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=3×10−4), Breslow thickness (P=5×10−10), ulceration (P=9.x10−8) and mitotic rate (P=3×10−7), 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.

Prospective validation of the prognostic 31‐gene expression profiling test in primary cutaneous melanoma

“…Nsengimana et al performed an independent validation of a whole-genome mRNA profiling classification. 17,18 Archival tumor tissues from 300 patients (224 primary and 76 metastatic) were evaluated. Gene signature classification was significantly correlated with Breslow thickness, ulceration, mitotic rate, and melanoma-specific survival.…”

The proportion cured of patients diagnosed with Stage III–IV cutaneous malignant melanoma in Sweden 1990–2007: A population‐based study

“…microscopic ulceration . A recent study showed that absence of primary CMM ulceration was independently associated with longer progression‐free survival (PFS) but not overall survival (OS) in Stage IV CMM‐patients treated with MAPK‐inhibitors . Ulceration status has earlier also been correlated to treatment outcome, i.e.…”

Consensus of Melanoma Gene Expression Subtypes Converges on Biological Entities

“…The "High-Immune" group was distinguished by elevated expression of immune genes, the "Normal-like" group by genes expressed in surrounding normal cells, the "MITF-high Pigmentation" and the "MITF-low Proliferative" groups displayed increased expression of cell-cycle genes, while the "MITF-low Proliferative" group had decreased expression of melanocyte differentiation genes. These subtypes were derived in stage IV tumors (Jönsson et al, 2010), but have since been recapitulated and firmly established in primary tumors (Harbst et al, 2012;Nsengimana et al, 2015) and stage III tumors (Cirenajwis et al, 2015). In 2015, the TCGA landmark study reported three melanoma gene expression subtypes (Cancer Genome Atlas Network, 2015).…”

“…The TCGA "Keratin" group consisted predominantly of the Lund "Normal-like" and M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 4 "MITF-high Pigmentation" groups, while the TCGA group "MITF-low" contained 76% of the Lund "MITF-low Proliferative" tumors. Next, we applied the TCGA subtypes to the published Bergen (Jönsson et al, 2010)(GSE33153), Lund (Cirenajwis et al, 2015)(GSE65904) and Leeds (Nsengimana et al, 2015)(E-MTAB-4725) datasets, which have pre-existing Lund subtype classifications. The fraction of subtypes differed between datasets, in accordance to specimen site.…”