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Solid Tumour Section
Review
Bladder: Urothelial carcinomas
Angela van Tilborg, Bas van Rhijn
Department of Pathology, Josephine Nefkens Institute, Erasmus University, 3000 DR Rotterdam, The
Netherlands (AVT, BVR)
Published in Atlas Database: October 2003
Online updated version : http://AtlasGeneticsOncology.org/Tumors/blad5001.html
DOI: 10.4267/2042/38056
This article is an update of: Huret JL, Léonard C. Bladder: Transitional cell carcinoma. Atlas Genet Cytogenet Oncol
Haematol.2000;4(4):212-217.
Huret JL, Léonard C. Bladder: Transitional cell carcinoma. Atlas Genet Cytogenet Oncol Haematol.1999;3(4):205-206.
Huret JL, Léonard C. Bladder cancer. Atlas Genet Cytogenet Oncol Haematol.1997;1(1):32-33.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Bladder cancer : gross pathology : the bladder wall is massively infiltered by an ulcerated and hemorragic tumor. Courtesy Pierre
Bedossa.
Classification
Clinics and pathology
Histologic types:
Urothelial carcinoma of the bladder, herein described,
Squamous cell carcinoma,
Adenocarcinoma (2%), rare,
Poorly differenciated carcinoma/small cell carcinoma,
exceptional.
Disease
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
Cancer of the urothelium.
Epidemiology
Urothelial carcinoma of the transitional epithelium is
the most frequent bladder cancer in Europe and in the
USA, representing 90-95 % of cases, while
41
Bladder: Urothelial carcinomas
van Tilborg AA, van Rhijn BW
Staging – Editor.
squamous cell carcinoma represents only 5% in these
countries, but up to 70-80% of cases in the Middle
East; annual incidence: 250/106, 2% of cancers, the
fourth cancer in males, the seventh in females, 3M/1F;
occurs mainly in the 6th-8th decades of life; risk
factors: cigarette smoking and occupational exposure
(aniline, benzidine, naphtylamine); 20 to 30 yrs latency
after exposure.
soon/often does it come back), progression and (disease
specific) survival are of importance. Patients with
superficial bladder cancer (pTa and pTis) are frequently
evaluated by cystoscopy to allow early detection of a
possible recurrence and to prevent disease progression
to invasive, potentially lethal, bladder cancer.
According to mutational status of FGFR3 and TP53;
tumors with an FGFR3 mutation have a lower
recurrence
rate,
tumors
with
elevated
immunohistochemical expression of p53 and MIB-1
have the highest recurrence rate: and the highest
propensity for progression and death of disease (see
figure below).
Clinics
Hematuria, irritation.
Pathology
Grading and staging: tumours are:
graded by the degree of cellular atypia (G1->G3), and
staged:
- Papilloma,
- Papillary tumor of low malignant potential (PTLMP),
- Papillary urothelial carcinomas low grade,
- Papillary urothelial carcinomas high grade.
Cytogenetics
Cytogenetics Morphological
Karyotype
Urothelial carcinomas exhibit pseudo diploid
karyotypes with only a few anomalies in early stages,
evolving towards pseudo-tetraploides complexes
karyotypes. Partial or complete monosomy 9 (-9) is an
early event, found in half cases. Deletion (11p) or -11 is
found in 20-50% of cases, more often in high grade and
invasive tumours. Del(13q) is found in 25% of cases
and correlated with high grade/stage; tumours with Rb
alterations are invasive. Del(17p) is a late event, found
in 40% of cases; TP53 alterations are correlated with
grade and stage, tumour progression, and a worse
prognosis. Del(1p), i(5q), +7, and many other
rearrangements - more often deletions than duplications
- are frequently found. These losses of heterozygocity
point to a multistep complex process involving tumor
suppressor genes.
Amplifications
Chromosome 1: P73 (1p36) is often over-expressed.
Chromosome 8: C-MYC (8q24) is rarely amplified.
Treatment
Resection (more or less extensive: electrofulguration -> cystectomy); chemo and/or radiotherapy, BCGtherapy.
Evolution
Recurrence is highly frequent.
Prognosis
According to the stage and the grade; pTa is of good
prognosis (> 90% are cured); prognosis is uncertain in
pT1 and G2 tumours. 20% survival at 1 yr (stable at 3
yrs) is found in T4 cases; however, identification of
individual patient's prognosis is often difficult,
although of major concern for treatment decision and
for follow up.
Multiple endpoints may be identified in bladder cancer.
