Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2001 Jul;85(2):204–208. doi: 10.1054/bjoc.2001.1855

Mutation analysis of the p73 gene in nonastrocytic brain tumours

M E Alonso 1, M J Bello 1, P Gonzalez-Gomez 1, J Lomas 1, D Arjona 1, J M de Campos 2, M E Kusak 2, J L Sarasa 3, A Isla 4, J A Rey 1
PMCID: PMC2364057  PMID: 11461077

Abstract

Loss of heterozygosity (LOH) involving the distal chromosome 1p36region occurs frequently in nonastrocytic brain tumours, but the tumour suppressor gene targeted by this deletion is unknown. p73is a novel gene that has high sequence homology and similar gene structure to thep53 gene; it has been mapped to 1p36, and may thus represent a candidate for this tumour suppressor gene. To determine whether p73is involved in nonastrocytic brain tumour development, we analysed 65 tumour samples including 26 oligodendrogliomas, 4 ependymomas, 5 medulloblastomas, 10 meningiomas, 2 meningeal haemangiopericytomas, 2 neurofibrosarcomas, 3 primary lymphomas, 8 schwannomas and 5 metastatic tumours to the brain, for p73 alterations. Characterization of allelic loss at 1p36–p35 showed LOH in about 50% of cases, primarily involving oligodendroglial tumours (22 of 26 cases analysed; 85%) and meningiomas (4 of 10; 40%). PCR-SSCP and direct DNA sequencing of exons 2 to 14 of p73 revealed a missense mutation in one primary lymphoma: a G-to-A transition, with Glu291Lys change. 8 additional cases displayed no tumour-specific alterations, as 3 distinct polymorphic changes were identified: a double polymorphic change of exon 5 was found in one ependymoma and both samples derived from an oligodendroglioma, as follows: a G-to-A transition with no change in Pro 146, and a C-to-T variation with no change in Asn 204: a delG at exon 3/+12 position was identified in 4 samples corresponding to 2 oligodendrogliomas, 1 ependymoma and 1 meningioma, and a C-to-T change at exon 2/+10 position was present in a metastatic tumour. Although both LOH at 1p36 and p73 sequence changes were evidenced in 4 cases, it is difficult to establish a causal role of the p73 variations and nonastrocytic brain tumours development. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: p73 gene, nonastrocytic tumours, LOH 1p36, primary brain lymphoma

Full Text

The Full Text of this article is available as a PDF (96.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bello M. J., Leone P. E., Nebreda P., de Campos J. M., Kusak M. E., Vaquero J., Sarasa J. L., García-Miguel P., Queizan A., Hernández-Moneo J. L. Allelic status of chromosome 1 in neoplasms of the nervous system. Cancer Genet Cytogenet. 1995 Sep;83(2):160–164. doi: 10.1016/0165-4608(95)00064-v. [DOI] [PubMed] [Google Scholar]
  2. Bello M. J., Leone P. E., Vaquero J., de Campos J. M., Kusak M. E., Sarasa J. L., Pestaña A., Rey J. A. Allelic loss at 1p and 19q frequently occurs in association and may represent early oncogenic events in oligodendroglial tumors. Int J Cancer. 1995 Jun 22;64(3):207–210. doi: 10.1002/ijc.2910640311. [DOI] [PubMed] [Google Scholar]
  3. Bello M. J., de Campos J. M., Vaquero J., Kusak M. E., Sarasa J. L., Rey J. A. High-resolution analysis of chromosome arm 1p alterations in meningioma. Cancer Genet Cytogenet. 2000 Jul 1;120(1):30–36. doi: 10.1016/s0165-4608(99)00249-6. [DOI] [PubMed] [Google Scholar]
  4. Bello M. J., de Campos J. M., Vaquero J., Ruiz-Barnés P., Kusak M. E., Sarasa J. L., Rey J. A. hRAD54 gene and 1p high-resolution deletion-mapping analyses in oligodendrogliomas. Cancer Genet Cytogenet. 2000 Jan 15;116(2):142–147. doi: 10.1016/s0165-4608(99)00122-3. [DOI] [PubMed] [Google Scholar]
