Comparison of p53 and DNA content abnormalities in adenocarcinoma of the oesophagus and gastric cardia

Abstract

Summary This study examined the association between 1 7p allelic loss, p53 gene mutation, p53 protein expression and DNA aneuploidy in a series of adenocarcinomas arising in the oesophagus and gastric cardia. 1 7p allelic loss was detected in 79% (15 of 19) of oesophageal and in 83% (29 of 35) of gastric adenocarcinomas. p53 mutations were detected in 70% (14 of 20) and 63% (26 of 41) of oesophageal and of gastric adenocarcinomas respectively. Both tumour types were associated with a predominance of base transitions at CpG dinucleotides. In five cases of oesophageal adenocarcinoma, the same mutation was detected both in tumour and in adjacent dysplastic Barrett's epithelium. Diffuse p53 protein expression was detected in 65% (13 of 20) and 59% (24 of 41) of oesophageal and of gastric tumours, respectively, and was associated with the presence of p53 missense mutation (Chi-squared, P < 0.0001). DNA aneuploidy was detected in 80% (16 of 20) of oesophageal and in 70% (28 of 40) of gastric tumours. No association was found between p53 or DNA content abnormalities and tumour stage or histological subtype. In conclusion, this study detected a similar pattern of p53 alterations in adenocarcinoma of the oesophagus and gastric cardia -molecular data consistent with the observation that these tumours demonstrate similar clinical and epidemiological features.

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

“…Several investigations have focused on the frequency of p53 allelic loss in oesophageal adenocarcinoma, with LOH analysis (Gleeson et al, 1998;Morgan et al, 1998;Dolan et al, 1999). This technique involves the detection of gene dosage imbalances by PCR-based microsatellite genotyping; however, there are a number of methodological difficulties (Tomlinson et al, 2002).…”

“…Complete loss of wild-type p53 protein within a cell rarely occurs as a result of homozygous deletions or a double mutation, the second allele is usually inactivated by an alternate mechanism to the first. When Barrett's metaplastic tissue was examined, it was found that 95 -100% of cases with 17p LOH also had p53 gene mutations (Gleeson et al, 1998;Barrett et al, 1999), while patients without LOH of the gene still carried a mutated p53 allele (Dolan et al, 1999). This suggests a mutation in one allele of the p53 gene probably occurs first followed by allelic loss of the second during neoplastic progression, resulting in a p53 null phenotype that can promote tumorigenesis in Barrett's oesophagus.…”

“…Loss of heterozygosity (LOH) of the p53 locus has been found in 75 -80% of oesophageal adenocarcinomas (Gleeson et al, 1998;Morgan et al, 1998;Wu et al, 1998), as well as in 79% of high-grade dysplasia (HGD), 42% of low-grade dysplasia (LGD) and in 14% of Barrett's metaplastic tissue (Wu et al, 1998). Hence, suggesting LOH of the p53 locus is an important change that develops early during Barrett's neoplastic progression.…”

“…Hence, suggesting LOH of the p53 locus is an important change that develops early during Barrett's neoplastic progression. p53 mutations frequently arise in both Barrett's oesophagus and oesophageal adenocarcinoma, occurring in 40 -88% of cancers (Hamelin et al, 1994;Gleeson et al, 1995Gleeson et al, , 1998Soslow et al, 1999) and 30 -66% of Barrett's epithelium with mild or no dysplasia (Hamelin et al, 1994;Neshat et al, 1994). Between 50 and 80% of documented Barrett's p53 mutations are mis-sense (GC-AT base transitions at CpG islands) and 10 -50% are nonsense (Huang et al, 1993;Gleeson et al, 1998).…”

“…p53 mutations frequently arise in both Barrett's oesophagus and oesophageal adenocarcinoma, occurring in 40 -88% of cancers (Hamelin et al, 1994;Gleeson et al, 1995Gleeson et al, , 1998Soslow et al, 1999) and 30 -66% of Barrett's epithelium with mild or no dysplasia (Hamelin et al, 1994;Neshat et al, 1994). Between 50 and 80% of documented Barrett's p53 mutations are mis-sense (GC-AT base transitions at CpG islands) and 10 -50% are nonsense (Huang et al, 1993;Gleeson et al, 1998). In both HGD and adenocarcinoma, mutations have been found between codons 152 -306, but the most common alterations are transitions, 53% of which occur at the CpG dinucleotide hotspot codons 175, 196, 213, 245, 248, 273 and 282 (www.iarc.fr).…”