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. 2015 May 10;6(13):11683-93.
doi: 10.18632/oncotarget.3549.

Independent replication of a melanoma subtype gene signature and evaluation of its prognostic value and biological correlates in a population cohort

Jérémie Nsengimana  1 , Jon Laye  1 , Anastasia Filia  2 , Christy Walker  1 , Rosalyn Jewell  3 , Joost J Van den Oord  4   5 , Pascal Wolter  6 , Poulam Patel  7   5 , Antje Sucker  8 , Dirk Schadendorf  8   5 , Göran B Jönsson  9 , D Timothy Bishop  1 , Julia Newton-Bishop  1
Affiliations

Independent replication of a melanoma subtype gene signature and evaluation of its prognostic value and biological correlates in a population cohort

Jérémie Nsengimana et al. Oncotarget. .

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.

Keywords: AJCC stage; ROC analysis; molecular subtype; telomere length; vitamin D.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1. A. Full dataset classification using the 4-class signature and Kaplan-Meir survival curves using primary tumors from LMC (melanoma specific and relapse free survival)
HI=high immune, NL=normal-like, PG=pigmentation, PRF=proliferative group. B. Full dataset classification using the 2-grade signature and Kaplan-Meir survival curves using primary tumors from LMC (melanoma specific and relapse free survival). Green = downregulation, red=upregulation.
Figure 2
Figure 2. Top panel: Melanoma specific survival of patients with primary tumors from the two datasets
Bottom panel: Melanoma specific survival of all patients (primary and metastatic tumors) in the two datasets. Left and right respectively for the 4-class and the 2-grade signatures. HI=high immune, NL=normal-like, PG=pigmentation, PRF=proliferative group.
Figure 3
Figure 3. Area under the ROC curves for relapse, death from melanoma and all-causes death
See this image and copyright information in PMC

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