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Integrin genetic variants and stage-specific tumor recurrence in patients with stage II and III colon cancer

The Pharmacogenomics Journal volume 15, pages 226–234 (2015)Cite this article

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Abstract

Integrins (ITGs) are key elements in cancer biology, regulating tumor growth, angiogenesis and lymphangiogenesis through interactions of the tumor cells with the microenvironment. Moving from the hypothesis that ITGs could have different effects in stage II and III colon cancer, we tested whether a comprehensive panel of germline single-nucleotide polymorphisms (SNPs) in ITG genes could predict stage-specific time to tumor recurrence (TTR). A total of 234 patients treated with 5-fluorouracil-based chemotherapy at the University of Southern California were included in this study. Whole-blood samples were analyzed for germline SNPs in ITG genes using PCR–restriction fragment length polymorphism or direct DNA sequencing. In the multivariable analysis, stage II colon cancer patients with at least one G allele for ITGB3 rs4642 had higher risk of recurrence (hazard ratio (HR)=4.027, 95% confidence interval (95% CI) 1.556–10.421, P=0.004). This association was also significant in the combined stage II–III cohort (HR=1.975, 95% CI 1.194–3.269, P=0.008). The predominant role of ITGB3 rs4642 in stage II diseases was confirmed using recursive partitioning, showing that ITGB3 rs4642 was the most important factor in stage II diseases. In contrast, in stage III diseases the combined analysis of ITGB1 rs2298141 and ITGA4 rs7562325 allowed to identify three distinct prognostic subgroups (P=0.009). The interaction between stage and the combined ITGB1 rs2298141 and ITGA4 rs7562325 on TTR was significant (P=0.025). This study identifies germline polymorphisms in ITG genes as independent stage-specific prognostic markers for stage II and III colon cancer. These data may help to select subgroups of patients who may benefit from ITG-targeted treatments.

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Acknowledgements

This work was funded by the Lanni Family Charitable Foundation and by the P30 CA P30 CA014089-27S1 grant. AG is supported in part by a research grant from the Austrian Society of Hematology and Oncology, the Bank Austria Visiting Scientists Program and the ‘Verein fuer Krebskranke’ of the Medical University Graz. Statement of translational relevance: In the era of personalized treatments, the identification of prognostic biomarkers in early stages of colon cancer is of critical importance for risk-adapted treatments/follow-up and for drug development. Recent data have shown that meaningful biomarkers may not be similar in stage II or in stage III colon cancer. In this study, we identified ITG variants that give stage-specific prognostic information, identifying patients at higher risk of tumor recurrence. Our data shows that ITGB3 is relevant is stage II colon cancer and suggest that drugs under development targeting this pathway should be tested in this setting. In contrast, our data support a leading role for the α4β1 heterodimer in stage III colon cancer, which is of major importance for future drug development. Furthermore, the variants identified in this study could predict benefit from agents targeting these pathways.

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Authors and Affiliations

  1. Division of Medical Oncology, Sharon A. Carpenter Laboratory, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    P Bohanes, F Loupakis, M J LaBonte, A Gerger, Y Ning, C Lenz, F Lenz, T Wakatsuki, W Zhang, L Benhaim, A El-Khoueiry, R El-Khoueiry & H-J Lenz

  2. Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    D Yang

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Bohanes, P., Yang, D., Loupakis, F. et al. Integrin genetic variants and stage-specific tumor recurrence in patients with stage II and III colon cancer. Pharmacogenomics J 15, 226–234 (2015). https://doi.org/10.1038/tpj.2014.66

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