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A Functional Epidermal Growth Factor (EGF) Polymorphism, EGF Serum Levels, and Esophageal Adenocarcinoma Risk and Outcome

Authors' Affiliations: ¹ Division of Thoracic Surgery, ² Massachusetts General Hospital Cancer Center, ³ Division of Surgical Oncology, ⁴ Pulmonary and Critical Care Unit, and ⁵ Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School; ⁶ Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts and ⁷ Divisions of Medical Oncology and Hematology and Applied Molecular Oncology, Ontario Cancer Institute and Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada

Requests for reprints: Michael Lanuti, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Blake 1570, Boston, MA 02114. Phone: 617-726-6751; Fax: 617-726-7667; E-mail: Mlanuti{at}partners.org.

Purpose: The epidermal growth factor (EGF) pathway is important in esophageal adenocarcinoma (EAC) tumorigenesis. We hypothesized that the EGF A61G homozygous variant genotype (GG) is (a) both a risk and poor prognostic factor for EAC and (b) associated with higher EGF serum levels in individuals with gastroesophageal reflux disease (GERD).

Experimental Design: Using unconditional logistic regression, we compared EGF A61G in 312 EAC cases and 447 GERD-free controls, adjusting for age, gender, smoking history, and healthy adult body mass index. Using the method of Kaplan and Meier, log-rank tests, and Cox proportional hazard models, we correlated EGF A61G with overall and failure-free survival in the EAC cases. Serum EGF levels and EGF genotype (G/G versus others) were correlated in 144 GERD patients using Wilcoxon rank sum tests.

Results: The EGF A61G G/G genotype conferred increased EAC risk, with an adjusted odds ratio of 1.81 (95% confidence interval, 1.2-2.7), and was even higher in the subgroup of EAC patients with concurrent Barrett's esophagus (adjusted odds ratio, 2.18; 95% confidence interval, 1.3-3.7). However, EGF A61G was not associated with a more aggressive phenotype or prognosis in EAC patients. Higher serum EGF levels were found in GERD patients carrying G/G compared with A/A or A/G (P = 0.03, Wilcoxon rank sum test).

Conclusion: The EGF A61G G/G genotype is associated with a near 2-fold greater risk of EAC. The G/G allele was also associated with higher EGF levels in tumor-free patients with GERD. EGF genotyping can potentially identify high-risk patients with GERD and Barrett's metaplasia who might benefit from increased surveillance.