Prognostic value of p53 mutations in oesophageal adenocarcinoma: final results of a 15-year prospective study.
OBJECTIVE
This study evaluates the clinical significance of p53 mutations in oesophageal adenocarcinoma (EADC).


METHODS
Between February 1991 and February 2006, 142 consecutive patients with EADC underwent potentially curative oesophageal resection. No patient received induction therapy. Strict clinicopathologic criteria were used to define primary EADC (Type I), excluding gastric cardia adenocarcinoma (Type II). Genomic DNA was extracted from oesophageal tumours, each with matched histologically normal oesophageal epithelium (internal control) from the resection margin. Polymerase chain reaction was used to amplify p53 exons 4-10, and mutations were characterised by direct DNA sequencing. The p53 mutations were correlated with clinicopathologic findings, p53 protein expression determined using immunohistochemistry, and outcome using Kaplan-Meier and Cox proportional hazards models.


RESULTS
For all patients, 5-year overall survival (OS) was 26.9%. Conventional predictors of reduced OS included advanced pathological tumour-node-metastasis (pTNM) stage (P<0.0001) and number of involved lymph nodes (0, 1-3, >3; P<0.0001). No p53 mutations were found in normal oesophageal epithelia. A total of 47% of tumours (67/142) had p53 mutations, predominantly G:C to A:T transitions at CpG dinucleotides (36/67). The p53 mutations were associated with p53 protein overexpression (P<0.0001) and poor tumour differentiation (P=0.037). Patients whose tumours had p53 mutations had significantly reduced 5-year OS (hazard ratio (HR): 1.54; 95% confidence interval (CI): 1.03-2.3; P=0.03).


CONCLUSIONS
Patterns of p53 mutations in EADC suggest endogenous molecular mechanisms. The p53 mutations are a predictor of significantly reduced postoperative survival following surgical resection of EADC, and would appear to be a clinically useful molecular prognostic biomarker.
Madani
Koroush
K
Department of Surgery, Royal University Hospital and the College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 0W8, Canada.
Zhao
Ronghua
R
Lim
Hyun Ja
HJ
Casson
Alan G
AG
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D004812:Epidemiologic Methods; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D016629:Esophagectomy; D005260:Female; D016158:Genes, p53; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D011379:Prognosis; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D014408:Biomarkers, Tumor; D016159:Tumor Suppressor Protein p53