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Tumour selection advantage of non-dominant negative P53 mutations in homozygotic MDM2-SNP309 colorectal cancer cells

¹ Molecular Oncology and Aging Research, Centre d’Investigacions en Bioquímica i Biologia Molecular (CIBBIM), Institut de Recerca Hospital Universitari Vall d’Hebron, Barcelona, Spain
² Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal
³ Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
⁴ First Department of Internal Medicine, Sapporo Medical University, Chuo-ku, Sapporo, Japan
⁵ Unidad de Genética, Departamento de Biología, Universidad Autónoma de Madrid, Madrid, Spain
⁶ Cancer Epidemiology Service, Institut Català d’Oncologia, L’Hospitalet, Barcelona, Spain
⁷ Translational Research Unit, Institut Català d’Oncologia, L’Hospitalet, Barcelona, Spain
⁸ IDIBELL-Institut de Recerca Oncològica, Barcelona, Spain

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] Background: Mdm2 is a natural inhibitor of p53 function and its overexpression impairs p53 transcriptional activity. TG 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.

Abbreviations: 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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