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  • Original Paper
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Quantitative real-time PCR does not show selective targeting of p14ARF but concomitant inactivation of both p16INK4A and p14ARF in 105 human primary gliomas


In many human cancers, the INK4A locus is frequently mutated by homozygous deletions. By alternative splicing this locus encodes two non-related tumor suppressor genes, p16INK4A and p14ARF (p19ARF in mice), which regulate cell cycle and cell survival in the retinoblastoma protein (pRb) and p53 pathways, respectively. In mice, the role of p16INK4A as the critical tumor suppressor gene at the INK4A locus was challenged when it was found that p19ARF only knock-out mice developed tumors, including gliomas. We have analysed the genetic status of the INK4A locus in 105 primary gliomas using both microsatellite mapping (MSM) and quantitative real-time PCR (QRT–PCR). Comparison of the results of the two methods revealed agreement in 67% of the tumors examined. In discordant cases, fluorescence in situ hybridization (FISH) analysis was always found to support QRT–PCR classification. Direct assessment of p14ARF exon 1β, p16INK4A exon 1α and exon 2 by QRT–PCR revealed 43 (41%) homozygous and eight (7%) hemizygous deletions at the INK4A locus. In 49 (47%) gliomas, both alleles were retained. In addition, QRT–PCR, but not MSM, detected hyperploidy in five (5%) tumors. Deletion of p14ARF was always associated with co-deletion of p16INK4A and increased in frequency upon progression from low to high grade gliomas. Shorter survival was associated with homozygous deletions of INK4A in the subgroup of glioblastoma patients older than 50 years of age (P=0.025, Anova test single factor, α=0.05).

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  • Cairns P, Polascik TJ, Eby Y, Tokino K, Califano J, Merlo A, Mao L, Herath J, Jenkins R, Westra W, Rutter JL, Buckler A, Gabrielson E, Tockman M, Cho KR, Hedrick L, Bova GS, Isaacs W, Koch W, Schwab D and Sidransky D. . 1995 Nat. Genet. 11: 210–212.

  • Cairns P, Tokino K, Eby Y and Sidransky D. . 1994 Cancer Res. 54: 1422–1424.

  • Carnero A, Hudson JD, Price CM and Beach DH. . 2000 Nat. Cell. Biol. 2: 148–155.

  • Duro D, Bernard O, Della Valle V, Berger R and Larsen CJ. . 1995 Oncogene 11: 21–29.

  • Fulci G, Labuhn M, Maier D, Lachat Y, Hausmann O, Hegi ME, Janzer RC, Merlo A and Van Meir EG. . 2000 Oncogene 19: 3816–3822.

  • Glendening JM, Flores JF, Walker GJ, Stone S, Albino AP and Fountain JW. . 1995 Cancer Res. 55: 5531–5535.

  • Gortz B, Roth J, Speel EJ, Krahenmann A, De Krijger RR, Matias-Guiu X, Muletta-Feurer S, Rutmann K, Saremaslani P, Heitz PU and Komminoth P. . 1999 Int. J. Cancer 80: 373–379.

  • Haber DA. . 1997 Cell 91: 555–558.

  • Hegi ME, zur Hausen A, Ruedi D, Malin G and Kleihues P. . 1997 Int. J. Cancer 73: 57–63.

  • Heyman M, Rasool O, Brandter LB, Liu Y, Grander D, Einhorn S and Soderhall S. . 1996 Blood 87: 1657–1658.

  • Ishii N, Maier D, Merlo A, Tada M, Sawamura Y, Diserens AC and Van Meir EG. . 1999 Brain Pathol. 9: 469–479.

  • Jen J, Harper JW, Bigner SH, Bigner DD, Papadopoulos N, Markowitz S, Willson JK, Kinzler KW and Vogelstein B. . 1994 Cancer Res. 54: 6353–6358.

  • Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day III RS, Johnson BE and Skolnick MH. . 1994 Science 264: 436–440.

  • Kamijo T, Bodner S, van de Kamp E, Randle DH and Sherr CJ. . 1999 Cancer Res. 59: 2217–2222.

  • Kamijo T, Zindy F, Roussel MF, Quelle DE, Downing JR, Ashmun RA, Grosveld G and Sherr CJ. . 1997 Cell 91: 649–659.

  • Kleihues P, Burger PC and Scheithauer BW. . 1993 Brain Pathol. 3: 255–268.

  • Kumar R, Sauroja I, Punnonen K, Jansen C and Hemminki K. . 1998 Genes Chromosomes Cancer 23: 273–277.

  • Li YJ, Hoang-Xuan K, Delattre JY, Poisson M, Thomas G and Hamelin R. . 1995 Oncogene 11: 597–600.

  • Lloyd AC. . 2000 Nat. Cell. Biol. 2: E48–E50.

  • Maier D, Comparone D, Taylor E, Zhang Z, Gratzl O, Van Meir EG, Scott RJ and Merlo A. . 1997 Oncogene 15: 997–1000.

