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Identification of Nicotinamide N-Methyltransferase as a Novel Serum Tumor Marker for Colorectal Cancer

Authors' Affiliations: ¹ Hoffmann-La Roche Ltd., Roche Center of Medical Genomics, Basel, Switzerland; ² Centralized Diagnostics, Roche Diagnostics GmbH, Nonnenwald, Penzberg; ³ Klinikum Kassel GmbH, Institute of Pathology and Biomedical Research, Kassel; ⁴ Institute of Gastroenterology, Hochtaunus-Kliniken gGmbH, Bad Homburg; ⁵ Stadtkrankenhaus Rüsselsheim, I. Medizinische Abteilung, Rüsselsheim; and ⁶ Krankenhaus Nordwest, Frankfurt am Main, Germany

Requests for reprints: Michael Tacke, Centralized Diagnostics, Roche Diagnostics GmbH, Nonnenwald 2, D-82377 Penzberg, Germany. Phone: 49-8856-60-3301; Fax: 49-8856-60-4194; E-mail: michael.tacke{at}roche.com.

Purpose: The goal of this study was to identify and validate novel serum markers of human colorectal cancer as potential candidates for noninvasive detection of early colorectal neoplasm.

Experimental Design: Employing two-dimensional gel electrophoresis and mass spectrometry, we analyzed 16 matched colorectal cancer and adjacent normal tissue samples. Proteins found to be elevated in cancer tissue were further validated by generating antibodies which were used for immunoblotting of tissue samples and for the development of highly sensitive immunoassays for assessment of serum samples.

Results: In total, 735 different proteins were identified in colon tissue. Strong elevation in colorectal cancer for five proteins was confirmed by immunoblot analysis: transforming growth factor-ß induced protein ig-h3 (ßIG-H3), nicotinamide N-methyltransferase (NNMT), nucleoside diphosphate kinase A (nm23-H1), purine nucleoside phosphorylase (PNPH), and mannose-6-phosphate receptor binding protein 1 (M6P1). Elevated levels of NNMT, which is not predicted to be secreted but is known as a cytoplasmic protein, were found in serum from patients with colorectal cancer. Employing a receiver-operating characteristic curve based on the measurement of 109 patients with colorectal cancer and 317 healthy controls, we obtained an area under the curve of 0.84 for NNMT, which was superior to the established tumor marker carcinoembryogenic antigen with an area under the curve of 0.78.

Conclusions: It is proposed that NNMT serum levels may have significance in the early detection and in the management of patients with colorectal cancer.

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