Validation, in silico and in vitro, of a gene-signature based risk score in cutaneous melanoma.

Abstract

9560 Background: Melanoma staging, as defined by the American Joint Committee on Cancer (AJCC), is limited in its ability to predict outcome. We have previously identified and validated a prognostic gene signature expressed in primary cutaneous melanoma and adjacent stroma. The signature comprises seven protective genes (down-regulated with tumor progression) and one risk-associated gene (up-regulated). A signature-based risk score independently predicts patient survival, across AJCC stages IA-IIIC, in formalin-fixed, paraffin-embedded (FFPE) melanomas (training cohort, n = 125; p = 0.0003, hazard ratio 1.85). The score has been validated in 206 melanomas, selected to be significantly mis-prognosticated by AJCC staging regarding patient survival (40.8% mis-prognostication). In this cohort, the score outperforms AJCC staging (p = 0.0005, hazard ratio 1.41 vs. p = n.s.), correcting 34.9% of AJCC-based mis-prognostications. Methods: Here, we report twofold external validation of the risk score, (i) prognostic performance in silico using the SurvExpress web tool (Aguirre-Gamboa et al., 2013), and (ii) technical performance in vitro(Dermatologikum Hamburg; IMGM Munich) . Results: (i) Kaplan Meier analysis and log-rank testing demonstrated that all signature genes combined predicted survival in four different cohorts of metastatic melanoma (from GEO Expression Omnibus or Cancer Genome Atlas; cohorts dichotomized at the median): see table. (ii) The risk score was re-analyzed in melanomas of the training cohort (n=69). The overall concordance of duplicate determinations was 90% (average scores of 1.12 ± 0.14 and 0.97 ± 0.14). Conclusions: In conclusion, we have validated a signature-based FFPE melanoma risk score, complementary to AJCC staging in predicting outcome: (i) Signature genes predicted patient survival in silico(n=449) (ii) The risk score proved to be reproducible and technically robust in vitro. The score improves risk stratification and decision making in melanoma, particularly regarding new adjuvant therapies. [Table: see text]