Diagnostic and prognostic utility of the epigenetic silencing of KISS-1 In colon cancer.

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 hypermethy- lation was tested in colon cancer cells (n05) before and after azacytidine treatment. KiSS-1 methylation was evaluated by methylation-specific PCR in colorectal cancer cells, and normal, benign, and tumor tissues (n0352) were grouped in a training set (n062) and two independent validation cohorts (n0100 and n0190). 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 azacyti- dine. 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 % (p00.002). Combination of KiSS-1 methylation and serum CEA (p00.001) increased the prognostic utility of CEA alone (p00.022). In the first validation set, KiSS-1 methylation correlated with tumor grade (p00.011), pre- dicted recurrence (p 00.009), metastasis (p 00.004), disease-free (p00.034), and overall survival (p00.015). In the second validation cohort, KiSS-1 methylation predicted disease-specific survival (p00.030). In the training set, cy- toplasmic KiSS-1 expression was significantly higher in nonneoplastic biopsies as compared to colorectal tumors (p<0.0005). In the validation set, loss of cytoplasmic ex- pression correlated with tumor stage (p00.007), grade (p0 0.035), recurrence (p00.017), and disease-specific survival (p00.022). 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.