Recurrence (does it come back), recurrence rate (how
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
42
Bladder: Urothelial carcinomas
van Tilborg AA, van Rhijn BW
LOH
LOH analysis in bladder cancer has so far not led to the
identification of tumor suppressor genes. LOH appears
to be numerous within a given chromosome (e.g. on
chromosome 9 five regions, 9p21, 9q22,
9q31-32, 9q33 and 9q34, and on chromosome 5 four
regions, 5q13.3-q22, 5q22-q31.1, 5q31.1-q32, and
5q34, and on chromosome 3 frequent LOH has been
found in three regions, 3p12-14, 3p21.3-22 and 3p24.225), but loci remain to be precised, as reports are
controversial. Due to the unique possibility to study
multiple recurrent tumors from the same patient, it is
now becoming apparent that loss of heterozygosity
(LOH) on chromosome 9 is almost never the
characteristic first step in tumor development. LOH can
be detected in up to 67% of markers tested. The regions
of loss are multiple and variable in different tumours
from the same patient and expand in subsequent
tumours. Moreover, the regions of loss on chromosome
9 vary from patient to patient. To explain the type and
extent of genetic damage in combination with the low
stage and grade of these tumors, it was hypothesized
that in bladder cancer pathogenesis an increased rate of
mitotic recombination is acquired early in the
tumorigenic process.
Chromosome 11: cyclin D1 is often over-expressed.
Amplifications 10q13-14, 13q21-31 and 17q22-23 have
been noted.
Losses
Chromosome 8: loss of 8p12-22.
The potential target is the FEZ1/LZTS1 gene, which is
downregulated in high-grade carcinomas.
Chromosome 9: Allelic loss on chromosome 9q is a
very frequent event in bladder carcinogenesis.
Monosomy 9 or deletions of chromosome 9 are found
in about 50% of cases; at times found as the sole
anomaly, demonstrating that it is an early event, found
equally in pTa stage and in more advanced stages; not
associated with a given grade, and not correlated with
p53 expression. Efforts have been directed towards
identifying the postulated tumour suppressor genes on
this chromosome arm by deletion mapping and
mutation analysis. However, no convincing candidate
genes have been identified. Homozygous deletions of
CDKN2A/MTS1/P16 (9p21) have been documented;
LOH + mutation on the second allele of CDKN2A are
rare, but of significance; CDKN2A is implicated in pTa
stage but not in pTIS, where p53 is found mutated;
CDKN2B/INK4B/P15 (9p21) is also implicated in a
small subset of cases. LOH + mutation on the second
allele of TSC1 (9q33-34) has been described.
Homozygous deletion and methylational silencing of a
candidate gene DBCCR1 (9q32-33) has been reported.
Chromosome 10: PTEN (10q23), appears to be
implicated in a very few percentage of cases
(homozygote
deletion
has
been
found);
Fas/APO1/CD95 (10q24): loss of one allele and
mutation in the second allele has been reported; a hotspot of mutations has been determined.
Chromosome 11: HRAS1 (11p15.5) is mutated in 15%
of cases.
Chromosome 13: an altered Rb (13q14) is expressed in
30 to 40% of tumours; these are high stage, invasive,
and indicate a short survival; 90% of tumours
expressing Rb are invasives; disregulation of the
normal P16-Rb interactions have been documented,
with hyper expression of Rb and loss of function of
P16.
Chromosome 17: P53 (17p13) alterations are correlated
with grade and stage (often PT3), and tumour
progression; P53 is mutated in more than 50% of high
grade/stage tumours, and in most PTIS; P53 is a
prognostic factor: by high grade/stage tumours, those
expressing P53 are of a worse prognosis; by low
grade/stage, those not expressing P53 are of better
outcome; there is usually LOH + mutation on the
second allele of P53; ERBB2 (HER2/Neu) (17q21) is
expressed in high grade/stages tumours, in metastases,
and is associated with relapses; NF1 (17q11)
expression may be very low in tumours.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
Cytogenetics Molecular
(Matrix) CGH
Array-based comparative genomic hybridization
detected high-level amplification of 6p22.3 (E2F3),
8p12 (FGFR1), 8q22.2 (CMYC), 11q13 (CCND1,
EMS1, INT2), and 19q13.1 (CCNE) and homozygous
deletion of 6p22 (TRAF6), 9p21.3 (CDKN2A/p16) and
8p23.1.
Genes involved and proteins
FGFR3
Note
The expression of a constitutively activated FGFR3 in a
large proportion of bladder cancers is the first evidence
of an oncogenic role for FGFR3 in these carcinomas.
FGFR3 currently appears to be the most frequently
mutated oncogene in bladder cancer: it is mutated in
more than 30% of cases. FGFR3 seems to mediate
opposite signals, acting as a negative regulator of
growth in bone and as an oncogene in several tumour
types. Complete elucidation of the role of FGFR3 in
normal and malignant tissues requires further
investigation. Missense mutations were observed
identical to those in thanatophoric dysplasia (R248C,
S249C, G372C, and K652E), achondroplasia and
SADDAN (G380/382R and K650/652M, respectively)
and Crouzon Syndrome with Acanthosis Nigricans
(A393E). Furthermore, a K650/652T mutation was
found not previously identified in carcinomas or
43
Bladder: Urothelial carcinomas
van Tilborg AA, van Rhijn BW
gains in bladder cancer detected by fluorescence in situ
hybridization. Am J Pathol. 1995 May;146(5):1131-9
thanatophoric dysplasia. In urothelial papilloma,
generally considered a benign lesion, 9/12 (75%)
mutations were found. Another novel finding was the
occurrence of two simultaneous FGFR3 mutations in
four tumours.
Sauter G, Moch H, Carroll P, Kerschmann R, Mihatsch MJ,
Waldman FM. Chromosome-9 loss detected by fluorescence in
situ hybridization in bladder cancer. Int J Cancer. 1995 Apr
21;64(2):99-103
TP53
Sauter G, Moch H, Wagner U, Novotna H, Gasser TC,
Mattarelli G, Mihatsch MJ, Waldman FM. Y chromosome loss
detected by FISH in bladder cancer. Cancer Genet Cytogenet.
1995 Jul 15;82(2):163-9
Note
The TP53 gene in bladder cancer is mainly an indicator
of progression and recurrence rate. Interestingly,
mutations in FGFR3 and TP53 are mutually exclusive
in bladder cancer.
Shackney SE, Berg G, Simon SR, Cohen J, Amina S,
Pommersheim W, Yakulis R, Wang S, Uhl M, Smith CA.
Origins and clinical implications of aneuploidy in early bladder
cancer. Cytometry. 1995 Dec 15;22(4):307-16
HRAS
Note
HRAS mutations are found in approximately 15% of
cases.
Tanaka M, Müllauer L, Ogiso Y, Fujita H, Moriya S, Furuuchi K,
Harabayashi T, Shinohara N, Koyanagi T, Kuzumaki N.
Gelsolin: a candidate for suppressor of human bladder cancer.
Cancer Res. 1995 Aug 1;55(15):3228-32
References
Voorter C, Joos S, Bringuier PP, Vallinga M, Poddighe P,
Schalken J, du Manoir S, Ramaekers F, Lichter P, Hopman A.
Detection of chromosomal imbalances in transitional cell
carcinoma of the bladder by comparative genomic
hybridization. Am J Pathol. 1995 Jun;146(6):1341-54
Elder PA, Bell SM, Knowles MA. Deletion of two regions on
chromosome 4 in bladder carcinoma: definition of a critical
750kB region at 4p16.3. Oncogene. 1994 Dec;9(12):3433-6
Mao L, Schoenberg MP, Scicchitano M, Erozan YS, Merlo A,
Schwab D, Sidransky D. Molecular detection of primary
bladder cancer by microsatellite analysis. Science. 1996 Feb
2;271(5249):659-62
Herr HW. Uncertainty, stage and outcome of invasive bladder
cancer. J Urol. 1994 Aug;152(2 Pt 1):401-2
Sandberg AA, Berger CS. Review of chromosome studies in
urological tumors. II. Cytogenetics and molecular genetics of
bladder cancer. J Urol. 1994 Mar;151(3):545-60
Saran KK, Gould D, Godec CJ, Verma RS. Genetics of bladder
cancer. J Mol Med. 1996 Aug;74(8):441-5
Spruck CH 3rd, Ohneseit PF, Gonzalez-Zulueta M, Esrig D,
Miyao N, Tsai YC, Lerner SP, Schmütte C, Yang AS, Cote R.
Two molecular pathways to transitional cell carcinoma of the
bladder. Cancer Res. 1994 Feb 1;54(3):784-8
Simoneau AR, Spruck CH 3rd, Gonzalez-Zulueta M, Gonzalgo
ML, Chan MF, Tsai YC, Dean M, Steven K, Horn T, Jones PA.
Evidence for two tumor suppressor loci associated with
proximal chromosome 9p to q and distal chromosome 9q in
bladder cancer and the initial screening for GAS1 and PTC
mutations. Cancer Res. 1996 Nov 1;56(21):5039-43
Wang MR, Perissel B, Taillandier J, Kémény JL, Fonck Y,
Lautier A, Benkhalifa M, Malet P. Nonrandom changes of
chromosome 10 in bladder cancer. Detection by FISH to
interphase nuclei. Cancer Genet Cytogenet. 1994 Mar;73(1):810
Stadler WM, Olopade OI. The 9p21 region in bladder cancer
cell lines: large homozygous deletion inactivate the CDKN2,
CDKN2B and MTAP genes. Urol Res. 1996;24(4):239-44
Chang WY, Cairns P, Schoenberg MP, Polascik TJ, Sidransky
D. Novel suppressor loci on chromosome 14q in primary
bladder cancer. Cancer Res. 1995 Aug 1;55(15):3246-9
Takle LA, Knowles MA. Deletion mapping implicates two tumor
suppressor genes on chromosome 8p in the development of
bladder cancer. Oncogene. 1996 Mar 7;12(5):1083-7
Droller MJ. New efforts to stage bladder cancer. J Urol. 1995
Aug;154(2 Pt 1):385-6
Voorter CE, Ummelen MI, Ramaekers FS, Hopman AH. Loss
of chromosome 11 and 11 p/q imbalances in bladder cancer
detected by fluorescence in situ hybridization. Int J Cancer.
1996 Jan 26;65(3):301-7
Kallioniemi A, Kallioniemi OP, Citro G, Sauter G, DeVries S,
Kerschmann R, Caroll P, Waldman F. Identification of gains
and losses of DNA sequences in primary bladder cancer by
comparative genomic hybridization. Genes Chromosomes
Cancer. 1995 Mar;12(3):213-9
Cappellen D, Gil Diez de Medina S, Chopin D, Thiery JP,
Radvanyi F. Frequent loss of heterozygosity on chromosome
10q in muscle-invasive transitional cell carcinomas of the
bladder. Oncogene. 1997 Jun 26;14(25):3059-66
Nemoto R, Nakamura I, Uchida K, Harada M. Numerical
chromosome aberrations in bladder cancer detected by in situ
hybridization. Br J Urol. 1995 Apr;75(4):470-6
Chaturvedi V, Li L, Hodges S, Johnston D, Ro JY, Logothetis
C, von Eschenbach AC, Batsakis JG, Czerniak B.
Superimposed histologic and genetic mapping of chromosome
17 alterations in human urinary bladder neoplasia. Oncogene.
1997 May 1;14(17):2059-70
Orlow I, Lacombe L, Hannon GJ, Serrano M, Pellicer I,
Dalbagni G, Reuter VE, Zhang ZF, Beach D, Cordon-Cardo C.
Deletion of the p16 and p15 genes in human bladder tumors. J
Natl Cancer Inst. 1995 Oct 18;87(20):1524-9
Gibas Z, Gibas L. Cytogenetics of bladder cancer. Cancer
Genet Cytogenet. 1997 May;95(1):108-15
Sarkis AS, Bajorin DF, Reuter VE, Herr HW, Netto G, Zhang
ZF, Schultz PK, Cordon-Cardo C, Scher HI. Prognostic value
of p53 nuclear overexpression in patients with invasive bladder
cancer treated with neoadjuvant MVAC. J Clin Oncol. 1995
Jun;13(6):1384-90
Habuchi T, Yoshida O, Knowles MA. A novel candidate tumour
suppressor locus at 9q32-33 in bladder cancer: localization of
the candidate region within a single 840 kb YAC. Hum Mol
Genet. 1997 Jun;6(6):913-9
Sauter G, Carroll P, Moch H, Kallioniemi A, Kerschmann R,
Narayan P, Mihatsch MJ, Waldman FM. c-myc copy number
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
Richter J, Jiang F, Görög JP, Sartorius G, Egenter C, Gasser
TC, Moch H, Mihatsch MJ, Sauter G. Marked genetic
44
Bladder: Urothelial carcinomas
van Tilborg AA, van Rhijn BW
differences between stage pTa and stage pT1 papillary bladder
cancer detected by comparative genomic hybridization. Cancer
Res. 1997 Jul 15;57(14):2860-4
Aveyard JS, Skilleter A, Habuchi T, Knowles MA. Somatic
mutation of PTEN in bladder carcinoma. Br J Cancer. 1999
May;80(5-6):904-8
Wagner U, Bubendorf L, Gasser TC, Moch H, Görög JP,
Richter J, Mihatsch MJ, Waldman FM, Sauter G. Chromosome
8p deletions are associated with invasive tumor growth in
urinary bladder cancer. Am J Pathol. 1997 Sep;151(3):753-9
Baud E, Catilina P, Bignon YJ. p16 involvement in primary
bladder tumors: analysis of deletions and mutations. Int J
Oncol. 1999 Mar;14(3):441-5
Benedict WF, Lerner SP, Zhou J, Shen X, Tokunaga H,
Czerniak B. Level of retinoblastoma protein expression
correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder
cancer. Oncogene. 1999 Feb 4;18(5):1197-203
Bartlett JM, Watters AD, Ballantyne SA, Going JJ, Grigor KM,
Cooke TG. Is chromosome 9 loss a marker of disease
recurrence in transitional cell carcinoma of the urinary bladder?
Br J Cancer. 1998 Jun;77(12):2193-8
Cappellen D, De Oliveira C, Ricol D, de Medina S, Bourdin J,
Sastre-Garau X, Chopin D, Thiery JP, Radvanyi F. Frequent
activating mutations of FGFR3 in human bladder and cervix
carcinomas. Nat Genet. 1999 Sep;23(1):18-20
Baud E, Catilina P, Boiteux JP, Bignon YJ. Human bladder
cancers and normal bladder mucosa present the same hot
spot of heterozygous chromosome-9 deletion. Int J Cancer.
1998 Sep 11;77(6):821-4
Chi SG, Chang SG, Lee SJ, Lee CH, Kim JI, Park JH. Elevated
and biallelic expression of p73 is associated withprogression of
human bladder cancer. Cancer Res. 1999 Jun 15;59(12):27913
Bruch J, Wöhr G, Hautmann R, Mattfeldt T, Brüderlein S,
Möller P, Sauter S, Hameister H, Vogel W, Paiss T.
Chromosomal changes during progression of transitional cell
carcinoma of the bladder and delineation of the amplified
interval on chromosome arm 8q. Genes Chromosomes
Cancer. 1998 Oct;23(2):167-74
Cairns P, Evron E, Okami K, Halachmi N, Esteller M, Herman
JG, Bose S, Wang SI, Parsons R, Sidransky D. Point mutation
and homozygous deletion of PTEN/MMAC1 in primary bladder
cancers. Oncogene. 1998 Jun 18;16(24):3215-8
Czerniak B, Chaturvedi V, Li L, Hodges S, Johnston D, Roy
JY, Luthra R, Logothetis C, Von Eschenbach AC, Grossman
HB, Benedict WF, Batsakis JG. Superimposed histologic and
genetic mapping of chromosome 9 in progression of human
urinary bladder neoplasia: implications for a genetic model of
multistep urothelial carcinogenesis and early detection of
urinary bladder cancer. Oncogene. 1999 Feb 4;18(5):1185-96
Erbersdobler A, Friedrich MG, Schwaibold H, Henke RP,
Huland H. Microsatellite alterations at chromosomes 9p, 13q,
and 17p in nonmuscle-invasive transitional cell carcinomas of
the urinary bladder. Oncol Res. 1998;10(8):415-20
Herr HW, Bajorin DF, Scher HI, Cordon-Cardo C, Reuter VE.
Can p53 help select patients with invasive bladder cancer for
bladder preservation? J Urol. 1999 Jan;161(1):20-2; discussion
22-3
Halachmi S, Madjar S, Moskovitz B, Nativ O. Genetic
alterations in bladder cancer. Cancer J. 1998;11:86-8.
Hornigold N, Devlin J, Davies AM, Aveyard JS, Habuchi T,
Knowles MA. Mutation of the 9q34 gene TSC1 in sporadic
bladder cancer. Oncogene. 1999 Apr 22;18(16):2657-61
Hovey RM, Chu L, Balazs M, DeVries S, Moore D, Sauter G,
Carroll PR, Waldman FM. Genetic alterations in primary
bladder cancers and their metastases. Cancer Res. 1998 Aug
15;58(16):3555-60
Junker K, Werner W, Mueller C, Ebert W, Schubert J,
Claussen U. Interphase cytogenetic diagnosis of bladder
cancer on cells from urine and bladder washing. Int J Oncol.
1999 Feb;14(2):309-13
Kavaler E, Landman J, Chang Y, Droller MJ, Liu BC. Detecting
human bladder carcinoma cells in voided urine samples by
assaying for the presence of telomerase activity. Cancer. 1998
Feb 15;82(4):708-14
Koo SH, Kwon KC, Ihm CH, Jeon YM, Park JW, Sul CK.
Detection of genetic alterations in bladder tumors by
comparative genomic hybridization and cytogenetic analysis.
Cancer Genet Cytogenet. 1999 Apr 15;110(2):87-93
Simon R, Bürger H, Brinkschmidt C, Böcker W, Hertle L, Terpe
HJ. Chromosomal aberrations associated with invasion in
papillary superficial bladder cancer. J Pathol. 1998
Aug;185(4):345-51
Lee SH, Shin MS, Park WS, Kim SY, Dong SM, Pi JH, Lee HK,
Kim HS, Jang JJ, Kim CS, Kim SH, Lee JY, Yoo NJ.
Alterations of Fas (APO-1/CD95) gene in transitional cell
carcinomas of urinary bladder. Cancer Res. 1999 Jul
1;59(13):3068-72
Tsutsumi M, Tsai YC, Gonzalgo ML, Nichols PW, Jones PA.
Early acquisition of homozygous deletions of p16/p19 during
squamous cell carcinogenesis and genetic mosaicism in
bladder cancer. Oncogene. 1998 Dec 10;17(23):3021-7
Mahdy E, Yoshihiro S, Zech L, Wester K, Pan Y, Busch C,
Döhner H, Kallioniemi O, Bergerheim U, Malmström PU.
Comparison
of
comparative
genomic
hybridization,
fluorescence in situ hybridization and flow cytometry in urinary
bladder cancer. Anticancer Res. 1999 Jan-Feb;19(1A):7-12
Van Tilborg AA, Hekman AC, Vissers KJ, van der Kwast TH,
Zwarthoff EC. Loss of heterozygosity on chromosome 9 and
loss of chromosome 9 copy number are separate events in the
pathogenesis of transitional cell carcinoma of the bladder. Int J
Cancer. 1998 Jan 5;75(1):9-14
Neuhaus M, Wagner U, Schmid U, Ackermann D, Zellweger T,
Maurer R, Alund G, Knönagel H, Rist M, Moch H, Mihatsch MJ,
Gasser TC, Sauter G. Polysomies but not Y chromosome
losses have prognostic significance in pTa/pT1 urinary bladder
cancer. Hum Pathol. 1999 Jan;30(1):81-6
Aaltonen V, Boström PJ, Söderström KO, Hirvonen O,
Tuukkanen J, Nurmi M, Laato M, Peltonen J. Urinary bladder
transitional cell carcinogenesis is associated with downregulation of NF1 tumor suppressor gene in vivo and in vitro.
Am J Pathol. 1999 Mar;154(3):755-65
Ohgaki K, Iida A, Ogawa O, Kubota Y, Akimoto M, Emi M.
Localization of tumor suppressor gene associated with distant
metastasis of urinary bladder cancer to a 1-Mb interval on
8p22. Genes Chromosomes Cancer. 1999 May;25(1):1-5
Adshead JM, Ogden CW, Penny MA, Stuart ET, Kessling AM.
The expression of PAX5 in human transitional cell carcinoma
of the bladder: relationship with de-differentiation. BJU Int.
1999 Jun;83(9):1039-44
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
Pycha A, Mian C, Hofbauer J, Brössner C, Haitel A, Wiener H,
Marberger M. Multifocality of transitional cell carcinoma results
45
Bladder: Urothelial carcinomas
van Tilborg AA, van Rhijn BW
from genetic instability of entire transitional epithelium.
Urology. 1999 Jan;53(1):92-7
multifocal bladder cancer. Eur J Cancer. 2000 Jul;36(11):144151
Richter J, Wagner U, Schraml P, Maurer R, Alund G, Knönagel
H, Moch H, Mihatsch MJ, Gasser TC, Sauter G. Chromosomal
imbalances are associated with a high risk of progression in
early invasive (pT1) urinary bladder cancer. Cancer Res. 1999
Nov 15;59(22):5687-91
Muscheck M, Sükösd F, Pesti T, Kovacs G. High density
deletion mapping of bladder cancer localizes the putative
tumor suppressor gene between loci D8S504 and D8S264 at
chromosome 8p23.3. Lab Invest. 2000 Jul;80(7):1089-93
Salem C, Liang G, Tsai YC, Coulter J, Knowles MA, Feng AC,
Groshen S, Nichols PW, Jones PA. Progressive increases in
de novo methylation of CpG islands in bladder cancer. Cancer
Res. 2000 May 1;60(9):2473-6
Simoneau M, Aboulkassim TO, LaRue H, Rousseau F, Fradet
Y. Four tumor suppressor loci on chromosome 9q in bladder
cancer: evidence for two novel candidate regions at 9q22.3
and 9q31. Oncogene. 1999 Jan 7;18(1):157-63
van Tilborg AA, de Vries A, de Bont M, Groenfeld LE, van der
Kwast TH, Zwarthoff EC. Molecular evolution of multiple
recurrent cancers of the bladder. Hum Mol Genet. 2000 Dec
12;9(20):2973-80
Stacey M, Matas N, Drake M, Payton M, Fakis G, Greenland J,
Sim E. Arylamine N-acetyltransferase type 2 (NAT2),
chromosome 8 aneuploidy, and identification of a novel NAT1
cosmid clone: an investigation in bladder cancer by interphase
FISH. Genes Chromosomes Cancer. 1999 Aug;25(4):376-83
Billerey C, Chopin D, Aubriot-Lorton MH, Ricol D, Gil Diez de
Medina S, Van Rhijn B, Bralet MP, Lefrere-Belda MA, Lahaye
JB, Abbou CC, Bonaventure J, Zafrani ES, van der Kwast T,
Thiery JP, Radvanyi F. Frequent FGFR3 mutations in papillary
non-invasive bladder (pTa) tumors. Am J Pathol. 2001
Jun;158(6):1955-9
Thygesen P, Risch A, Stacey M, Fakis G, Giannoulis F, Takle
L, Knowles M, Sim E. Genes for human arylamine Nacetyltransferases in relation to loss of the short arm of
chromosome 8 in bladder cancer. Pharmacogenetics. 1999
Feb;9(1):1-8
Le Frère-Belda MA, Cappellen D, Daher A, Gil-Diez-de-Medina
S, Besse F, Abbou CC, Thiery JP, Zafrani ES, Chopin DK,
Radvanyi F. p15(INK4b) in bladder carcinomas: decreased
expression in superficial tumours. Br J Cancer. 2001 Nov
16;85(10):1515-21
van Tilborg AA, Groenfeld LE, van der Kwast TH, Zwarthoff
EC. Evidence for two candidate tumour suppressor loci on
chromosome 9q in transitional cell carcinoma (TCC) of the
bladder but no homozygous deletions in bladder tumour cell
lines. Br J Cancer. 1999 May;80(3-4):489-94
van Rhijn BW, Lurkin I, Radvanyi F, Kirkels WJ, van der Kwast
TH, Zwarthoff EC. The fibroblast growth factor receptor 3
(FGFR3) mutation is a strong indicator of superficial bladder
cancer with low recurrence rate. Cancer Res. 2001 Feb
15;61(4):1265-8
Yokomizo A, Mai M, Tindall DJ, Cheng L, Bostwick DG, Naito
S, Smith DI, Liu W. Overexpression of the wild type p73 gene
in human bladder cancer. Oncogene. 1999 Feb 25;18(8):162933
Zhao J, Richter J, Wagner U, Roth B, Schraml P, Zellweger T,
Ackermann D, Schmid U, Moch H, Mihatsch MJ, Gasser TC,
Sauter G. Chromosomal imbalances in noninvasive papillary
bladder neoplasms (pTa). Cancer Res. 1999 Sep
15;59(18):4658-61
van Tilborg AA, de Vries A, Zwarthoff EC. The chromosome 9q
genes TGFBR1, TSC1, and ZNF189 are rarely mutated in
bladder cancer. J Pathol. 2001 May;194(1):76-80
Ørntoft TF, Thykjaer T, Waldman FM, Wolf H, Celis JE.
Genome-wide study of gene copy numbers, transcripts, and
protein levels in pairs of non-invasive and invasive human
transitional cell carcinomas. Mol Cell Proteomics. 2002
Jan;1(1):37-45
Awata S, Sakagami H, Tozawa K, Sasaki S, Ueda K, Kohri K.
Aberration of chromosomes 8 and 11 in bladder cancer as
detected by fluorescence in situ hybridization. Urol Res. 2000
Jun;28(3):185-90
van Rhijn BW, Montironi R, Zwarthoff EC, Jöbsis AC, van der
Kwast TH. Frequent FGFR3 mutations in urothelial papilloma.
J Pathol. 2002 Oct;198(2):245-51
Böhm M, Kleine-Besten R, Wieland I. Loss of heterozygosity
analysis on chromosome 5p defines 5p13-12 as the critical
region involved in tumor progression of bladder carcinomas. Int
J Cancer. 2000 Mar 20;89(2):194-7
van Rhijn BW, van Tilborg AA, Lurkin I, Bonaventure J, de
Vries A, Thiery JP, van der Kwast TH, Zwarthoff EC, Radvanyi
F. Novel fibroblast growth factor receptor 3 (FGFR3) mutations
in bladder cancer previously identified in non-lethal skeletal
disorders. Eur J Hum Genet. 2002 Dec;10(12):819-24
Brennan P, Bogillot O, Cordier S, Greiser E, Schill W, Vineis P,
Lopez-Abente G, Tzonou A, Chang-Claude J, Bolm-Audorff U,
Jöckel KH, Donato F, Serra C, Wahrendorf J, Hours M,
T'Mannetje A, Kogevinas M, Boffetta P. Cigarette smoking and
bladder cancer in men: a pooled analysis of 11 case-control
studies. Int J Cancer. 2000 Apr 15;86(2):289-94
van Tilborg AA, de Vries A, de Bont M, Groenfeld LE,
Zwarthoff EC. The random development of LOH on
chromosome 9q in superficial bladder cancers. J Pathol. 2002
Nov;198(3):352-8
Choi C, Kim MH, Juhng SW, Oh BR. Loss of heterozygosity at
chromosome segments 8p22 and 8p11.2-21.1 in transitionalcell carcinoma of the urinary bladder. Int J Cancer. 2000 May
15;86(4):501-5
Williams SV, Sibley KD, Davies AM, Nishiyama H, Hornigold
N, Coulter J, Kennedy WJ, Skilleter A, Habuchi T, Knowles
MA. Molecular genetic analysis of chromosome 9 candidate
tumor-suppressor loci in bladder cancer cell lines. Genes
Chromosomes Cancer. 2002 May;34(1):86-96
Czerniak B, Li L, Chaturvedi V, Ro JY, Johnston DA, Hodges
S, Benedict WF. Genetic modeling of human urinary bladder
carcinogenesis. Genes Chromosomes Cancer. 2000
Apr;27(4):392-402
Dyrskjøt L, Thykjaer T, Kruhøffer M, Jensen JL, Marcussen N,
Hamilton-Dutoit S, Wolf H, Orntoft TF. Identifying distinct
classes of bladder carcinoma using microarrays. Nat Genet.
2003 Jan;33(1):90-6
Louhelainen J, Wijkström H, Hemminki K. Allelic losses
demonstrate monoclonality of multifocal bladder tumors. Int J
Cancer. 2000 Aug 15;87(4):522-7
Hoque MO, Lee CC, Cairns P, Schoenberg M, Sidransky D.
Genome-wide genetic characterization of bladder cancer: a
comparison of high-density single-nucleotide polymorphism
Louhelainen J, Wijkström H, Hemminki K. Initiationdevelopment modelling of allelic losses on chromosome 9 in
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
46
Bladder: Urothelial carcinomas
van Tilborg AA, van Rhijn BW
arrays and PCR-based microsatellite analysis. Cancer Res.
2003 May 1;63(9):2216-22
progression using cDNA microarrays. Am J Pathol. 2003
Aug;163(2):505-16
Munro NP, Knowles MA. Fibroblast growth factors and their
receptors in transitional cell carcinoma. J Urol. 2003
Feb;169(2):675-82
Veltman JA, Fridlyand J, Pejavar S, Olshen AB, Korkola JE,
DeVries S, Carroll P, Kuo WL, Pinkel D, Albertson D, CordonCardo C, Jain AN, Waldman FM. Array-based comparative
genomic hybridization for genome-wide screening of DNA copy
number in bladder tumors. Cancer Res. 2003 Jun
1;63(11):2872-80
Obermann EC, Junker K, Stoehr R, Dietmaier W, Zaak D,
Schubert J, Hofstaedter F, Knuechel R, Hartmann A. Frequent
genetic alterations in flat urothelial hyperplasias and
concomitant papillary bladder cancer as detected by CGH,
LOH, and FISH analyses. J Pathol. 2003 Jan;199(1):50-7
This article should be referenced as such:
van Tilborg AA, van Rhijn BW. Bladder: Urothelial carcinomas.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):41-47.
Sanchez-Carbayo M, Socci ND, Lozano JJ, Li W,
Charytonowicz E, Belbin TJ, Prystowsky MB, Ortiz AR, Childs
G, Cordon-Cardo C. Gene discovery in bladder cancer
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
47