  5. Bender B., Wiestler O. D., von Deimling A. A device for processing large acrylamide gels. Biotechniques. 1994 Feb;16(2):204–206. [PubMed] [Google Scholar]
  6. Corn P. G., Kuerbitz S. J., van Noesel M. M., Esteller M., Compitello N., Baylin S. B., Herman J. G. Transcriptional silencing of the p73 gene in acute lymphoblastic leukemia and Burkitt's lymphoma is associated with 5' CpG island methylation. Cancer Res. 1999 Jul 15;59(14):3352–3356. [PubMed] [Google Scholar]
  7. De Laurenzi V. D., Catani M. V., Terrinoni A., Corazzari M., Melino G., Costanzo A., Levrero M., Knight R. A. Additional complexity in p73: induction by mitogens in lymphoid cells and identification of two new splicing variants epsilon and zeta. Cell Death Differ. 1999 May;6(5):389–390. doi: 10.1038/sj.cdd.4400521. [DOI] [PubMed] [Google Scholar]
  8. Fillippovich I., Sorokina N., Gatei M., Haupt Y., Hobson K., Moallem E., Spring K., Mould M., McGuckin M. A., Lavin M. F. Transactivation-deficient p73alpha (p73Deltaexon2) inhibits apoptosis and competes with p53. Oncogene. 2001 Jan 25;20(4):514–522. doi: 10.1038/sj.onc.1204118. [DOI] [PubMed] [Google Scholar]
  9. Han S., Semba S., Abe T., Makino N., Furukawa T., Fukushige S., Takahashi H., Sakurada A., Sato M., Shiiba K. Infrequent somatic mutations of the p73 gene in various human cancers. Eur J Surg Oncol. 1999 Apr;25(2):194–198. doi: 10.1053/ejso.1998.0626. [DOI] [PubMed] [Google Scholar]
  10. Herranz M., Urioste M., Santos J., Martinez-Delgado J. B., Rivas C., Benitez J., Fernández-Piqueras J. Allelic losses and genetic instabilities of PTEN and p73 in non-Hodgkin lymphomas. Leukemia. 2000 Jul;14(7):1325–1327. doi: 10.1038/sj.leu.2401813. [DOI] [PubMed] [Google Scholar]
  11. Hollstein M., Sidransky D., Vogelstein B., Harris C. C. p53 mutations in human cancers. Science. 1991 Jul 5;253(5015):49–53. doi: 10.1126/science.1905840. [DOI] [PubMed] [Google Scholar]
  12. Husemann K., Wolter M., Büschges R., Boström J., Sabel M., Reifenberger G. Identification of two distinct deleted regions on the short arm of chromosome 1 and rare mutation of the CDKN2C gene from 1p32 in oligodendroglial tumors. J Neuropathol Exp Neurol. 1999 Oct;58(10):1041–1050. doi: 10.1097/00005072-199910000-00002. [DOI] [PubMed] [Google Scholar]
  13. Ichimiya S., Nimura Y., Kageyama H., Takada N., Sunahara M., Shishikura T., Nakamura Y., Sakiyama S., Seki N., Ohira M. p73 at chromosome 1p36.3 is lost in advanced stage neuroblastoma but its mutation is infrequent. Oncogene. 1999 Jan 28;18(4):1061–1066. doi: 10.1038/sj.onc.1202390. [DOI] [PubMed] [Google Scholar]
  14. Jost C. A., Marin M. C., Kaelin W. G., Jr p73 is a simian [correction of human] p53-related protein that can induce apoptosis. Nature. 1997 Sep 11;389(6647):191–194. doi: 10.1038/38298. [DOI] [PubMed] [Google Scholar]
  15. Kaghad M., Bonnet H., Yang A., Creancier L., Biscan J. C., Valent A., Minty A., Chalon P., Lelias J. M., Dumont X. Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell. 1997 Aug 22;90(4):809–819. doi: 10.1016/s0092-8674(00)80540-1. [DOI] [PubMed] [Google Scholar]
  16. Kawano S., Miller C. W., Gombart A. F., Bartram C. R., Matsuo Y., Asou H., Sakashita A., Said J., Tatsumi E., Koeffler H. P. Loss of p73 gene expression in leukemias/lymphomas due to hypermethylation. Blood. 1999 Aug 1;94(3):1113–1120. [PubMed] [Google Scholar]
  17. Leone P. E., Bello M. J., de Campos J. M., Vaquero J., Sarasa J. L., Pestaña A., Rey J. A. NF2 gene mutations and allelic status of 1p, 14q and 22q in sporadic meningiomas. Oncogene. 1999 Apr 1;18(13):2231–2239. doi: 10.1038/sj.onc.1202531. [DOI] [PubMed] [Google Scholar]
  18. Levrero M., De Laurenzi V., Costanzo A., Gong J., Melino G., Wang J. Y. Structure, function and regulation of p63 and p73. Cell Death Differ. 1999 Dec;6(12):1146–1153. doi: 10.1038/sj.cdd.4400624. [DOI] [PubMed] [Google Scholar]
  19. Levrero M., De Laurenzi V., Costanzo A., Gong J., Wang J. Y., Melino G. The p53/p63/p73 family of transcription factors: overlapping and distinct functions. J Cell Sci. 2000 May;113(Pt 10):1661–1670. doi: 10.1242/jcs.113.10.1661. [DOI] [PubMed] [Google Scholar]
  20. Lissy N. A., Davis P. K., Irwin M., Kaelin W. G., Dowdy S. F. A common E2F-1 and p73 pathway mediates cell death induced by TCR activation. Nature. 2000 Oct 5;407(6804):642–645. doi: 10.1038/35036608. [DOI] [PubMed] [Google Scholar]
  21. Liu W., Mai M., Yokomizo A., Qian C., Tindall D. J., Smith D. I., Thibodeau S. N. Differential expression and allelotyping of the p73 gene in neuroblastoma. Int J Oncol. 2000 Jan;16(1):181–185. [PubMed] [Google Scholar]
  22. Mai M., Huang H., Reed C., Qian C., Smith J. S., Alderete B., Jenkins R., Smith D. I., Liu W. Genomic organization and mutation analysis of p73 in oligodendrogliomas with chromosome 1 p-arm deletions. Genomics. 1998 Aug 1;51(3):359–363. doi: 10.1006/geno.1998.5387. [DOI] [PubMed] [Google Scholar]
  23. Mashiyama S., Murakami Y., Yoshimoto T., Sekiya T., Hayashi K. Detection of p53 gene mutations in human brain tumors by single-strand conformation polymorphism analysis of polymerase chain reaction products. Oncogene. 1991 Aug;6(8):1313–1318. [PubMed] [Google Scholar]
  24. Mendiola M., Bello M. J., Alonso J., Leone P. E., Vaquero J., Sarasa J. L., Kusak M. E., De Campos J. M., Pestaña A., Rey J. A. Search for mutations of the hRAD54 gene in sporadic meningiomas with deletion at 1p32. Mol Carcinog. 1999 Apr;24(4):300–304. doi: 10.1002/(sici)1098-2744(199904)24:4<300::aid-mc8>3.0.co;2-g. [DOI] [PubMed] [Google Scholar]
  25. Mitelman F., Mertens F., Johansson B. A breakpoint map of recurrent chromosomal rearrangements in human neoplasia. Nat Genet. 1997 Apr;15(Spec No):417–474. doi: 10.1038/ng0497supp-417. [DOI] [PubMed] [Google Scholar]
  26. Nomoto S., Haruki N., Kondo M., Konishi H., Takahashi T., Takahashi T., Takahashi T. Search for mutations and examination of allelic expression imbalance of the p73 gene at 1p36.33 in human lung cancers. Cancer Res. 1998 Apr 1;58(7):1380–1383. [PubMed] [Google Scholar]
  27. Ohgaki H., Eibl R. H., Wiestler O. D., Yasargil M. G., Newcomb E. W., Kleihues P. p53 mutations in nonastrocytic human brain tumors. Cancer Res. 1991 Nov 15;51(22):6202–6205. [PubMed] [Google Scholar]
  28. Peng C. Y., Tsai S. L., Yeh C. T., Hung S. P., Chen M. F., Chen T. C., Chu C. M., Liaw Y. F. Genetic alternations of p73 are infrequent but may occur in early stage hepatocellular carcinoma. Anticancer Res. 2000 May-Jun;20(3A):1487–1492. [PubMed] [Google Scholar]
  29. Reifenberger J., Reifenberger G., Liu L., James C. D., Wechsler W., Collins V. P. Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p. Am J Pathol. 1994 Nov;145(5):1175–1190. [PMC free article] [PubMed] [Google Scholar]
