title: Diminished levels of the soluble form of RAGE are related to poor survival in malignant melanoma.
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.
authors.affiliation: Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
authors.forename: Nikolaus B
authors.initials: NB
authors.lastname: Wagner
authors.affiliation: Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Weide
authors.affiliation: Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Reith
authors.affiliation: Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Tarnanidis
authors.affiliation: Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
authors.forename: Coretta
authors.initials: C
authors.lastname: Kehrel
authors.affiliation: Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
authors.forename: Ramtin
authors.initials: R
authors.lastname: Lichtenberger
authors.affiliation: Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Pflugfelder
authors.affiliation: NCT Tissue Bank, National Center of Tumor Diseases (NCT), Heidelberg, Germany.|Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Herpel
authors.affiliation: Department of Dermatology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Eubel
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Kristian
authors.initials: K
authors.lastname: Ikenberg
authors.affiliation: Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Busch
authors.affiliation: Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Holland-Letz
authors.affiliation: Department of Dermatology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Naeher
authors.affiliation: Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Garbe
authors.affiliation: Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
authors.forename: Viktor
authors.initials: V
authors.lastname: Umansky
authors.affiliation: Department of Dermatology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Enk
authors.affiliation: Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Utikal
authors.affiliation: Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Gebhardt
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics; D055815:Young Adult
chemical_list: C000593871:AGER protein, human; D014408:Biomarkers, Tumor; D000067759:Receptor for Advanced Glycation End Products
keywords: RAGE; biomarker; melanoma; overall survival; sRAGE