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Annals of Oncology Advance Access first published online on July 21, 2009
This version published online on July 24, 2009
Annals of Oncology, doi:10.1093/annonc/mdp280
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© The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Genetic variations in angiogenesis pathway genes associated with clinical outcome in localized gastric adenocarcinoma

G. Lurje1,{dagger}, H. Husain1,{dagger}, D. G. Power2, D. Yang3, S. Groshen3, A. Pohl1, W. Zhang1, Y. Ning1, P. C. Manegold1, A. El-Khoueiry1, S. Iqbal1, L. H. Tang4, M. A. Shah2 and H.-J. Lenz1,3,*

1 Division of Medical Oncology, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA
2 Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, Cornell University, New York, NY
3 Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA
4 Department of Pathology, Memorial Sloan-Kettering Cancer Center, Cornell University, New York, NY, USA

* Correspondence to: Dr. H.-J. Lenz, Division of Medical Oncology, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA. Tel: +1-323-865-3967; Fax: +1-323-865-0061; E-mail: lenz{at}usc.edu

Background: Angiogenesis has been attributed to be a well-recognized aspect of human cancer biology. As such, proteinase-activated receptor (PAR)-1, endostatin (ES) and interleukin-8 (IL-8) mediate the regulation of early-onset angiogenesis and in turn impact the process of tumor-growth and disease progression.

Patients and methods: Formalin-fixed paraffin-embedded tissues were obtained from 137 patients with localized gastric cancer at University of Southern California and Memorial Sloan-Kettering Cancer Center medical facilities. DNA was extracted and genotyping was carried out using PCR–restriction fragment length polymorphism-based protocols.

Results: In false discovery rate-adjusted univariate analysis, PAR-1 –506 ins/del (P < 0.001), ES +4349 G>A (P = 0.004), and IL-8 –251 T>A (P < 0.0001) were associated with time to tumor recurrence (TTR). Further, PAR-1 –506 ins/del and IL-8 –251 were associated with overall survival (OS). After adjusting for covariates, IL-8 remained significantly associated with TTR (adjusted P = 0.003) and OS (adjusted P = 0.049), whereas ES was significantly associated with TTR (adjusted P = 0.026).

Conclusions: Polymorphisms in PAR-1, ES, and IL-8 may serve as independent molecular prognostic markers in patients with localized gastric adenocarcinoma. The assessment of the patients’ individual risk on the basis of interindividual genotypes may therefore help to identify patient subgroups at high risk for poor clinical outcome.

angiogenesis, gastric adenocarcinoma, IL-8, PAR-1, tumor recurrence

{dagger} Both authors contributed equally to this work. Presented in part at the 44th Annual Meeting of the American Society of Cilnical Onocology, Chicago, IL, May 30-June 3 (Abstract ID: 4559)

The name of the corresponding author has been corrected.

Received for publication December 4, 2008. Revision received April 13, 2009. Accepted for publication April 15, 2009.


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