A Prognostic Gene Signature Expressed in Primary Cutaneous Melanoma: Synergism With Conventional Staging

Abstract

Background Current clinico-pathological American Joint Committee on Cancer (AJCC) staging of primary cutaneous melanoma is limited in its ability to determine clinical outcome, and complementary biomarkers are not available for routine prognostic assessment. We therefore adapted a gene signature, previously identified in fresh-frozen (FF) melanomas and adjacent stroma, to formalin-fixed paraffin-embedded (FFPE) melanomas. The aim was to develop a gene expression profiling (GEP) score to define patient survival probability at the time of first diagnosis. Methods Expression of 11 FF melanoma signature genes was quantified by reverse transcription polymerase chain reaction in an FFPE melanoma training cohort (n = 125), corresponding to the combined FF melanoma training and validation cohorts. The resulting GEP score was validated technically and clinically in an independent FFPE melanoma cohort (n = 211). All statistical tests were two-sided. Results We identified a prognostic eight-gene signature in the tumor area (tumor and adjacent tissue) of AJCC stage I–III melanomas. A signature-based GEP score correlated with melanoma-specific survival (MSS; Kaplan-Meier analysis: P < .0001) was independent of tumor stage (multivariable regression analysis: P = .0032) and stroma content (<5%–90%) and complemented conventional AJCC staging (receiver operating characteristic curve analysis: area under the curve = 0.91). In the clinical validation cohort, the GEP score remained statistically significant (P = .0131) in a multivariable analysis accounting for conventional staging. The GEP score was technically robust (reproducibility: 93%; n = 84) and clinically useful, as a binary as well as a continuous score, in predicting stage-specific patient MSS. Conclusions The GEP score is a clinically significant prognostic tool, contributes additional information regarding the MSS of melanoma patients, and complements conventional staging.

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

“…Gene signature classification was significantly correlated with Breslow thickness, ulceration, mitotic rate, and melanoma‐specific survival. Other gene expression profiles for melanoma have been described and reported additive prognostic values in addition to clinical and histological factors . MicroRNA‐21, ‐137, and ‐203 have been evaluated in primary melanoma tissues and found to be independently associated with survival .…”

Clinical validation of a prognostic 11-gene expression profiling score in prospectively collected FFPE tissue of patients with AJCC v8 stage II cutaneous melanoma

“…GEPS determination was previously described in detail [21]. Briefly, total RNA was prepared from whole FFPE tissue sections using RNeasy FFPE Kits (Qiagen, Hilden, Germany).…”

“…The MelaGenixâ score can be used as a binary or continuous variable to stratify clinical outcomes within each of the AJCC stages I, II and III [21].…”

“…This cut-off value zero was chosen in order to reliably detect patients with clearly above-average MSS (10-y MSS > 90%). The algorithm previously defined [21]…”

Überdiagnose von Melanomen – Ursachen, Konsequenzen und Lösungsansätze

“…Zur Unterscheidung von Melanomen und Nävi eignen sie sich damit nur sehr eingeschränkt [64]. Derzeit sind Gensignatur-basierte Prognosetests für das maligne Melanom in der Entwicklung, die die Präzision zur Einschätzung der Metastasenbildung, des Rückfallrisikos beziehungsweise der Lebenserwartung über die "klassischen" Prognosefaktoren hinaus erhöhen könnten [65,66]. Sie haben in ersten Studien vielversprechende Ergebnisse erbracht, müssen aber noch weiter untersucht werden.…”