Sentinel Lymph Node Gene Expression Signature Predicts Recurrence-Free Survival in Cutaneous Melanoma

SIMPLE SUMMARY: Despite a negative SLN status, patients with Stage IIB/IIC melanoma demonstrate poor melanoma-specific survival when compared to Stage IIIA patients. In this study, we hypothesized that a molecular profile at the level of the SLN would provide potential insights into risk of disease recurrence and serve as a prognostic biomarker of patient outcomes regardless of the presence of SLN melanoma metastases. Gene expression profiling was performed on SLN biopsies using U133A 2.0 Affymetrix gene chips. Our study suggests a novel 12-gene SLN signature risk score which may predict disease recurrence in cutaneous melanoma patients managed with wide excision of the primary tumor and SLN biopsy. ABSTRACT: We sought to develop a sentinel lymph node gene expression signature score predictive of disease recurrence in patients with cutaneous melanoma. Gene expression profiling was performed on SLN biopsies using U133A 2.0 Affymetrix gene chips. The top 25 genes associated with recurrence-free survival (RFS) were selected and a penalized regression function was used to select 12 genes with a non-zero coefficient. A proportional hazards regression model was used to evaluate the association between clinical covariates, gene signature score, and RFS. Among the 45 patients evaluated, 23 (51%) had a positive SLN. Twenty-one (46.7%) patients developed disease recurrence. For the top 25 differentially expressed genes (DEG), 12 non-zero penalized coefficients were estimated (CLGN, C1QTNF3, ADORA3, ARHGAP8, DCTN1, ASPSCR1, CHRFAM7A, ZNF223, PDE6G, CXCL3, HEXIM1, HLA-DRB). This 12-gene signature score was significantly associated with RFS (p < 0.0001) and produced a bootstrap C index of 0.888. In univariate analysis, Breslow thickness, presence of primary tumor ulceration, SLN positivity were each significantly associated with RFS. After simultaneously adjusting for these prognostic factors in relation to the gene signature, the 12-gene score remained a significant independent predictor for RFS (p < 0.0001). This SLN 12-gene signature risk score is associated with melanoma recurrence regardless of SLN status and may be used as a prognostic factor for RFS.