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Tumour selection advantage of non-dominant negative P53 mutations in homozygotic MDM2-SNP309 colorectal cancer cells
  1. Hafid Alazzouzi1,
  2. Gianpaolo Suriano2,
  3. Angel Guerra1,
  4. Alberto Plaja1,
  5. Eloi Espín1,
  6. Manel Armengol1,
  7. Pia Alhopuro3,
  8. Sergia Velho3,
  9. Yasuhisa Shinomura4,
  10. Juan José González-Aguilera5,
  11. Hiroyuki Yamamoto4,
  12. Lauri A Aaltonen3,
  13. Víctor Moreno6,
  14. Gabriel Capellà7,
  15. Miguel Angel Peinado8,
  16. Raquel Seruca2,
  17. Diego Arango1,
  18. Simó Schwartz, Jr1
  1. 1Molecular Oncology and Aging Research, Centre d’Investigacions en Bioquímica i Biologia Molecular (CIBBIM), Institut de Recerca Hospital Universitari Vall d’Hebron, Barcelona, Spain
  2. 2Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal
  3. 3Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
  4. 4First Department of Internal Medicine, Sapporo Medical University, Chuo-ku, Sapporo, Japan
  5. 5Unidad de Genética, Departamento de Biología, Universidad Autónoma de Madrid, Madrid, Spain
  6. 6Cancer Epidemiology Service, Institut Català d’Oncologia, L’Hospitalet, Barcelona, Spain
  7. 7Translational Research Unit, Institut Català d’Oncologia, L’Hospitalet, Barcelona, Spain
  8. 8IDIBELL-Institut de Recerca Oncològica, Barcelona, Spain
  1. Correspondence to:
 Dr S Schwartz Jr
 Molecular Oncology and Aging Group, Centre d’Investigacions en Bioquímica i Biologia Molecular (CIBBIM), Institut de Recerca Hospital Universitari Vall d’Hebron, Passeig Vall d’Hebron 119–129, Barcelona 08035, Spain;sschwartz{at}ir.vhebron.net

Abstract

Background: Mdm2 is a natural inhibitor of p53 function and its overexpression impairs p53 transcriptional activity. T→G single-nucleotide polymorphism at position 309 (SNP309) of mdm2 induces overexpression of mdm2, but inhibits p53.

Objectives: To determine whether SNP309 is a risk-modifier polymorphism in colorectal cancer (CRC) and whether tumour selection of P53 mutations are influenced by SNP309.

Methods: Single-stranded conformation polymorphism and automatic sequencing were performed.

Results: SNP309 is not associated with the risk of CRC or recurrence of tumours. These data do not over-ride the tumour-selection capabilities of P53 mutations in CRC. However, a significant association with non-dominant-negative P53 mutations (p = 0.02) was found.

Conclusions:MDM2-SNP309 favours tumour selection of non-dominant negative P53 mutations in CRC, which also show an earlier age of tumour onset.

  • CRC, colorectal cancer
  • LOH, loss of heterozygosity
  • PCR, polymerase chain reaction
  • SNP309, single-nucleotide polymorphism at position 309
  • SSCP, single-stranded conformation polymorphism

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Footnotes

  • Funding: This work was supported by the Spanish Fondo de Investigaciones Sanitarias (grant numbers 01/1350, 01–0282 and 04–0236) and the Ministerio de Ciencia y Tecnología (grant number SAF2003/5821), Spain, grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by grants-in-aid for cancer research from the Ministry of Health, Labor and Welfare of Japan. Publication costs were supported by the Departament d’Universitats, Recerca i Societat de la Informació from the Generalitat de Catalunya.

  • Competing interests: None.

  • Published Online First 6 July 2006

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