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The prognostic impact of CDX2 correlates with the underlying mismatch repair status and BRAF mutational status but not with distant metastasis in colorectal cancer

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Abstract

Loss of CDX2 expression has been proposed to be a prognostic biomarker in colorectal cancer (CRC) correlating with shorter overall (OS) and progression-free survival (PFS). Since metastatic disease, mismatch repair (MMR) deficiency, and the mutational status of BRAF are considered to be important prognostic determinants in CRC, the present study aimed to analyze CDX2 expression in correlation with these parameters. Immunohistochemistry for CDX2, hMLH1, and hMSH2 was applied to a study cohort of 503 CRC specimens (FIRE-3) and a matched case-control collection of 50 right-sided CRC specimens with synchronous distant metastases and 50 right-sided CRCs without distant metastases. Furthermore, the mutational status of BRAF gene was analyzed utilizing pyrosequencing. CDX2 expression significantly correlates with reduced OS (p = 0.008) within the study population. In both cohorts, a significant correlation of CDX2 expression and MMR deficiency as well as the presence of a BRAF mutation (each p > 0.001) was observed, whereas no correlation of CDX2 expression and synchronous metastasis could be obtained. In the case-control study, only patients with proficient MMR status showed a correlation of CDX2 loss and synchronous metastasis, whereas in patients with deficient MMR status and CDX2 loss, no distant metastases at the time of diagnosis were found (p = 0.003). We could demonstrate that the reduced OS of CDX2-negative CRC patients is not caused by higher rates of distant metastases. Furthermore, our data indicate that the prognostic impact of CDX2 depends on the MMR status and the BRAF mutational status of the tumors. Thus, it could be concluded that CDX2 is not an independent prognostic biomarker in CRC.

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Acknowledgments

We thank Jessica Kövi, Annegret Schäfer, and Carina Windhorst for excellent technical assistance.

Funding

The study received support from Merck Serono GmbH, an affiliate of Merck KGaA, Darmstadt, Germany.

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Authors and Affiliations

  1. Institute of Pathology, Medical Faculty, Ludwig-Maximilians-Universität München, Thalkirchner Straße 36, 80337, Munich, Germany

    Jens Neumann & Thomas Kirchner

  2. Department of Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-Universität München, Munich, Germany

    Volker Heinemann & Sebastian Stintzing

  3. German Cancer Consortium (DKTK), 69120, Heidelberg, Germany

    Volker Heinemann & Thomas Kirchner

  4. German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany

    Volker Heinemann & Thomas Kirchner

  5. Munich Cancer Registry (MCR) of the Munich Tumor Centre (TZM) at the Department of Medical Information Processing, Biometry and Epidemiology (IBE), Ludwig-Maximilians-Universität München, Munich, Germany

    Jutta Engel

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  1. Jens Neumann
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  3. Jutta Engel
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Corresponding author

Correspondence to Jens Neumann.

Ethics declarations

This study was carried out according to the recommendations of the ethics committee of the Medical Faculty of the Ludwig-Maximilians-University Munich, Germany.

The study was performed according to the standards set in the Declaration of Helsinki 1975. All researchers were blinded from patient data during experimental analysis.

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The authors declare that they have no conflict of interest.

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Merck KGaA reviewed the manuscript for medical accuracy only before journal submission. The authors are fully responsible for the content of this manuscript, and the views and opinions described in the publication reflect solely those of the authors.

For guidance on industry ties, see http://annals.org/aim/fullarticle/2424869/good-publication-practice-communicating-company-sponsored-medical-research-gpp3 section “2.6: Disclosures” for guidance.

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Neumann, J., Heinemann, V., Engel, J. et al. The prognostic impact of CDX2 correlates with the underlying mismatch repair status and BRAF mutational status but not with distant metastasis in colorectal cancer. Virchows Arch 473, 199–207 (2018). https://doi.org/10.1007/s00428-018-2360-y

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  • DOI: https://doi.org/10.1007/s00428-018-2360-y

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