title: Potential Role of Soluble c-Met as a New Candidate Biomarker of Metastatic Uveal Melanoma.
abstract: OBJECTIVE
  Conventional melanoma serum biomarkers (S100 and lactate dehydrogenase [LDH]) perform poorly in patients with uveal melanoma, and the search for new biomarkers is needed. A high expression of the oncoprotein c-Met in primary uveal melanoma is associated with metastatic progression, and c-Met is released as a soluble ectodomain through ADAM10- and ADAM17-mediated cleavage, suggesting a possible role as biomarker.
  
  
  OBJECTIVE
  To determine the potential role of soluble c-Met (sc-Met) as a biomarker of uveal melanoma progression in comparison with S100 and LDH.
  
  
  METHODS
  Soluble c-Met was studied in the conditioned medium of 9 uveal melanoma cell lines and in the blood serum samples of 24 mice with uveal melanoma xenografts, 57 patients with uveal melanoma (17 patients whose tumors metastasized and 40 patients whose tumors did not metastasize), and 37 healthy donors. We collected blood samples for as long as 5 years after treatment of the primary tumor. The concentration of sc-Met was measured using enzyme-linked immunosorbent assays, and the receiver operating characteristic curve was used to evaluate sensitivity and specificity in the identification of metastatic uveal melanoma. The study began on May 2, 2011, and the last samples were collected in January 2015.
  
  
  METHODS
  Levels of sc-Met in uveal melanoma cell cultures and in the blood serum samples of xenotransplanted mice, of healthy donors, and of patients with uveal melanoma during follow-up.
  
  
  RESULTS
  The conditioned medium of uveal melanoma cell lines and the blood serum samples of mice with uveal melanoma xenografts contained significant levels of sc-Met. Patients with metastatic disease had significantly higher serum levels of sc-Met (median level, 590 ng/mL [range, 246-12,856 ng/mL]) than did patients without metastatic disease (median level, 296 ng/mL [range, 201-469 ng/mL]) (P < .001) and healthy donors (median level, 285 ng/mL [range, 65-463 ng/mL]) (P < .001). Analysis of receiver operating characteristic curves for sc-Met levels in patients with nonmetastatic uveal melanoma vs patients with metastatic uveal melanoma yielded an area under the curve of 0.82 (95% CI, 0.68-0.95) (P < .001), which was superior to the areas under the curve achieved with S100 or LDH markers. Patients with progressive metastatic disease showed further increases in sc-Met level, whereas stable patients did not.
  
  
  CONCLUSIONS
  The present pilot study suggests that sc-Met should be further exploited as a biomarker for monitoring of uveal melanoma.
authors.affiliation: Department of Integrated Oncology Therapies, Istituto di Ricovero e Cura a Carattere Scientifico, Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Gaia
authors.initials: G
authors.lastname: Barisione
authors.affiliation: Department of Integrated Oncology Therapies, Istituto di Ricovero e Cura a Carattere Scientifico, Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Fabbi
authors.affiliation: Department of Integrated Oncology Therapies, Istituto di Ricovero e Cura a Carattere Scientifico, Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Gino
authors.affiliation: Department of Integrated Oncology Therapies, Istituto di Ricovero e Cura a Carattere Scientifico, Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Queirolo
authors.affiliation: Department of Integrated Oncology Therapies, Istituto di Ricovero e Cura a Carattere Scientifico, Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Orgiano
authors.affiliation: Department of Integrated Oncology Therapies, Istituto di Ricovero e Cura a Carattere Scientifico, Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Spano
authors.affiliation: Department of Integrated Oncology Therapies, Istituto di Ricovero e Cura a Carattere Scientifico, Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Virginia
authors.initials: V
authors.lastname: Picasso
authors.affiliation: Department of Technologically Complex Diagnostics, Pathology, and Therapy, Istituto di Ricovero e Cura a Carattere Scientifico, Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pfeffer
authors.affiliation: Ocular Oncology Center, Galliera Hospital, Genoa, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Mosci
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Jager
authors.affiliation: Department of Integrated Oncology Therapies, Istituto di Ricovero e Cura a Carattere Scientifico, Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Silvano
authors.initials: S
authors.lastname: Ferrini
authors.affiliation: Department of Integrated Oncology Therapies, Istituto di Ricovero e Cura a Carattere Scientifico, Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Gangemi
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000097:blood*; D045744:Cell Line, Tumor; D005260:Female; D064593:Heterografts; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D008545:Melanoma / Q000097:blood* / Q000556:secondary; D008546:Melanoma, Experimental / Q000097:blood*; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D008875:Middle Aged; D010865:Pilot Projects; D019859:Proto-Oncogene Proteins c-met / Q000097:blood*; D012372:ROC Curve; D009418:S100 Proteins / Q000097:blood; D012680:Sensitivity and Specificity; D014604:Uveal Neoplasms / Q000097:blood* / Q000556:secondary; D000098943:Uveal Melanoma
chemical_list: D014408:Biomarkers, Tumor; D009418:S100 Proteins; D007770:L-Lactate Dehydrogenase; D019859:Proto-Oncogene Proteins c-met