Skip to main content
PMC home page
Brain Pathology logoLink to Brain Pathology
. 2006 Apr 5;9(4):639–643. doi: 10.1111/j.1750-3639.1999.tb00545.x

Homozygous Deletions of the CDKN2C/p 18INK4C Gene on the Short Arm of Chromosome 1 in Anaplastic Oligodendrogliomas

Ute Pohl 1, J Gregory Cairncross 2, David N Louis 1,✉
PMCID: PMC8098363  PMID: 10517502

Abstract

Allelic deletions of the short arm of chromosome 1 are common in oligodendrogliomas and have been correlated with chemosensitivity and better prognosis in patients with high‐grade oligodendrogliomas. In these tumors, 1p loss is also inversely related to deletions of the CDKN2A gene on 9p, which encodes the key cell cycle regulatory molecule p16INK4A. Because the CDKN2C gene, which encodes the homologous p18INK4C cell cycle regulatory protein, maps to chromosomal band 1p32, CDKN2C is an attractive candidate for the oligodendroglioma suppressor gene on chromosome 1. To evaluate this possibility, we studied 39 high‐grade oligodendrogliomas for homozygous deletions and point mutations of the CDKN2C gene, as well as for allelic loss of 1p. Although no mutations were detected in the CDKN2C coding region, two tumors had homozygous deletions that involved CDKN2C. Interestingly, these cases did not have CDKN2A gene deletions. Coupled with the recent report of rare point mutations of CDKN2C in oligodendrogliomas, these findings suggest that CDKN2C inactivation may be oncogenic in a small percentage of human oligodendrogliomas.

Full Text

The Full Text of this article is available as a PDF (61.5 KB).

