Genetic variations in angiogenesis pathway genes predict tumor recurrence in localized adenocarcinoma of the esophagus.
OBJECTIVE
The aim of this study was to determine whether the risk of systemic disease after esophagectomy could be predicted by angiogenesis-related gene polymorphisms.


BACKGROUND
Systemic tumor recurrence after curative resection continues to impose a significant problem in the management of patients with localized esophageal adenocarcinoma (EA). The identification of molecular markers of prognosis will help to better define tumor stage, indicate disease progression, identify novel therapeutic targets, and monitor response to therapy. Proteinase-activated-receptor 1 (PAR-1) and epidermal growth factor (EGF) have been shown to mediate the regulation of local and early-onset angiogenesis, and in turn may impact the process of tumor growth and disease progression.


METHODS
We investigated tissue samples from 239 patients with localized EA treated with surgery alone. DNA was isolated from formalin-fixed paraffin-embedded normal esophageal tissue samples and polymorphisms were analyzed using polymerase chain reaction-restriction fragment length polymorphism and 5'-end [gamma-P] ATP-labeled polymerase chain reaction methods.


RESULTS
PAR-1 -506 ins/del (adjusted P value=0.011) and EGF +61 A>G (adjusted P value=0.035) showed to be adverse prognostic markers, in both univariate and multivariable analyses. In combined analysis, grouping alleles into favorable versus nonfavorable alleles, high expression variants of PAR-1 -506 ins/del (any insertion allele) and EGF +61 A>G (A/A) were associated with a higher likelihood of developing tumor recurrence (adjusted P value<0.001).


CONCLUSIONS
This study supports the role of functional PAR-1 and EGF polymorphisms as independent prognostic markers in localized EA and may therefore help to identify patient subgroups at high risk for tumor recurrence.
Lurje
Georg
G
Division of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA 90033, USA.
Leers
Jessica M
JM
Pohl
Alexandra
A
Oezcelik
Arzu
A
Zhang
Wu
W
Ayazi
Shahin
S
Winder
Thomas
T
Ning
Yan
Y
Yang
Dongyun
D
Klipfel
Nancy E
NE
Chandrasoma
Parakrama
P
Hagen
Jeffrey A
JA
DeMeester
Steven R
SR
DeMeester
Tom R
TR
Lenz
Heinz-Josef
HJ
D000230:Adenocarcinoma / Q000235:genetics* / Q000601:surgery; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D043169:Endostatins / Q000235:genetics; D004815:Epidermal Growth Factor / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000601:surgery; D016629:Esophagectomy; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D016209:Interleukin-8 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000235:genetics*; D011379:Prognosis; D044463:Receptor, PAR-1 / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
D014408:Biomarkers, Tumor; D043169:Endostatins; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D044463:Receptor, PAR-1; D042461:Vascular Endothelial Growth Factor A; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D040301:Vascular Endothelial Growth Factor Receptor-2