title: Role of p53 in the progression of gastric cancer.
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.
authors.affiliation: Cancer Genetics and Genomics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Rita A
authors.initials: RA
authors.lastname: Busuttil
authors.affiliation: Molecular Pathology Research and Development Laboratory, Department of Pathology Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia. Translational Genomics and Epigenomics Laboratory, Ludwig Institute for Cancer Research, Olivia Newton-John Cancer and Wellness Centre, Heidelberg, VIC, Australia.
authors.forename: Giada V
authors.initials: GV
authors.lastname: Zapparoli
authors.affiliation: Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. Molecular Pathology Research and Development Laboratory, Department of Pathology Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia. Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia.
authors.forename: Sue
authors.initials: S
authors.lastname: Haupt
authors.affiliation: Cancer Genetics and Genomics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia.
authors.forename: Christina
authors.initials: C
authors.lastname: Fennell
authors.affiliation: Molecular Pathology Research and Development Laboratory, Department of Pathology Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia.
authors.forename: Stephen Q
authors.initials: SQ
authors.lastname: Wong
authors.affiliation: Molecular Pathology Research and Development Laboratory, Department of Pathology Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia. Department of Pathology, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Jia-Min B
authors.initials: JM
authors.lastname: Pang
authors.affiliation: Molecular Pathology Research and Development Laboratory, Department of Pathology Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Takeno
authors.affiliation: Molecular Pathology Research and Development Laboratory, Department of Pathology Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia.
authors.forename: Catherine
authors.initials: C
authors.lastname: Mitchell
authors.affiliation: Cancer Genetics and Genomics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia.
authors.forename: Natasha
authors.initials: N
authors.lastname: Di Costanzo
authors.affiliation: Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. Molecular Pathology Research and Development Laboratory, Department of Pathology Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia. Department of Pathology, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Fox
authors.affiliation: Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. Translational Genomics and Epigenomics Laboratory, Ludwig Institute for Cancer Research, Olivia Newton-John Cancer and Wellness Centre, Heidelberg, VIC, Australia. Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia. Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia.
authors.forename: Ygal
authors.initials: Y
authors.lastname: Haupt
authors.affiliation: Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. Molecular Pathology Research and Development Laboratory, Department of Pathology Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia. Translational Genomics and Epigenomics Laboratory, Ludwig Institute for Cancer Research, Olivia Newton-John Cancer and Wellness Centre, Heidelberg, VIC, Australia. Department of Pathology, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dobrovic
authors.affiliation: Cancer Genetics and Genomics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia. Department of Gastroenterology, Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: Alex
authors.initials: A
authors.lastname: Boussioutas
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D018797:Cell Cycle Proteins; D004252:DNA Mutational Analysis; D018450:Disease Progression; D006801:Humans; D007150:Immunohistochemistry; D009154:Mutation; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2