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Association of HDM2 transcript levels with age of onset and prognosis in soft tissue sarcomas.
- Source :
-
Molecular cancer research : MCR [Mol Cancer Res] 2008 Oct; Vol. 6 (10), pp. 1575-81. - Publication Year :
- 2008
-
Abstract
- The p53 stress response is crucial for the prevention of tumor formation. The oncogene HDM2 is one of the key negative regulators of p53 and is a central node in the p53 pathway. P53 and HDM2 form an oscillating feedback loop. HDM2 expression is regulated by different promoters. To evaluate its clinical relevance, we determined the levels of HDM2 transcripts originating from the constitutive P1 and p53-sensitive P2 promoter in 133 soft tissue sarcomas and correlated the results with the age of diagnosis and the patients' outcome. We show that only high levels of the HDM2-P1 transcript but not the P2 transcript are associated with an 11-year earlier age of onset (50.5 years) compared with low P1 levels (61.5 years; P < 0.0001, t test). In addition, low P1 and P2 mRNA expression levels were independent predictors of poor outcome for patients with soft tissue sarcomas (low P1: relative risk, 3.7; P < 0.0001; low P2: relative risk, 2.5; P = 0.001). A change in the expression levels of the HDM2 transcripts originating from the two HDM2 promoters could disrupt the oscillating P53-HDM2 feedback loop in a way that elevated levels of HDM2-P1 transcript are associated with an earlier age of tumor onset and that reduced levels of HDM2-P1 or HDM2-P2 transcripts are correlated with poor prognosis of patients with soft tissue sarcomas.
- Subjects :
- Age of Onset
Feedback, Physiological
Female
Gene Expression Regulation, Neoplastic
Germany epidemiology
Humans
Male
Models, Biological
Multivariate Analysis
Polymorphism, Single Nucleotide genetics
Prognosis
Promoter Regions, Genetic genetics
Proportional Hazards Models
RNA, Messenger genetics
RNA, Messenger metabolism
Sarcoma diagnosis
Survival Analysis
Tumor Suppressor Protein p53 metabolism
Proto-Oncogene Proteins c-mdm2 genetics
Sarcoma epidemiology
Sarcoma genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1541-7786
- Volume :
- 6
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Molecular cancer research : MCR
- Publication Type :
- Academic Journal
- Accession number :
- 18922973
- Full Text :
- https://doi.org/10.1158/1541-7786.MCR-07-2150