Clinical Research Papers:
Independent replication of a melanoma subtype gene signature and evaluation of its prognostic value and biological correlates in a population cohort
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Jérémie Nsengimana1, Jon Laye1, Anastasia Filia2, Christy Walker1, Rosalyn Jewell3, Joost J. Van den Oord4,9, Pascal Wolter5, Poulam Patel6,9, Antje Sucker7, Dirk Schadendorf7,9, Göran B. Jönsson8, D. Timothy Bishop1 and Julia Newton-Bishop1
1 Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK
2 National Heart and Lung Institute, Imperial College, London, UK
3 Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK
4 Department of Pathology, University Hospitals Leuven, Leuven, Belgium
5 Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium
6 School of Medicine, University of Nottingham, Nottingham, UK
7 Department of Dermatology, Essen University Hospital, Essen, and German Consortium of Translational Cancer Research (DKTK), Heidelberg, Germany
8 Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden
9 European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group, Brussels, Belgium
Jérémie Nsengimana, email:
Keywords: molecular subtype, AJCC stage, ROC analysis, vitamin D, telomere length
Received: January 12, 2015 Accepted: February 10, 2015 Published: March 12, 2015
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=3x10-4), Breslow thickness (P=5x10-10), ulceration (P=9.x10-8) and mitotic rate (P=3x10-7), 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.
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