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Diminished levels of the soluble form of RAGE are related to poor survival in malignant melanoma


Wagner, N B; Weide, B; Reith, M; Tarnanidis, K; Kehrel, C; Lichtenberger, R; Pflugfelder, A; Herpel, E; Eubel, J; Ikenberg, K; Busch, C; Holland-Letz, T; Naeher, H; Garbe, C; Umansky, V; Enk, A; Utikal, J; Gebhardt, C (2015). Diminished levels of the soluble form of RAGE are related to poor survival in malignant melanoma. International Journal of Cancer, 137(11):2607-2617.

Abstract

RAGE is a central driver of tumorigenesis by sustaining an inflammatory tumor microenvironment. This study links the soluble forms of RAGE (sRAGE and esRAGE) with clinical outcome of melanoma patients. Moreover, tissue expression of RAGE was analyzed using immunohistochemistry on two independent tissue microarrays (TMA) containing 35 or 257 primary melanomas, and 41 or 22 benign nevi, respectively. Serum concentrations of sRAGE and esRAGE were measured in 229 stage III-IV patients using ELISA and plasma concentrations of sRAGE were analyzed in an independent second cohort with 173 samples of stage I-IV patients. In this cohort, three well-described SNPs in the RAGE gene were analyzed. RAGE protein expression was highly upregulated in primary melanomas compared to benign nevi in the two TMA (p < 0.001 and p = 0.005) as well as in sun-exposed melanomas (p = 0.046). sRAGE and esRAGE were identified as prognostic markers for survival as diminished sRAGE (p = 0.034) and esRAGE (p = 0.012) serum levels correlated with poor overall survival (OS). Multivariate Cox regression analysis showed that diminished serum sRAGE was independently associated with poor survival (p = 0.009). Moreover, diminished sRAGE was strongly associated with impaired OS in the second cohort (p < 0.001). Multivariate Cox regression analysis including the investigated SNPs revealed an independent correlation of the two interacting promoter SNPs with impaired OS. In conclusion, the soluble forms of RAGE and variants in its genetic locus are prognostic markers for survival in melanoma patients with high risk for progression.

RAGE is a central driver of tumorigenesis by sustaining an inflammatory tumor microenvironment. This study links the soluble forms of RAGE (sRAGE and esRAGE) with clinical outcome of melanoma patients. Moreover, tissue expression of RAGE was analyzed using immunohistochemistry on two independent tissue microarrays (TMA) containing 35 or 257 primary melanomas, and 41 or 22 benign nevi, respectively. Serum concentrations of sRAGE and esRAGE were measured in 229 stage III-IV patients using ELISA and plasma concentrations of sRAGE were analyzed in an independent second cohort with 173 samples of stage I-IV patients. In this cohort, three well-described SNPs in the RAGE gene were analyzed. RAGE protein expression was highly upregulated in primary melanomas compared to benign nevi in the two TMA (p < 0.001 and p = 0.005) as well as in sun-exposed melanomas (p = 0.046). sRAGE and esRAGE were identified as prognostic markers for survival as diminished sRAGE (p = 0.034) and esRAGE (p = 0.012) serum levels correlated with poor overall survival (OS). Multivariate Cox regression analysis showed that diminished serum sRAGE was independently associated with poor survival (p = 0.009). Moreover, diminished sRAGE was strongly associated with impaired OS in the second cohort (p < 0.001). Multivariate Cox regression analysis including the investigated SNPs revealed an independent correlation of the two interacting promoter SNPs with impaired OS. In conclusion, the soluble forms of RAGE and variants in its genetic locus are prognostic markers for survival in melanoma patients with high risk for progression.

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3 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Surgical Pathology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:27 May 2015
Deposited On:08 Jul 2015 10:18
Last Modified:28 May 2016 00:00
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0020-7136
Additional Information:This is the peer reviewed version of the following article: Wagner N B et al: Diminished levels of the soluble form of RAGE are related to poor survival in malignant melanoma, International Journal of Cancer, which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1002/ijc.29619/. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
Publisher DOI:https://doi.org/10.1002/ijc.29619
PubMed ID:26018980
Permanent URL: https://doi.org/10.5167/uzh-111322

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