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

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.

[1]  Sandya Liyanarachchi,et al.  p53 Codon 72 and MDM2 SNP309 Polymorphisms and Age of Colorectal Cancer Onset in Lynch Syndrome , 2005, Clinical Cancer Research.

[2]  S. Markowitz,et al.  Genetic and epigenetic alterations in colon cancer. , 2002, Annual review of genomics and human genetics.

[3]  T. Fujimori,et al.  Dysfunction of p53 pathway in human colorectal cancer: analysis of p53 gene mutation and the expression of the p53-associated factors p14ARF, p33ING1, p21WAF1 and MDM2. , 2004, International journal of oncology.

[4]  L. Donehower,et al.  Overexpression of Mdm2 in mice reveals a p53-independent role for Mdm2 in tumorigenesis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[5]  D. Evans,et al.  A detailed study of loss of heterozygosity on chromosome 17 in tumours from Li – Fraumeni patients carrying a mutation to the TP53 gene , 1997, Oncogene.

[6]  S Srivastava,et al.  A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. , 1998, Cancer research.

[7]  J. Manfredi,et al.  Multiple roles of the tumor suppressor p53 , 2002, Current opinion in oncology.

[8]  L. Aaltonen,et al.  The MDM2 promoter polymorphism SNP309T→G and the risk of uterine leiomyosarcoma, colorectal cancer, and squamous cell carcinoma of the head and neck , 2005, Journal of Medical Genetics.

[9]  U. Moll,et al.  The MDM2-p53 interaction. , 2003, Molecular cancer research : MCR.

[10]  A. Levine,et al.  A Single Nucleotide Polymorphism in the MDM2 Promoter Attenuates the p53 Tumor Suppressor Pathway and Accelerates Tumor Formation in Humans , 2004, Cell.

[11]  A. Levine,et al.  A Chromatin-associated and Transcriptionally Inactive p53-Mdm2 Complex Occurs in mdm2 SNP309 Homozygous Cells* , 2005, Journal of Biological Chemistry.

[12]  R. Bertorelle,et al.  Association between MDM2-SNP309 and age at colorectal cancer diagnosis according to p53 mutation status. , 2006, Journal of the National Cancer Institute.

[13]  F. Collins,et al.  Mutations in the p53 gene occur in diverse human tumour types , 1989, Nature.

[14]  C. Cordon-Cardo,et al.  MDM2 and prognosis. , 2004, Molecular cancer research : MCR.

[15]  R. Tjian,et al.  Repression of p53-mediated transcription by MDM2: a dual mechanism. , 1997, Genes & development.

[16]  B. Krishnan,et al.  MDM2/p53 protein expression in the development of colorectal adenocarcinoma , 2007, Journal of Gastrointestinal Surgery.

[17]  A. Levine,et al.  Functions of the MDM2 oncoprotein , 1999, Cellular and Molecular Life Sciences CMLS.

[18]  Hui Wang,et al.  Anti-Tumor Efficacy of a Novel Antisense Anti-MDM2 Mixed-Backbone Oligonucleotide in Human Colon Cancer Models: p53-Dependent and p53-Independent Mechanisms , 2002, Molecular medicine.