Abstract
Multifocality and recurrence of urothelial carcinoma may result from either the field effect of carcinogens leading to oligoclonal tumors or monoclonal tumor spread. Previous molecular studies, favoring the monoclonality hypothesis, are mostly limited to the urinary bladder. We investigated genetic alterations in a total of 94 synchronous or metachronous multifocal tumors from 19 patients with at least one tumor both in the upper and lower urinary tract. Loss of heterozygosity (LOH) was determined using eight markers on chromosome 9 and one marker on 17p13 (p53). Microsatellite instability was investigated at six loci and protein expression of MSH2 and MLH1 was evaluated by immunohistochemistry. In addition, exons 5–9 of the p53 gene were sequenced. Deletions at chromosome 9 were found in 73% of tumors and at 17p13 in 18% of tumors. There was no significant difference in the frequency of LOH in the upper and lower urinary tract. Deletions at 9p21 were significantly correlated with invasive tumor growth. The pattern of deletion revealed monoclonality of all tumors in nine patients. In five patients there were at least two tumor clones with different genetic alterations. In four of these patients the different clones occured in the bladder and subsequently in the ureter and renal pelvis. All four patients with p53 mutations revealed identical mutations in all tumors. Thus, multifocal urothelial carcinomas are frequently monoclonal, whereas others show oligoclonality, providing molecular evidence for field cancerization. Intraluminal tumor cell seeding appears to be an important mechanism of multifocal occurence and recurrence of urothelial carcinomas.
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References
Aarnio M, Mecklin JP, Aaltonen LA, Nystrom-Lahti M, Jarvinen HJ . 1995 Int. J. Cancer 64: 430–433
Arzimanoglou II, Gilbert F, Barber HR . 1998 Cancer 82: 1808–1820
Bender CM, Jones PA . 1998 Carcinoma of the Bladder: Innovations in Management. Petrovich Z, Baert L and Brady LW (ed) Springer: Heidelberg/New York pp. 37–51
Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN, Srivastava S . 1998 Cancer Res. 58: 5248–5257
Dietmaier W, Wallinger S, Bocker T, Kullmann F, Fishel R, Rüschoff J . 1997 Cancer Res. 57: 4749–4756
Dietmaier W, Hartmann A, Wallinger S, Heinmöller E, Kerner T, Endl E, Jauch K-W, Hofstädter F, Rüschoff J . 1999 Am. J. Pathol. 154: 83–95
Franklin WA, Gazdar AF, Haney J, Wistuba II, La Rosa FG, Kennedy T, Ritchey DM, Miller YE . 1997 J. Clin. Invest. 100: 2133–2137
Habuchi T, Takahashi R, Yamada H, Kakehi Y, Sugiyama T, Yoshida O . 1993 Lancet 342: 1087–1088
Harris AL, Neal DE . 1992 N. Engl. J. Med. 326: 737–740
Hartmann A, Roesner U, Schlake G, Dietmaier W, Zaak D, Hofstaedter F, Knuechel R . 2000 Lab. Invest. 80: 709–718
Heney NM, Daly J, Prout GR, Nieh PT, Heaney JA, Trebeck NE . 1978 J. Urol. 120: 559–560
Hermanek P, Hutter RVP, Sobin LH, Wagner G, Wittekind C (ed) . 1998 TNM-Classification of Malignant Tumors. 4th edition Springer: Berlin, Heidelberg, New York
Li M, Cannizzaro A . 1999 Hum. Pathol. 30: 1197–1200
Orlow I, Lacombe L, Hannon GJ, Serrano M, Pellicer I, Dalbagni G, Reuter VE, Zhang ZF, Beach D, Cordon-Cardo C . 1995 J. Natl. Cancer Inst. 87: 1524–1529
Paiss T, Woehr GM, Vogel W, Kleinschmidt K, Hautmann RE . 1997 J. Urol. 157: 161
Partridge M, Emilion S, Pateromichelakis S, Phillips E, Langdon J . 1997 Oral Oncol. 33: 332–337
Radovanovic Z, Krajinovic S, Jankovic S, Hall PW, Petkovic S . 1985 J. Cancer Res. Clin. Oncol. 110: 181–183
Sidransky D, von Eschenbach A, Tsai YC, Jones P, Summerhayes I, Marshall F, Paul M, Green P, Hamilton SR, Frost P . 1991 Science 252: 706–709
Sidransky D, Frost P, von Eschenbach A, Oyasu R, Preisinger A, Vogelstein B . 1992 N. Engl. J. Med. 326: 737–740
Simon R, Elize E, Schafer KL, Burger H, Semjonow A, Hertle L, Dockhorn-Dwornicz HJ, Bocker W . 2001 Cancer Res. 61: 355–362
Simoneau M, Aboulkassim TO, LaRue H, Rousseau F, Fradet Y . 1999 Oncogene 18: 157–163
Spruck CH, Ohneseit PF, Gonzalez-Zulueta M, Esrid D, Miyao N, Tsai YC, Lerner SP, Schmütte C, Yang AS, Cote R, Dubeau L, Nichols PW, Hermann GG, Steven K, Horn T, Skinner DG, Jones PA . 1994 Cancer Res. 54: 784–788
Steiner G, Schoenberg MP, Linn JF, Mao L, Sidransky D . 1997 Nature Medicine 3: 621–624
Takahashi T, Habuchi T, Kakehi Y, Mitsumori K, Akao T, Terachi T, Yoshida O . 1998 Cancer Res. 58: 5835–5841
Takahashi T, Kakehi Y, Mitsumori K, Akao T, Terachi T, Kato T, Ogawa O, Habuchi T . 2001 J. Urol. 165: 672–677
Waridel F, Estreicher A, Bron L, Flaman JM, Fontolliet C, Monnier P, Frebourg T, Iggo R . 1997 Oncogene 14: 163–169
Xu X, Stower MJ, Reid N, Garner RC, Burns PA . 1996 Clin. Cancer Res. 2: 1795–1800
Yamamoto S, Tatematsu M, Yamamoto M, Fukami H, Fukushima S . 1998 Carcinogenesis 19: 855–860
Acknowledgements
We thank Monika Kerscher, Astrid Köhler, Rene Krieg, Anne Pietryga-Krieger, Joachim Rauch, Andrea Schneider, Silvia Seegers and Lisa Weber for excellent technical support. This research was supported by Grant 10-1096-HaI from the Dr Mildred Scheel Foundation of Cancer Research to A Hartmann and R Knuechel.
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Hafner, C., Knuechel, R., Zanardo, L. et al. Evidence for oligoclonality and tumor spread by intraluminal seeding in multifocal urothelial carcinomas of the upper and lower urinary tract. Oncogene 20, 4910–4915 (2001). https://doi.org/10.1038/sj.onc.1204671
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DOI: https://doi.org/10.1038/sj.onc.1204671
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