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KiSS-1 methylation and protein expression patterns contribute to diagnostic and prognostic assessments in tissue specimens for colorectal cancer

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Tumor Biology

Abstract

KISS1 is a metastasis suppressor lost in several solid malignancies. We evaluated the clinical relevance of KiSS-1 methylation and its protein expression in colorectal cancer. The epigenetic silencing of KiSS-1 by hypermethylation was tested in colon cancer cells (n = 5) before and after azacytidine treatment. KiSS-1 methylation was evaluated by methylation-specific PCR in colorectal cancer cells, and normal, benign, and tumor tissues (n = 352) were grouped in a training set (n = 62) and two independent validation cohorts (n = 100 and n = 190). KiSS-1 protein expression was analyzed by immunohistochemistry on tissue arrays. KiSS-1 hypermethylation correlated with transcript and protein expression loss, being increased in vitro by azacytidine. Methylation rates were 53.1, 70.0, and 80.0 % in the training and validation sets, respectively. In the training set, KiSS-1 methylation rendered a diagnostic accuracy of 72.7 % (p = 0.002). Combination of KiSS-1 methylation and serum CEA (p = 0.001) increased the prognostic utility of CEA alone (p = 0.022). In the first validation set, KiSS-1 methylation correlated with tumor grade (p = 0.011), predicted recurrence (p = 0.009), metastasis (p = 0.004), disease-free (p = 0.034), and overall survival (p = 0.015). In the second validation cohort, KiSS-1 methylation predicted disease-specific survival (p = 0.030). In the training set, cytoplasmic KiSS-1 expression was significantly higher in nonneoplastic biopsies as compared to colorectal tumors (p < 0.0005). In the validation set, loss of cytoplasmic expression correlated with tumor stage (p = 0.007), grade (p = 0.035), recurrence (p = 0.017), and disease-specific survival (p = 0.022). KiSS-1 was revealed epigenetically modified in colorectal cancer. The diagnostic and prognostic utility of KiSS-1 methylation and expression patterns suggests their assessment for the clinical management of colorectal cancer patients.

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Acknowledgments

We thank all the members of the laboratory of M. Sánchez-Carbayo for the technical support and constructive suggestions in the preparation of this manuscript. We also would like to thank the Tumor Bank belonging to the Molecular Pathology Program at the Spanish National Cancer Center and all the members of our clinical collaborators at the different institutions involved in this study, for the support in facilitating the tumor specimens as well as the clinical follow-up of the colorectal cancer cases analyzed in this study. M. Sánchez-Carbayo received grant supports from Spanish Ministry of Science and Innovation grant SAF2009-13035 and Mutua Madrileña 2010.

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Authors and Affiliations

  1. Tumor Markers Group, Molecular Pathology Program, Spanish National Cancer Center, Madrid, Spain

    Patricia Moya, Sergio Esteban & Marta Sánchez-Carbayo

  2. Biochemistry Department, Hospital Alto Guadalquivir, Andujar, Jaén, Spain

    Antonio Fernandez-Suarez

  3. Biochemistry Department, Hospital Clinico Universitario, Madrid, Spain

    Marisa Maestro

  4. Tumor Bank Unit, Molecular Pathology Program, Spanish National Cancer Center, Madrid, Spain

    Manuel Morente

  5. Tumor Markers Group, 310A, Spanish National Cancer Research Center, Melchor Fernandez Almagro 3, 28029, Madrid, Spain

    Marta Sánchez-Carbayo

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  1. Patricia Moya
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  2. Sergio Esteban
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  4. Marisa Maestro
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  6. Marta Sánchez-Carbayo
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Correspondence to Marta Sánchez-Carbayo.

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Moya, P., Esteban, S., Fernandez-Suarez, A. et al. KiSS-1 methylation and protein expression patterns contribute to diagnostic and prognostic assessments in tissue specimens for colorectal cancer. Tumor Biol. 34, 471–479 (2013). https://doi.org/10.1007/s13277-012-0572-3

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  • DOI: https://doi.org/10.1007/s13277-012-0572-3

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