Potential role of soluble c-met as a new Candidate biomarker of metastatic uveal melanoma

Gaia Barisione, Marina Fabbi, Alice Gino, Paola Queirolo, Laura Orgiano, Laura Spano, Virginia Picasso, Ulrich Pfeffer, Carlo Mosci, Martine J. Jager, Silvano Ferrini, Rosaria Gangemi

Research output: Contribution to journalArticle

Abstract

Importance 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. Design, Setting, and ParticipantsSoluble c-Metwas 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. MAIN OUTCOMES AND MEASURES 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 progressivemetastatic disease showed further increases in sc-Met level, whereas stable patients did not. CONCLUSIONS AND RELEVANCE The present pilot study suggests that sc-Met should be further exploited as a biomarker for monitoring of uveal melanoma.

Original languageEnglish
Pages (from-to)1013-1021
Number of pages9
JournalJAMA Ophthalmology
Volume133
Issue number9
DOIs
Publication statusPublished - Sep 1 2015

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Biomarkers
Serum
Tissue Donors
Conditioned Culture Medium
Uveal melanoma
Heterografts
ROC Curve
Area Under Curve
Cell Line
Neoplasms
Oncogene Proteins
L-Lactate Dehydrogenase
Melanoma
Cell Culture Techniques
Enzyme-Linked Immunosorbent Assay
Outcome Assessment (Health Care)
Sensitivity and Specificity

ASJC Scopus subject areas

  • Ophthalmology
  • Medicine(all)

Cite this

Potential role of soluble c-met as a new Candidate biomarker of metastatic uveal melanoma. / Barisione, Gaia; Fabbi, Marina; Gino, Alice; Queirolo, Paola; Orgiano, Laura; Spano, Laura; Picasso, Virginia; Pfeffer, Ulrich; Mosci, Carlo; Jager, Martine J.; Ferrini, Silvano; Gangemi, Rosaria.

In: JAMA Ophthalmology, Vol. 133, No. 9, 01.09.2015, p. 1013-1021.

Research output: Contribution to journalArticle

Barisione, Gaia ; Fabbi, Marina ; Gino, Alice ; Queirolo, Paola ; Orgiano, Laura ; Spano, Laura ; Picasso, Virginia ; Pfeffer, Ulrich ; Mosci, Carlo ; Jager, Martine J. ; Ferrini, Silvano ; Gangemi, Rosaria. / Potential role of soluble c-met as a new Candidate biomarker of metastatic uveal melanoma. In: JAMA Ophthalmology. 2015 ; Vol. 133, No. 9. pp. 1013-1021.
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AU - Barisione, Gaia

AU - Fabbi, Marina

AU - Gino, Alice

AU - Queirolo, Paola

AU - Orgiano, Laura

AU - Spano, Laura

AU - Picasso, Virginia

AU - Pfeffer, Ulrich

AU - Mosci, Carlo

AU - Jager, Martine J.

AU - Ferrini, Silvano

AU - Gangemi, Rosaria

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N2 - Importance 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. Design, Setting, and ParticipantsSoluble c-Metwas 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. MAIN OUTCOMES AND MEASURES 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 progressivemetastatic disease showed further increases in sc-Met level, whereas stable patients did not. CONCLUSIONS AND RELEVANCE The present pilot study suggests that sc-Met should be further exploited as a biomarker for monitoring of uveal melanoma.

AB - Importance 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. Design, Setting, and ParticipantsSoluble c-Metwas 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. MAIN OUTCOMES AND MEASURES 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 progressivemetastatic disease showed further increases in sc-Met level, whereas stable patients did not. CONCLUSIONS AND RELEVANCE The present pilot study suggests that sc-Met should be further exploited as a biomarker for monitoring of uveal melanoma.

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