Cross-platform comparison of independent datasets identifies an immune signature associated with improved survival in metastatic melanoma

Abstract

// Ricardo D. Lardone 1 , Seema B. Plaisier 1 , Marian S. Navarrete 1 , Jaime M. Shamonki 2 , John R. Jalas 3 , Peter A. Sieling 1, * , Delphine J. Lee 1, * 1 Department of Translational Immunology, Dirks/Dougherty Laboratory for Cancer Research, John Wayne Cancer Institute, Santa Monica, CA 90404, USA 2 California Cryobank, Los Angeles, CA 90025, USA 3 Department of Pathology at Providence Saint John’s Health Center, Santa Monica, CA 90404, USA * These authors have contributed equally to this work Correspondence to: Delphine J. Lee, e-mail: leedj@jwci.org Ricardo D. Lardone, e-mail: rlardone@gmail.com Keywords: metastatic melanoma, tumor immunology, bioinformatics, rank-rank hypergeometric overlap, B cells Received: November 02, 2015     Accepted: January 29, 2016     Published: February 13, 2016 ABSTRACT Platform and study differences in prognostic signatures from metastatic melanoma (MM) gene expression reports often hinder consensus arrival. We performed survival/outcome-based pairwise comparisons of three independent MM gene expression profiles using the threshold-free algorithm rank-rank hypergeometric overlap analysis (RRHO). We found statistically significant overlap for genes overexpressed in favorable outcome (FO) groups, but no overlap for poor outcome (PO) groups. This “favorable outcome signature” (FOS) of 228 genes coinciding on all three overlapping gene lists showed immune function predominated in FO MM. Surprisingly, specific cell signature-enrichment analysis showed B cell-associated genes enriched in FO MM, along with T cell-associated genes. Higher levels of B and T cells (p<0.05) and their relative proximity (p<0.05) were detected in FO-to-PO tumor comparisons from an independent MM patients cohort. Finally, expression of FOS in two independent Stage III MM tumor datasets correctly predicted clinical outcome in 12/14 and 44/70 patients using a weighted gene voting classifier (area under the curve values 0.96 and 0.75, respectively). This RRHO-based, cross-study analysis emphasizes the RRHO approach power, confirms T cells relevance for prolonged MM survival, supports a favorable role for B cells in anti-melanoma immunity, and suggests B cells potential as means of intervention in melanoma treatment.