  30. Rey J. A., Bello M. J., Jimenez-Lara A. M., Vaquero J., Kusak M. E., de Campos J. M., Sarasa J. L., Pestaña A. Loss of heterozygosity for distal markers on 22q in human gliomas. Int J Cancer. 1992 Jul 9;51(5):703–706. doi: 10.1002/ijc.2910510507. [DOI] [PubMed] [Google Scholar]
  31. Simon M., von Deimling A., Larson J. J., Wellenreuther R., Kaskel P., Waha A., Warnick R. E., Tew J. M., Jr, Menon A. G. Allelic losses on chromosomes 14, 10, and 1 in atypical and malignant meningiomas: a genetic model of meningioma progression. Cancer Res. 1995 Oct 15;55(20):4696–4701. [PubMed] [Google Scholar]
  32. Smith J. S., Alderete B., Minn Y., Borell T. J., Perry A., Mohapatra G., Hosek S. M., Kimmel D., O'Fallon J., Yates A. Localization of common deletion regions on 1p and 19q in human gliomas and their association with histological subtype. Oncogene. 1999 Jul 15;18(28):4144–4152. doi: 10.1038/sj.onc.1202759. [DOI] [PubMed] [Google Scholar]
  33. Takahashi H., Ichimiya S., Nimura Y., Watanabe M., Furusato M., Wakui S., Yatani R., Aizawa S., Nakagawara A. Mutation, allelotyping, and transcription analyses of the p73 gene in prostatic carcinoma. Cancer Res. 1998 May 15;58(10):2076–2077. [PubMed] [Google Scholar]
  34. Tsujimoto T., Mochizuchi S., Iwadate Y., Namba H., Nagai M., Kawamoto T., Sunahara M., Yamaura A., Nakagawara A., Sakiyama S. The p73 gene is not mutated in oligodendrogliomas which frequently have a deleted region at chromosome 1p36.3. Anticancer Res. 2000 Jul-Aug;20(4):2495–2497. [PubMed] [Google Scholar]
  35. Van Gele M., Kaghad M., Leonard J. H., Van Roy N., Naeyaert J. M., Geerts M. L., Van Belle S., Cocquyt V., Bridge J., Sciot R. Mutation analysis of P73 and TP53 in Merkel cell carcinoma. Br J Cancer. 2000 Feb;82(4):823–826. doi: 10.1054/bjoc.1999.1006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Versteeg R., Caron H., Cheng N. C., van der Drift P., Slater R., Westerveld A., Voûte P. A., Delattre O., Laureys G., Van Roy N. 1p36: every subband a suppressor? Eur J Cancer. 1995;31A(4):538–541. doi: 10.1016/0959-8049(95)00037-j. [DOI] [PubMed] [Google Scholar]
  37. White E., Prives C. DNA damage enables p73. Nature. 1999 Jun 24;399(6738):734-5, 737. doi: 10.1038/21539. [DOI] [PubMed] [Google Scholar]
  38. Yang A., Kaghad M., Wang Y., Gillett E., Fleming M. D., Dötsch V., Andrews N. C., Caput D., McKeon F. p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol Cell. 1998 Sep;2(3):305–316. doi: 10.1016/s1097-2765(00)80275-0. [DOI] [PubMed] [Google Scholar]
  39. Yang A., Walker N., Bronson R., Kaghad M., Oosterwegel M., Bonnin J., Vagner C., Bonnet H., Dikkes P., Sharpe A. p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours. Nature. 2000 Mar 2;404(6773):99–103. doi: 10.1038/35003607. [DOI] [PubMed] [Google Scholar]
  40. Yokozaki H., Shitara Y., Fujimoto J., Hiyama T., Yasui W., Tahara E. Alterations of p73 preferentially occur in gastric adenocarcinomas with foveolar epithelial phenotype. Int J Cancer. 1999 Oct 8;83(2):192–196. doi: 10.1002/(sici)1097-0215(19991008)83:2<192::aid-ijc8>3.0.co;2-e. [DOI] [PubMed] [Google Scholar]
  41. Yoshikawa H., Nagashima M., Khan M. A., McMenamin M. G., Hagiwara K., Harris C. C. Mutational analysis of p73 and p53 in human cancer cell lines. Oncogene. 1999 Jun 3;18(22):3415–3421. doi: 10.1038/sj.onc.1202677. [DOI] [PubMed] [Google Scholar]
  42. von Deimling A., Louis D. N., Wiestler O. D. Molecular pathways in the formation of gliomas. Glia. 1995 Nov;15(3):328–338. doi: 10.1002/glia.440150312. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES