Characterisation of p53 status at the gene, chromosomal and protein levels in oesophageal adenocarcinoma.
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.
Human Molecular Pathology Group, School of Biological Sciences, University of Wales, Swansea SA2 8PP, UK. 145263@swansea.ac.uk
S H
SH
Doak
G J S
GJ
Jenkins
E M
EM
Parry
A P
AP
Griffiths
V
V
Shah
J N
JN
Baxter
J M
JM
Parry
D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001471:Barrett Esophagus / Q000150:complications; D004252:DNA Mutational Analysis; D004938:Esophageal Neoplasms / Q000209:etiology / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics*; D014852:Wales
D016159:Tumor Suppressor Protein p53