References

  • 1. Bello MJ, Leone PE, Nebreda P, De Campos JM, Kusak ME, Vaquera J, Sarasa JL, Garcia‐Miguel P, Queizan A, Hernandez‐Moneo JL, Pestaña A, Rey JA (1995) Allelic status of chromosome 1 in neoplasms of the nervous system. Cancer Genet Cytogenet 83: 160–4. [DOI] [PubMed] [Google Scholar]
  • 2. Blais A, Labrie Y, Pouliot F, Lachance Y, Labrie C (1998) Structure of the gene encoding the human cyclin‐dependent kinase inhibitor p18 and mutational analysis in breast cancer. Biochem Biophys Res Commun 247: 146–53. [DOI] [PubMed] [Google Scholar]
  • 3. Cairncross JG, Macdonald DR (1988) Successful chemotherapy for recurrent malignant oligodendroglioma. Ann Neurol 23: 360–4. [DOI] [PubMed] [Google Scholar]
  • 4. Cairncross JG, Ueki K, Zlatescu MC, Lisle DK, Finkelstein DM, Hammond RR, Silver JS, Stark PC, Macdonald DR, Ino Y, Ramsay DA, Louis DN (1998) Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 90: 1473–9. [DOI] [PubMed] [Google Scholar]
  • 5. Gemma A, Takenoshita S, Hagiwara K, Okamoto A, Spillare EA, McMemamin MG, Hussain SP, Forrester K, Zariwala M, Xiong Y, Harris CC (1996) Molecular analysis of the cyclin‐dependent kinase inhibitor genes p15INK4b/MTS2, p16INK4/MTS1, p18 and p19 in human cancer cell lines. Int J Cancer 68: 605–11. [DOI] [PubMed] [Google Scholar]
  • 6. Guan KL, Jenkins CW, Li Y, Nichols MA, Wu X, O'Keefe CL, Matera AG, Xiong Y (1994) Growth suppression by p18, a p16INK4/MTS1‐ and p14INK4B/MTS2‐related CDK6 inhibitor, correlates with wild‐type pRb function. Genes Dev 8: 2939–52. [DOI] [PubMed] [Google Scholar]
  • 7. Haber D, Harlow E (1997) Tumour‐suppressor genes: evolving definitions in the genomic age. Nat Genet 16: 320–2. [DOI] [PubMed] [Google Scholar]
  • 8. Hannon GJ, Beach D (1994) p15INK4B is a potential effector of TGF‐b induced cell‐cycle arrest. Nature 371: 257–261. [DOI] [PubMed] [Google Scholar]
  • 9. Hashimoto N, Ichikawa D, Arakawa Y, Date K, Ueda S, Nakagawa Y, Horii A, Nakamura Y, Abe T, Inazawa J (1995) Frequent deletions of material from chromosome arm 1p in oligodendroglial tumors revealed by double‐target fluorescence in situ hybridization and microsatellite analysis. Genes Chromosomes Cancer 14: 295–300. [DOI] [PubMed] [Google Scholar]
  • 10. Hirai H, Roussel MF, Kato JY, Ashmun RA, Sherr CJ (1995) Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D‐dependent kinases CDK4 and CDK6. Mol Cell Biol 15: 2672–81. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Iolascon A, Giordani L, Moretti A, Tonini GP, Lo Cunsolo C, Mastropietro S, Borriello A, Ragione FD (1998) Structural and functional analysis of cyclin‐dependent kinase inhibitor genes (CDKN2A, CDKN2B, and CDKN2C) in neuroblastoma. Pediatr Res 43: 139–44. [DOI] [PubMed] [Google Scholar]
  • 12. Kamb A, Gruis NA, Weaver‐Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day RS 3rd, Johnson BE, Skolnick MH (1994) A cell cycle regulator potentially involved in genesis of many tumor types. Science 264: 436–40. [DOI] [PubMed] [Google Scholar]
  • 13. Kleihues P, Burger PC, Scheithauer BW (1993) Histological typing of tumours of the central nervous system, 2nd Edition, Springer Verlag: Berlin . [Google Scholar]
  • 14. Kraus JA, Koopmann J, Kaskel P, Maintz D, Brandner S, Schramm J, Louis DN, Wiestler OD, von Deimling A (1995) Shared allelic losses on chromosomes 1p and 19q suggest a common origin of oligodendroglioma and oligoastrocytoma. J Neuropathol Exp Neurol 54: 91–5. [DOI] [PubMed] [Google Scholar]
  • 15. Louis DN, von Deimling A, Chung RY, Rubio MP, Whaley JM, Eibl RH, Ohgaki H, Wiestler OD, Thor AD, Seizinger BR (1993) Comparative study of p53 gene and protein alterations in human astrocytic tumors. J Neuropathol Exp Neurol 52: 31–8. [DOI] [PubMed] [Google Scholar]
  • 16. Louis DN, von Deimling A, Seizinger BR (1992) A (CA)n dinucleotide repeat assay for evaluating loss of allelic heterozygosity in small and archival human brain tumor specimens. Am J Pathol 141: 777–82. [PMC free article] [PubMed] [Google Scholar]
  • 17. Mason W, Louis DN, Cairncross JG (1997) Chemosensitive gliomas in adults: which ones and why J Clin Oncol 15: 3423–6. [DOI] [PubMed] [Google Scholar]
  • 18. Noh SJ, Li Y, Xiong Y, Guan KL (1999) Identification of functional elements of p18INK4C essential for binding and inhibition of cyclin‐dependent kinase (CDK) 4 and CDK6. Cancer Res 59: 558–64. [PubMed] [Google Scholar]
  • 19. Ono Y, Tamiya T, Ichikawa T, Kunishio K, Matsumoto K, Furuta T, Ohmoto T, Ueki K, Louis DN (1996) Malignant astrocytomas with homozygous CDKN2/p16 gene deletions have higher Ki‐67 proliferation indices. J Neuropathol Exp Neurol 55: 1026–31. [PubMed] [Google Scholar]
  • 20. Perry JR, Louis DN, Cairncross JG (1999) Current treatment of oligodendrogliomas. Arch Neurol 56: 434–6. [DOI] [PubMed] [Google Scholar]
  • 21. Platz A, Hansson J, Ringborg U (1998) Screening of germline mutations in the CDK4, CDKN2C and TP53 genes in familial melanoma: a clinic‐based population study. Int J Cancer 78: 13–5. [DOI] [PubMed] [Google Scholar]
  • 22. Reifenberger G, Husemann K, Wolter M, Büschges R, Boström J (1999) Molecular genetic analysis of oligodendroglial tumors for allelic deletions on 1p and mutations of the CDKN2C gene at 1p32. (Abstract). J Neuropathol Exp Neurol 58: 513. [DOI] [PubMed] [Google Scholar]
  • 23. Reifenberger J, Reifenberger G, Liu L, James CD, Wechsler W, Collins VP (1994) Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p. Am J Pathol 145: 1175–90. [PMC free article] [PubMed] [Google Scholar]
  • 24. Rosenberg JE, Lisle DK, Burwick JA, Ueki K, von Deimling A, Mohrenweiser HW, Louis DN (1996) Refined deletion mapping of the chromosome 19q glioma tumor suppressor gene to the D19S412‐STD interval. Oncogene 13: 2483–5. [PubMed] [Google Scholar]
  • 25. Rosso SM, Van Dekken H, Krishnadath KK, Alers JC, Kros JM (1997) Detection of chromosomal changes by interphase cytogenetics in biopsies of recurrent astrocytomas and oligodendrogliomas. J Neuropathol Exp Neurol 56: 1125–31. [DOI] [PubMed] [Google Scholar]
  • 26. Rubio MP, von Deimling A, Yandell DW, Wiestler OD, Gusella JF, Louis DN (1993) Accumulation of wild type p53 protein in human astrocytomas. Cancer Res 53: 3465–7. [PubMed] [Google Scholar]
  • 27. Smith JS, Alderete B, Minn Y, Borell TJ, Perry A, Mohapatra G, Hosek S, Kimmel D, O'Fallon J, Yates A, Feuerstein BG, Burger PC, Scheithauer BW, Jenkins JB (1999) Localization of common deletion regions on 1p and 19q in human gliomas and their association with histological subtype. Oncogene (in Press). [DOI] [PubMed] [Google Scholar]
  • 28. Sulman EP, Dumanski JP, White PS, Zhao H, Maris JM, Mathiesen T, Bruder C, Cnaan A, Brodeur GM (1998) Identification of a consistent region of allelic loss on 1p32 in meningiomas: correlation with increased morbidity. Cancer Res 58: 3226–30. [PubMed] [Google Scholar]
  • 29. Ueki K, Ono Y, Henson JW, Efird JT, von Deimling A, Louis DN (1996) CDKN2/p16 or RB alterations occur in the majority of glioblastomas and are inversely correlated. Cancer Res 56: 150–3. [PubMed] [Google Scholar]
  • 30. von Deimling A, Louis DN, von Ammon K, Petersen I, Wiestler OD, Seizinger BR (1992) Evidence for a tumor suppressor gene on chromosome 19q associated with human astrocytomas, oligodendrogliomas, and mixed gliomas. Cancer Res 52: 4277–9. [PubMed] [Google Scholar]

Articles from Brain Pathology are provided here courtesy of Wiley

RESOURCES