p53 alterations in oesophageal cancer: association with clinicopathological features, risk factors, and survival.
OBJECTIVE
To characterise the spectrum of p53 alterations (gene mutations and protein accumulation) in a consecutive series of surgically resected oesophageal cancers, and to evaluate associations with clinicopathological findings (age, sex, tumour histology, grade, and stage), potential risk factors (alcohol, tobacco, hot beverage consumption, history of gastrooesophageal reflux disease and antacid use), and survival.


METHODS
The case series comprised 61 sequentially accrued patients with primary oesophageal carcinomas. Genomic DNA was extracted from banked (frozen) tumours and matched normal mucosal tissue; p53 mutations (exons 4-10) were studied by means of polymerase chain reaction (PCR)/single strand conformation polymorphism (SSCP) analysis and DNA sequencing. Immunohistochemistry (DO7, CM1) was used to assess cell nuclear p53 protein accumulation. Risk factor data, overall and disease free survival were measured prospectively, and analysis was carried out at the univariate level using Kaplan-Meier survival curves with log rank tests, and in multivariate analysis using Cox's proportional hazards models (parsimonious and fully adjusted).


RESULTS
p53 mutations were found in 59% (36 of 61) and p53 protein accumulation was detected in 39% (24 of 61) of oesophageal cancers. Eighty eight per cent (23 of 26) of poorly differentiated tumours had p53 alterations compared with 57% (20 of 35) of moderate/well differentiated tumours (odds ratio (OR) = 5.575; p = 0.013). p53 mutations increased significantly with increasing consumption of hot beverages (measured by the average temperature of beverage, number consumed daily, and an index made by multiplying the two variables together) using both univariate (OR = 18.6; p = 0.0025) and multivariate (OR = 24.5; p = 0.0025) analysis. p53 alterations were associated with reduced disease free and overall survival (p = 0.051, log rank), with a univariate (unadjusted) hazard ratio (HR) of 2.241 (95% confidence limits (CL) = 0.973, 5.159; p = 0.058) for overall survival. By multivariate analysis adjusted for other relevant variables, the HR for tumours with p53 alterations was estimated at 2.913 (95% CL = 1.069, 7.936; p = 0.036) for overall survival.


CONCLUSIONS
This study reports novel p53 mutations (exon 10), and an association between increasing consumption of hot beverages as a risk factor for p53 mediated oesophageal cancer. p53 is a potentially useful prognostic marker in this disease.
University of Warwick, Department of Biological Sciences, Coventry, UK.
A G
AG
Casson
M
M
Tammemagi
S
S
Eskandarian
M
M
Redston
J
J
McLaughlin
H
H
Ozcelik
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D016158:Genes, p53; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000378:metabolism; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53