, Takaki Y, Kamada M, Baba M, Sakai N, Kishida T, Kaneko S, Yao M, Ohno S, Shuin T. Direct interaction of the beta-domain of VHL tumor suppressor protein with the regulatory domain of atypical PKC isotypes. Biochem Biophys Res Commun. 1999 Sep 24;263(2):491-7

Pack SD, Zbar B, Pak E, Ault DO, Humphrey JS, Pham T, Hurley K, Weil RJ, Park WS, Kuzmin I, Stolle C, Glenn G, Liotta LA, Lerman MI, Klausner RD, Linehan WM, Zhuang Z. Constitutional von Hippel-Lindau (VHL) gene deletions detected in VHL families by fluorescence in situ hybridization. Cancer Res. 1999 Nov 1;59(21):5560-4

Stebbins CE, Kaelin WG Jr, Pavletich NP. Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function. Science. 1999 Apr 16;284(5413):455-61

Zbar B, Kaelin W, Maher E, Richard S. Third International Meeting on von Hippel-Lindau disease. Cancer Res. 1999 May 1;59(9):2251-3

Brauch H, Weirich G, Brieger J, Glavac D, Rödl H, Eichinger M, Feurer M, Weidt E, Puranakanitstha C, Neuhaus C, Pomer S, Brenner W, Schirmacher P, Störkel S, Rotter M, Masera A, Gugeler N, Decker HJ. VHL alterations in human clear cell renal cell carcinoma: association with advanced tumor stage and a novel hot spot mutation. Cancer Res. 2000 Apr 1;60(7):1942-8

Couch V, Lindor NM, Karnes PS, Michels VV. von Hippel-Lindau disease. Mayo Clin Proc. 2000 Mar;75(3):265-72

Murgia A, Martella M, Vinanzi C, Polli R, Perilongo G, Opocher G. Somatic mosaicism in von Hippel-Lindau Disease. Hum Mutat. 2000 Jan;15(1):114

Richard S, David P, Marsot-Dupuch K, Giraud S, Béroud C, Resche F. Central nervous system hemangioblastomas, endolymphatic sac tumors, and von Hippel-Lindau disease. Neurosurg Rev. 2000 Mar;23(1):1-22; discussion 23-4

Sgambati MT, Stolle C, Choyke PL, Walther MM, Zbar B, Linehan WM, Glenn GM. Mosaicism in von Hippel-Lindau disease: lessons from kindreds with germline mutations identified in offspring with mosaic parents. Am J Hum Genet. 2000 Jan;66(1):84-91

Vortmeyer AO, Huang SC, Koch CA, Governale L, Dickerman RD, McKeever PE, Oldfield EH, Zhuang Z. Somatic von Hippel-Lindau gene mutations detected in sporadic endolymphatic sac tumors. Cancer Res. 2000 Nov 1;60(21):5963-5

Woodward ER, Buchberger A, Clifford SC, Hurst LD, Affara NA, Maher ER. Comparative sequence analysis of the VHL tumor suppressor gene. Genomics. 2000 May 1;65(3):253-65

Baba M, Hirai S, Kawakami S, Kishida T, Sakai N, Kaneko S, Yao M, Shuin T, Kubota Y, Hosaka M, Ohno S. Tumor suppressor protein VHL is induced at high cell density and mediates contact inhibition of cell growth. Oncogene. 2001 May 17;20(22):2727-36



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Blancher C, Moore JW, Robertson N, Harris AL. Effects of ras and von Hippel-Lindau (VHL) gene mutations on hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, and vascular endothelial growth factor expression and their regulation by the phosphat

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