  • Maier D, Zhang Z, Taylor E, Hamou MF, Gratzl O, Van Meir EG, Scott RJ and Merlo A. . 1998 Oncogene 16: 3331–3335.

  • Mao L, Merlo A, Bedi G, Shapiro GI, Edwards CD, Rollins BJ and Sidransky D. . 1995 Cancer Res. 55: 2995–2997.

  • Merlo A, Gabrielson E, Mabry M, Vollmer R, Baylin SB and Sidransky D. . 1994 Cancer Res. 54: 2322–2326.

  • Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger PC, Baylin SB and Sidransky D. . 1995 Nat. Med. 1: 686–692.

  • Newcomb EW, Cohen H, Lee SR, Bhalla SK, Bloom J, Hayes RL and Miller DC. . 1998 Brain Pathol. 8: 655–667.

  • Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K and Carson DA. . 1994 Nature 368: 753–756.

  • Pomerantz J, Schreiber-Agus N, Leigeois NJ, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I, Lee HW, Cordon-Cardo C and DePinho RA. . 1998 Cell 92: 713–723.

  • Quelle DE, Cheng M, Ashmun RA and Sherr CJ. . 1997 Proc. Natl. Acad. Sci. USA 94: 669–673.

  • Quelle DE, Zindy F, Ashmun RA and Sherr CJ. . 1995 Cell 83: 993–1000.

  • Robertson KD and Jones PA. . 1998 Mol. Cell. Biol. 18: 6457–6473.

  • Rocchi M, Archidiancono N, Ward DC and Baldini A. . 1991 Genomics 9: 517–523.

  • Rubin GM, Yandell MD, Wortman JR, Gabor Miklos GL, Nelson CR, Hariharan IK, Fortini ME, Li PW, Apweiler R, Fleischmann W, Cherry JM, Henikoff S, Skupski MP, Misra S, Ashburner M, Birney E, Boguski MS, Brody T, Brokstein P, Celniker SE, Chervitz SA, Coates D, Cravchik A, Gabrielian A, Galle RF, Gelbart WM, George RA, Goldstein LS, Gong F, Guan P, Harris NL, Hay BA, Hoskins RA, Li J, Li Z, Hynes RO, Jones SJ, Kuehl PM, Lemaitre B, Littleton JT, Morrison DK, Mungall C, O'Farrell PH, Pickeral OK, Shue C, Vosshall LB, Zhang J, Zhao Q, Zheng XH, Zhong F, Zhong W, Gibbs R, Venter JC, Adams MD and Lewis S. . 2000 Science 287: 2204–2215.

  • Serrano M, Hannon GJ and Beach D. . 1993 Nature 366: 704–707.

  • Serrano M, Lee H, Chin L, Cordon-Cardo C, Beach D and DePinho RA. . 1996 Cell 85: 27–37.

  • Speel EJ, Ramaekers FC and Hopman AH. . 1997 J. Histochem. Cytochem. 45: 1439–1446.

  • Stott FJ, Bates S, James MC, McConnell BB, Starborg M, Brookes S, Palmero I, Ryan K, Hara E, Vousden KH and Peters G. . 1998 EMBO J. 17: 5001–5014.

  • Sun P, Dong P, Dai K, Hannon GJ and Beach D. . 1998 Science 282: 2270–2272.

  • Wang Y, Hung SC, Linn JF, Steiner G, Glazer AN, Sidransky D and Mathies RA. . 1997 Electrophoresis 18: 1742–1749.

  • Weber JD, Jeffers JR, Rehg JE, Randle DH, Lozano G, Roussel MF, Sherr CJ and Zambetti GP. . 2000 Genes Dev. 14: 2358–2365.

  • Zhang Y and Xiong Y. . 1999 Mol. Cell. 3: 579–591.

  • Zhang Y, Xiong Y and Yarbrough WG. . 1998 Cell 92: 725–734.

  • Zhuang Z, Vortmeyer AO, Pack S, Huang S, Pham TA, Wang C, Park WS, Agarwal SK, Debelenko LV, Kester M, Guru SC, Manickam P, Olufemi SE, Yu F, Heppner C, Crabtree JS, Skarulis MC, Venzon DJ, Emmert-Buck MR, Spiegel AM, Chandrasekharappa SC, Collins FS, Burns AL, Marx SJ, Jensen RT, Liotta LA and Lubensky IA. . 1997 Cancer Res. 57: 4682–4686.

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We would like to thank Annie-Claire Diserens and Marie-France Hamou for technical assistance. Supported by grants from the Swiss National Science Foundation (No. 31053746.98, to A Merlo; No. 3153625.98 to EJM Speel; No. 3149194.96 to EG Van Meir) and the Swiss Cancer League (No. 614-2-1998 to A Merlo; No. 649-2-1998 to EJM Speel; No. 728-9-1998 and No. 904-09-1999 to ME Hegi).

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Labuhn, M., Jones, G., Speel, E. et al. Quantitative real-time PCR does not show selective targeting of p14ARF but concomitant inactivation of both p16INK4A and p14ARF in 105 human primary gliomas. Oncogene 20, 1103–1109 (2001).

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