Characterisation of p53 status at the gene, chromosomal and protein levels in oesophageal adenocarcinoma

Abstract

p53 mutations and loss of heterozygosity have been commonly associated with oesophageal adenocarcinoma. In this investigation, the p53 status of a Welsh population of Barrett's-associated oesophageal adenocarcinomas were fully characterised at the gene sequence, chromosomal, mRNA and protein levels. In total, 31 tumours were examined for p53 gene sequence mutations using RFLP with sequencing, allelic loss of the gene was characterised by FISH, mRNA expression by p53 pathway signalling arrays and protein levels by p53 immunohistochemistry. In all, 9.6% of adenocarcinomas harboured p53 mutations, 24% displayed p53 allelic loss and 83% exhibited p53 protein accumulation. Point mutations and deletions of the gene did not coexist within the same samples. All samples containing p53 mutations also displayed positive immunostaining; however; in the majority of cases, p53 protein accumulation developed in the absence of mutations. The gene expression analysis demonstrated no differences in p53 and mdm-2 transcription levels between the p53 immunonegative and immunopositive samples, indicating other mechanisms underlie the proteins' overexpression. In conclusion, p53 mutations and deletions do not appear to be frequent events in oesophageal adenocarcinomas; however, abnormal accumulation of the protein is present in a vast majority of cases. P53 gene mutations are not the primary cause of protein overexpression -an alternative mechanism is responsible for the positive p53 immunohistochemistry detected.

A population-based study of immunohistochemical detection of p53 alteration in bladder cancer

“…The significance of the discordance between IHC-positive tumours and p53 mutation is unclear, although it is commonly reported (Gao et al, 2000;Babjuk et al, 2002;Doak et al, 2003). This discordance may suggest several hypotheses.…”

Clinical Use of p53 in Barrett's Esophagus

“…However, 9 (26%) of these cases were strongly positive for p53 by immunohistochemistry. A more recent study found that whereas 19 of 29 adenocarcinomas strongly expressed p53 by immunohistochemistry, only 2 of these tumors had p53 mutations (26). Thus, it is clear that not all p53 mutations result in p53 protein accumulation and not all p53 protein accumulation is due to a p53 mutation.…”

“…Approximately 90% of the mutations in p53 are point mutations (20). Many p53 mutations are thought to arise by oxidative damage to cytosine bases in exons 5 to 8 (26). Acid suppressive therapies may decrease oxidative DNA damage, although preceding p53 mutations seem to prevent this reduction (27).…”

Loss of P16 in Esophageal Adenocarcinoma Detected by Fluorescence in situ Hybridization and Immunohistochemistry

“…Endoscopic brushing cytology specimens are normally used for FISH analysis of molecular changes in EAC, but FFPE tissue is also an attractive and proven option [30]. Moreover, use of FFPE tissue allows retrospective sample analysis [31].…”