Improved survival in metastatic melanoma is associated with immune genes expressed at the site of disease

LARDONE, RICARDO D; PLAISIER, SEEMA; SIELING, PETER A; LEE, DELPHINE J

Atlanta

Congreso; 2015 Annual Meeting of the Society for Investigative Dermatology; 2015

Society for Investigative Dermatology

Metastatic melanoma (MM) has a median survival rate of less than one year. Thus, a more thorough knowledge of biological factors linked to MM survival should direct more effective outcome prediction and therapy development. To increase the sensitivity of finding conserved gene expression signatures, we used Rank-Rank Hypergeometric Overlap analysis (RRHO), a threshold-free algorithm that compares two independent high-throughput gene expression profiles and identifies an overlapping gene set with greatest statistical significance. RRHO uses genome wide comparisons based on ranked gene expression changes instead of raw expression values or fold-changes, which are more responsive to experimental differences between patient studies. We performed RRHO pairwise comparisons of three independent, publicly available MM gene expression profiles, examining common signatures in outcome/survival gene expression. Comparing groups based on patient outcome, pairwise RRHO comparisons showed no statistically significant overlap of genes overexpressed in tumors from patients with poor survival/outcome. In contrast, we found overlap among genes overexpressed in favorable outcome groups (number of overlapping genes/hypergeometric overlap p-values: 394/10−19; 1423/10−57; 887/10−89). Pathways analysis of each overlapping gene list showed immune function was repeatedly the predominant functional group enriched in favorable outcome; 228 genes coincided on all three overlapping gene lists. In fact, the expression of this subset of 228 genes in an independent set of Stage III MM tumors correctly predicted clinical outcome in 12/14 patients. We also used Gene Enrichment Profiler to analyze the 228 genes for enrichment of specific cell signatures. Surprisingly, B cell-associated genes were enriched in those MM subjects with favorable outcomes, in addition to T and NK cell-associated genes. This cross-study analysis suggests the power of the RRHO approach and indicates a role for anti-melanoma immunity in MM survival.