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Comprehensive mapping of p53 pathway alterations in sarcomas reveals an apparent role for MDM2 SNP309 in sarcomagenesis

Ito, Moriko and Barys, Louise and O'Reilly, Terence and Young, Sophie and Gorbatcheva, Bella and Monahan, John and Zumstein-Mecker, Sabine and Choong, Peter F.M. and Dickinson, Ian and Crowe, Philip J and Hemmings, Chris and Desai, Jayesh and Thomas, David M and Hergovich Lisztwan, Joanna (2011) Comprehensive mapping of p53 pathway alterations in sarcomas reveals an apparent role for MDM2 SNP309 in sarcomagenesis. Clinical Cancer Research, 17 (3). pp. 416-426. ISSN 1078-0432

Abstract

Re-activation of p53 tumour suppressor activity in diseases such as soft tissue sarcomas is considered an attractive means of targeted therapy. To assess the pattern of mutations affecting the p53 pathway, we have comprehensively mapped mutational events in a panel of 192 bone and soft-tissue sarcomas. These include TP53 and CDKN2A mutational and SNP status, MDM2 and MDM4 amplification and MDM2 SNP309 status. Overall, we found an inverse relationship between MDM2 amplification and TP53 mutations in our samples. Although CDKN2A exon and gene deletions were observed, ARF was found to be predominantly wild-type. Alternatively, a high rate of point mutations in TP53 was observed in leiomyosarcoma and osteosarcoma. Our data show the expected high level of MDM2 amplification in well- and de-differentiated liposarcomas, as well subtype specific patterns. Similarly, MDM4 was amplified in a subtype specific manner. Notably, MDM2 and MDM4 amplification events were found to be frequently associated. We have also analysed the risk allele frequencies for MDM2 SNP309, and show that homozygosity for the G SNP was strongly associated with both liposarcomas and MDM2 amplification. Moreover, our data on a set of tumour-matched normal controls indicates a clear directional progression of the MDM2 SNP309 G allele in tumour samples. In summary, our data suggest that at least 70% of sarcomas sustain some type of genetic alterations in the p53 pathway, of which most impinge on either MDM2 or MDM4. We propose, therefore, that these tumour types should be suitable candidates for trials of MDM2 antagonists.

Item Type: Article
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Keywords: p53, sarcoma, SNP309, genotyping, MDM2, MDM4
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/3139

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