DNA alteration-based classification of uveal melanoma gives better prognostic stratification than immune infiltration, which has a neutral effect in high-risk group.

Deepti Narasimhaiah,Miikka Vikkula,Marco Munda,Diane Damotte,Romain Remark,Catherine Legrand,Patrick De Potter,Catherine Godfraind,Pierre G Coulie

doi:10.1002/cam4.2122

Abstract

BackgroundIn uveal melanomas, immune infiltration is a marker of poor prognosis. This work intended to decipher the biological characteristics of intra‐tumor immune population, compare it to other established biomarkers and to patients' outcome.MethodsPrimary, untreated, and mainly large uveal melanomas with retinal detachment were analyzed using: transcriptomic profiling (n = 15), RT‐qPCR (n = 36), immunohistochemistry (n = 89), Multiplex Ligation‐dependent Probe Amplification (MLPA) for copy number alterations (CNA) analysis (n = 89), array‐CGH (n = 17), and survival statistics (n = 86).ResultsGene expression analysis divided uveal melanomas into two groups, according to the IFNγ/STAT1‐IRF1 pathway activation. Tumors with IFNγ‐signature had poorer prognosis and showed increased infiltration of CD8+ T lymphocytes and macrophages. Cox multivariate analyses of immune cell infiltration with MLPA data delineated better prognostic value for three prognostic groups (three‐tier stratification) than two (two‐tier stratification). CNA‐based model comprising monosomy 3, 8q amplification, and LZTS1and NBL1 deletions emerged as the best predictor for disease‐free survival. It outperformed immune cell infiltration in receiver operating characteristic curves. The model that combined CNA and immune infiltration defined risk‐groups according to the number of DNA alterations. Immune cell infiltration was increased in the high‐risk group (73.7%), where it did not correlate with patient survival, while it was associated with poorer outcome in the intermediate risk‐group.ConclusionsHigh degree of immune cell infiltration occurs in a subset of uveal melanomas, is interferon‐gamma‐related, and associated with poor survival. It allows for two‐tier stratification, which is prognostically less efficient than a three‐tier one. The best prognostic stratification is by CNA model with three risk‐groups where immune cell infiltration impacts only some subgroups.

Highlights

The omics era has ushered in a better understanding of the molecular underpinnings of tumors that have resulted in identification of molecular subgroups within each cancer type
In addition to validating the present copy number alterations (CNA) model comprising monosomy 3 (M3), 8q gain, LZTS1, and NBL1 deletions on the The Cancer Genome Atlas (TCGA) data, the mutations associated with the tumors in high, intermediate and low‐risk groups were assessed
External validation of the impact of immune cell infiltration The TCGA uveal melanomas were classified into immune‐ high and immune‐low categories based on the combined tumor‐infiltrating‐lymphocyte density and tumor‐associated‐ macrophage density (Supplementary Methods, Table M4)

Summary

| INTRODUCTION

The omics era has ushered in a better understanding of the molecular underpinnings of tumors that have resulted in identification of molecular subgroups within each cancer type This has led to development of treatments targeting the underlying genetic alterations with better patient stratification and improved survival rates in many solid tumors. There are lacunae with regard to the role of immune infiltrate as a biomarker, and its prognostic relevance when compared to genetic and clinical parameters. We addressed these shortcomings by combining copy number alterations with transcriptomic profiling, expression of selected immune genes, and immunohistochemistry for immune cell infiltration. We have applied these methods to generate risk‐stratification models on a series of 91 primary, untreated, large choroidal and ciliochoroidal melanomas, most of them with retinal detachment

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION