Abstract
The chromosomal region 12q13-q15 is recurrently amplified in bladder cancer. Putative target genes located in this region include MDM2, CDK4, and GLI. To evaluate the involvement of these genes in bladder cancer, we screened a tissue microarray (TMA) containing 2317 samples by fluorescence in situ hybridization (FISH). Amplification was found for MDM2 in 5.1%, for CDK4 in 1.1%, and for GLI in 0.4% of interpretable tumors. Among tumors having amplification of at least one of these 12q13-q15 genes, 76.6% had amplification of MDM2 alone and 6.4% had amplification of CDK4 alone. Coamplifications were seen of MDM2 and CDK4 in 10.6%, and of CDK4 and GLI in 6.4%. Neither coamplifications of all three genes nor isolated GLI amplifications were found. These data suggest a prominent role of MDM2 as a 12q13-q15 amplification target in bladder cancer. However, independent CDK4 amplifications do also occur suggesting either two non-overlapping amplification sites or else a minimal overlapping region between MDM2 and CDK4 perhaps containing another yet unknown oncogene. The frequency of amplification increased significantly from stage pTa to pT1-4 (P<0.04) and from low to high grade (P<0.005). These data are consistent with a high level of genetic instability in invasively growing and high-grade bladder tumors.
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References
An HX, Beckman MW, Reifenberger G, Bender HG, Niederacher D . 1999 Am. J. Pathol. 154: 113–118
Berner JM, Forus A, Elkahloun A, Meltzer PS, Fodstad O, Myklebost O . 1996 Genes Chromosomes Cancer 17: 254–259
Elkahloun AG, Bittner M, Hoskins K, Gemmill R, Meltzer PS . 1996 Genes Chromosomes Cancer 17: 205–214
Fischer U, Meltzer P, Meese E . 1996 Hum. Genet. 98: 625–628
Forus A, Florenes VA, Maelandsmo GM, Meltzer PS, Fodstad O, Myklebost O . 1993 Cell Growth Differ. 4: 1065–1070
Galanis E, Buckner J, Kimmel D, Jenkins R, Alderete B, O'Fallon J, Wang CH, Scheithauer BW, James CD . 1998 Int. J. Oncol. 13: 717–724
Gamberi G, Ragazzini P, Benassi MS, Ferrari C, Sollazzo MR, Molendini L, Merli M, Magagnoli G, Ruggieri P, Balladelli A, Orlando C, Bacchini P, Pazzagli M, Picci P . 2000 Clin. Orthop 195–204
Gisselsson D, Mandahl N, Palsson E, Gorunova L, Hoglund M . 2000 Genes Chromosomes Cancer 28: 347–352
Habuchi T, Kinoshita H, Yamada H, Kakehi Y, Ogawa O, Wu WJ, Takahashi R, Sugiyama T, Yoshida O . 1994 J. Natl. Cancer Inst. 86: 1331–1335
Ioachim E, Charchanti A, Stavropoulos NE, Skopelitou A, Athanassiou ED, Agnantis NJ . 2000 Histol. Histopathol. 15: 721–727
Jahnson S, Karlsson MG . 2000 Cancer 89: 619–629
Jones SN, Sands AT, Hancock AR, Vogel H, Donehower LA, Linke SP, Wahl GM, Bradley A . 1996 Proc. Natl. Acad. Sci. USA 93: 14106–14111
Kallioniemi AH, Kallioniemi OP, Citro G, Sauter G, DeVries S, Kerschmann R, Caroll P, Waldman F . 1995 Genes Chromosomes Cancer 12: 213–219
Kanoe H, Nakayama T, Murakami H, Hosaka T, Yamamoto H, Nakashima Y, Tsuboyama T, Nakamura T, Sasaki MS, Toguchida J . 1998 Anticancer Res. 18: 2317–2321
Khatib ZA, Matsushime H, Valentine M, Shapiro DN, Sherr CJ, Look AT . 1993 Cancer Res. 53: 5535–5541
Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S, Torhorst J, Mihatsch MJ, Sauter G, Kallioniemi OP . 1998 Nat. Med. 4: 844–847
Koo SH, Kwon KC, Ihm CH, Jeon YM, Park JW, Sul CK . 1999 Cancer Genet. Cytogenet. 110: 87–93
Korkolopoulou P, Christodoulou P, Kapralos P, Exarchakos M, Bisbiroula A, Hadjiyannakis M, Georgountzos C, Thomas-Tsagli E . 1997 Pathol. Res. Pract. 193: 767–775
Lianes P, Orlow I, Zhang ZF, Oliva MR, Sarkis AS, Reuter VE, Cordon-Cardo C . 1994 J. Natl. Cancer Inst. 86: 1325–1330
Lu S, Tsai SY, Tsai MJ . 1997 Cancer Res. 57: 4511–4516
Masciullo V, Scambia G, Marone M, Giannitelli C, Ferrandina G, Bellacosa A, Benedetti Panici P, Mancuso S . 1997 Int. J. Cancer 74: 390–395
Momand J, Jung D, Wilczynski S, Niland J . 1998 Nucleic Acids Res. 26: 3453–3459
Mostofi F, Sobin LH, Torloni H . 1973 Histological typing of urinary bladder tumors. International classification of tumors. No 10 World Health Organization, Geneva
Oya M, Schmidt B, Schmitz-Drager BJ, Schulz WA . 1998 Jpn. J. Cancer Res. 89: 719–726
Pedeutour F, Suijkerbuijk RF, Forus A, Van Gaal J, Van de Klundert W, Coindre JM, Nicolo G, Collin F, Van Haelst U, Huffermann K, Turc-Carel C . 1994 Genes Chromosomes Cancer 10: 85–94
Pfister C, Larue H, Moore L, Lacombe L, Veilleux C, Tetu B, Meyer F, Fradet Y . 2000 Int. J. Cancer 89: 100–104
Pfister C, Moore L, Allard P, Larue H, Lacombe L, Tetu B, Meyer F, Fradet Y . 1999 Clin. Cancer Res. 5: 4079–4084
Pilotti S, Della Torre G, Mezzelani A, Tamborini E, Azzarelli A, Sozzi G, Pierotti MA . 2000 Br. J. Cancer 82: 1271–1275
Reed SI . 1997 Cancer Surv. 29: 7–23
Reifenberger G, Ichimura K, Reifenberger J, Elkahloun AG, Meltzer PS, Collins VP . 1996 Cancer Res. 56: 5141–5145
Richter J, Beffa L, Wagner U, Schraml P, Gasser TC, Moch H, Mihatsch MJ, Sauter G . 1998 Am. J. Pathol. 153: 1615–1621
Richter J, Jiang F, Gorog JP, Sartorius G, Egenter C, Gasser TC, Moch H, Mihatsch MJ, Sauter G . 1997 Cancer Res. 57: 2860–2864
Richter J, Wagner U, Kononen J, Fijan A, Bruderer J, Schmid U, Ackermann D, Maurer R, Alund G, Knonagel H, Rist M, Wilber K, Anabitarte M, Hering F, Hardmeier T, Schonenberger A, Flury R, Jager P, Luc Fehr J, Schraml P, Moch H, Mihatsch MJ, Gasser T, Kallioniemi OP, Sauter G . 2000 Am. J. Pathol. 157: 787–794
Richter J, Wagner U, Schraml P, Maurer R, Alund G, Knonagel H, Moch H, Mihatsch MJ, Gasser TC, Sauter G . 1999 Cancer Res. 59: 5687–5691
Rollbrocker B, Waha A, Louis DN, Wiestler OD, von Deimling A . 1996 Acta Neuropathol. (Berl.) 92: 70–74
Schmitz-Drager BJ, Kushima M, Goebell P, Jax TW, Gerharz CD, Bultel H, Schulz WA, Ebert T, Ackermann R . 1997 Eur. Urol. 32: 487–493
Schraml P, Kononen J, Bubendorf L, Moch H, Bissig H, Nocito A, Mihatsch MJ, Kallioniemi OP, Sauter G . 1999 Clin. Cancer Res. 5: 1966–1975
Shiina H, Igawa M, Shigeno K, Yamasaki Y, Urakami S, Yoneda T, Wada Y, Honda S, Nagasaki M . 1999 Oncology 56: 239–247
Simon R, BĂ¼rger H, Brinkschmidt C, Böcker W, Hertle L, Terpe HJ . 1998 J. Pathol. 185: 345–351
Simon R, BĂ¼rger H, Semjonow A, Hertle L, Terpe HJ, Böcker W . 2000 Int. J. Oncol. 17: 1025–1029
Takano Y, Takenaka H, Kato Y, Masuda M, Mikami T, Saegusa M, Okayasu I . 1999 J. Cancer Res. Clin. Oncol. 125: 505–512
UICC. 1997 TNM classification of malignant tumors 5th edn New York: Wiley-Liss
Voorter C, Joos S, Bringuier PP, Vallinga M, Poddighe P, Schalken J, du Manoir S, Ramaekers F, Lichter P, Hopman A . 1995 Am. J. Pathol. 146: 1341–1354
Wei G, Lonardo F, Ueda T, Kim T, Huvos AG, Healey JH, Ladanyi M . 1999 Int. J. Cancer 80: 199–204
Wolf M, Aaltonen LA, Szymanska J, Tarkkanen M, Blomqvist C, Berner JM, Myklebost O, Knuutila S . 1997 Genes Chromosomes Cancer 18: 66–70
Zhao J, Richter J, Wagner U, Roth B, Schraml P, Zellweger T, Ackermann D, Schmid U, Moch H, Mihatsch MJ, Gasser TC, Sauter G . 1999 Cancer Res. 59: 4658–4661
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Simon, R., Struckmann, K., Schraml, P. et al. Amplification pattern of 12q13-q15 genes (MDM2, CDK4, GLI) in urinary bladder cancer. Oncogene 21, 2476–2483 (2002). https://doi.org/10.1038/sj.onc.1205304
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DOI: https://doi.org/10.1038/sj.onc.1205304
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