Original Article | Published:

Genetic variants associated with colorectal brain metastases susceptibility and survival

The Pharmacogenomics Journal volume 17, pages 2935 (2017) | Download Citation

Abstract

Colorectal brain metastases (BM) are rare (1–2%) and a late-stage disease manifestation. Molecular mechanisms for BM development are not well understood. We tested whether variants within genes involved in overcoming the blood–brain barrier (BBB) are associated with BM susceptibility and survival in patients with BM. Germline single-nucleotide polymorphisms (SNPs, n=17) in seven genes (CXCR4, MMP9, ST6GALNAC5, ITGAV, ITGB1, ITGB3, KLF4) were analyzed from germline DNA in patients with resected BM (n=70) or no clinical evidence of BM after at least 24 months from diagnosis (control group, n=45). SNPs were evaluated for association with BM susceptibility and overall survival (OS) from BM diagnosis. ST6GALNAC5 rs17368584 and ITGB3 rs3809865 were significantly associated with BM susceptibility. In multivariable analysis adjusted for patient characteristics, KLF4 rs2236599, ITGAV rs10171481, ST6GALNAC5 rs1883778, CXCR4 rs2680880 and ITGB3 rs5918 were significant for OS. This study shows for the first time that variants within genes involved in breaching the BBB are associated with BM susceptibility and survival. These findings warrant further validation to develop better screening guidelines and to identify novel therapy targets for patients with BM.

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Acknowledgements

Stefan Stremitzer is a recipient of an Erwin Schrödinger fellowship of the Austrian Science Fund (J 3501-B13). Ana Sebio is a recipient of a Rio Hortega Research Grant from the Insituto de Salud Carlos III (CM11/00102). Sebastian Stintzing is supported by a postdoctoral fellowship from the German Cancer Aid (Mildred-Scheel Foundation). Martin D. Berger is supported by a grant from the Swiss Cancer League (BIL KLS-3334-02-2014). Peter Birner is supported by the Theodor Kery Stiftung. Heinz-Josef Lenz receives financial support by the P30CA014089 NIH grant, and the Daniel Butler Research Fund.

Author information

Affiliations

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

    • S Stremitzer
    • , N B Volz
    • , W Zhang
    • , S Stintzing
    • , Y Ning
    • , Y Sunakawa
    • , S Yamauchi
    • , A Sebio
    • , S Matsusaka
    • , S Okazaki
    • , D Hanna
    • , A Parekh
    • , A Mendez
    • , M D Berger
    • , R El-Khoueiry
    •  & H-J Lenz
  2. Department of Surgery, Medical University Vienna, Vienna, Austria

    • S Stremitzer
  3. Comprehensive Cancer Center Vienna, Medical University Vienna, Vienna, Austria

    • S Stremitzer
    • , A S Berghoff
    • , P Birner
    •  & M Preusser
  4. Clinical Institute of Neurology, Medical University Vienna, Vienna, Austria

    • A S Berghoff
  5. Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    • D Yang
  6. Department of Pathology, Medical University Vienna, Vienna, Austria

    • P Birner
  7. Department of Medicine I, Medical University Vienna, Vienna, Austria

    • M Preusser

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The authors declare no conflict of interest.

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Correspondence to H-J Lenz.

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DOI

https://doi.org/10.1038/tpj.2015.86

Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website (http://www.nature.com/tpj)