title: Independent replication of a melanoma subtype gene signature and evaluation of its prognostic value and biological correlates in a population cohort.
abstract: Development and validation of robust molecular biomarkers has so far been limited in melanoma research. In this paper we used a large population-based cohort to replicate two published gene signatures for melanoma classification. We assessed the signatures prognostic value and explored their biological significance by correlating them with factors known to be associated with survival (vitamin D) or etiological routes (nevi, sun sensitivity and telomere length). Genomewide microarray gene expressions were profiled in 300 archived tumors (224 primaries, 76 secondaries). The two gene signatures classified up to 96% of our samples and showed strong correlation with melanoma specific survival (P=3 x 10(-4)), Breslow thickness (P=5 x 10(-10)), ulceration (P=9.x10-8) and mitotic rate (P=3 x 10(-7)), adding prognostic value over AJCC stage (adjusted hazard ratio 1.79, 95%CI 1.13-2.83), as previously reported. Furthermore, molecular subtypes were associated with season-adjusted serum vitamin D at diagnosis (P=0.04) and genetically predicted telomere length (P=0.03). Specifically, molecular high-grade tumors were more frequent in patients with lower vitamin D levels whereas high immune tumors came from patients with predicted shorter telomeres. Our data confirm the utility of molecular biomarkers in melanoma prognostic estimation using tiny archived specimens and shed light on biological mechanisms likely to impact on cancer initiation and progression.
authors: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
authors: Jérémie
authors: J
authors: Nsengimana
authors: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
authors: Jon
authors: J
authors: Laye
authors: National Heart and Lung Institute, Imperial College, London, UK.
authors: Anastasia
authors: A
authors: Filia
authors: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
authors: Christy
authors: C
authors: Walker
authors: Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
authors: Rosalyn
authors: R
authors: Jewell
authors: Department of Pathology, University Hospitals Leuven, Leuven, Belgium.|European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group, Brussels, Belgium.
authors: Joost J
authors: JJ
authors: Van den Oord
authors: Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
authors: Pascal
authors: P
authors: Wolter
authors: School of Medicine, University of Nottingham, Nottingham, UK.|European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group, Brussels, Belgium.
authors: Poulam
authors: P
authors: Patel
authors: Department of Dermatology, Essen University Hospital, Essen, and German Consortium of Translational Cancer Research (DKTK), Heidelberg, Germany.
authors: Antje
authors: A
authors: Sucker
authors: Department of Dermatology, Essen University Hospital, Essen, and German Consortium of Translational Cancer Research (DKTK), Heidelberg, Germany.|European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group, Brussels, Belgium.
authors: Dirk
authors: D
authors: Schadendorf
authors: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors: Göran B
authors: GB
authors: Jönsson
authors: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
authors: D Timothy
authors: DT
authors: Bishop
authors: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
authors: Julia
authors: J
authors: Newton-Bishop
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000145:classification / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010641:Phenotype; D011237:Predictive Value of Tests; D012372:ROC Curve; D015203:Reproducibility of Results; D012307:Risk Factors; D012621:Seasons; D012878:Skin Neoplasms / Q000145:classification / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D016615:Telomere / Q000235:genetics; D059506:Telomere Shortening; D013997:Time Factors; D014807:Vitamin D / Q000097:blood; D014808:Vitamin D Deficiency / Q000097:blood / Q000401:mortality; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D014807:Vitamin D
keywords: AJCC stage; ROC analysis; molecular subtype; telomere length; vitamin D