Oncotarget

Research Papers:

Role of p53 in the progression of gastric cancer

Rita A. Busuttil, Giada V. Zapparoli, Sue Haupt, Christina Fennell, Stephen Q. Wong, Jia-Min B. Pang, Elena A. Takeno, Catherine Mitchell, Natasha Di Costanzo, Stephen Fox, Ygal Haupt, Alexander Dobrovic and Alex Boussioutas _

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Oncotarget. 2014; 5:12016-12026. https://doi.org/10.18632/oncotarget.2434

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Abstract

Rita A. Busuttil1,2,3, Giada V. Zapparoli4,5, Sue Haupt2,4,6, Christina Fennell1, Stephen Q. Wong4, Jia-Min B. Pang4,7, Elena A. Takeno4, Catherine Mitchell4, Natasha Di Costanzo1, Stephen Fox2,4,7, Ygal Haupt2,5,6,8, Alexander Dobrovic2,4,5,7 and Alex Boussioutas1,2,3,9

1 Cancer Genetics and Genomics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia

2 Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia

3 Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia

4 Molecular Pathology Research and Development Laboratory, Department of Pathology Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia

5 Translational Genomics and Epigenomics Laboratory, Ludwig Institute for Cancer Research, Olivia Newton-John Cancer and Wellness Centre, Heidelberg, VIC, Australia

6 Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia

7 Department of Pathology, University of Melbourne, Parkville, VIC, Australia

8 Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia

9 Department of Gastroenterology, Royal Melbourne Hospital, Parkville, VIC, Australia

Correspondence:

Alex Boussioutas, email:

Keywords: Intestinal metaplasia, gastric cancer, TP53, mutation, Mdmx

Received: August 28, 2014 Accepted: September 02, 2014 Published: September 03, 2014

Abstract

Intestinal metaplasia (IM) is a premalignant lesion associated with gastric cancer (GC) but is poorly described in terms of molecular changes. Here, we explored the role of TP53, a commonly mutated gene in GC, to determine if p53 protein expression and/or the presence of somatic mutations in TP53 can be used as a predictive marker for patients at risk of progressing to GC from IM. Immunohistochemistry and high resolution melting were used to determine p53 protein expression and TP53 mutation status respectively in normal gastric mucosa, IM without concurrent GC (IM-GC), IM with concurrent GC (IM+GC) and GC. This comparative study revealed an incremental increase in p53 expression levels with progression of disease from normal mucosa, via an IM intermediate to GC. TP53 mutations however, were not detected in IM but occurred frequently in GC. Further, we identified increased protein expression of Mdm2/x, both powerful regulators of p53, in 100% of the IM+GC cohort with these samples also exhibiting high levels of wild-type p53 protein. Our data suggests that TP53 mutations occur late in gastric carcinogenesis contributing to the final transition to cancer. We also demonstrated involvement of Mdmx in GC.


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