P53 ALTERATIONS IN ESOPHAGEAL CANCER - ASSOCIATION WITH CLINICOPATHOLOGICAL FEATURES, RISK-FACTORS, AND SURVIVAL

Aim-To characterise the spectrum of p53 alterations (gene mutations an d protein accumulation) in a consecutive series of surgically resected oesophageal cancers, and to evaluate associations with clinicopatholo gical findings (age, sex, tumour histology, grade, and stage), potenti al risk factors (alcohol, tobacco, hot beverage consumption, history o f gastrooesophageal reflux disease and antacid use), and survival. Met hods-The case series comprised 61 sequentially accrued patients with p rimary oesophageal carcinomas. Genomic DNA was extracted from banked ( frozen) tumours and matched normal mucosal tissue; p53 mutations (exon s 4-10) were studied by means of polymerase chain reaction (PCR)/singl e strand conformation polymorphism (SSCP) analysis and DNA sequencing. Immunohistochemistry (DO7, CM1) was used to assess cell nuclear p53 p rotein accumulation. Risk factor data, overall and disease free surviv al were measured prospectively, and analysis was carried out at the un ivariate 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 o f 61) of oesophageal cancers. Eighty eight per cent (23 of 26) of poor ly 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 con sumption of hot beverages (measured by the average temperature of beve rage, 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 as sociated with reduced disease fi ee and overall survival (p = 0.051, l og rank), with a univariate (unadjusted) hazard ratio (HR) of 2.241 (9 5% confidence limits (CL) = 0.973, 5.159; p = 0.058) for overall survi val. By multivariate analysis adjusted for other relevant variables, t he 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 inc reasing consumption of hot beverages as a risk factor for p53 mediated oesophageal cancer. p53 is a potentially useful prognostic marker in this disease.