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

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

Publication date: Apr 25, 2019

In 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.

Primary, 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).

Gene 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.

High 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.

Narasimhaiah, D., Legrand, C., Damotte, D., Remark, R., Munda, M., De Potter, P., Coulie, P.G., Vikkula, M., and Godfraind, C. DNA alteration-based classification of uveal melanoma gives better prognostic stratification than immune infiltration, which has a neutral effect in high-risk group. 22432. 2019 Cancer Med.

Concepts Keywords
Array CGH Gene expression
Biomarkers J. William Harbour
CD8 DecisionDx-UM
Immunohistochemistry RTT
Interferon Gamma Health
Lymphocytes Neoplasms
Macrophages Medicine
Melanomas Uveal melanoma
Monosomy Melanoma
Multivariate Tumors
Prognosis Classification uveal melanoma
QPCR Predictor disease
Receiver Operating Characteristic Risk groups
Retinal Detachment Prognostic prognostic groups
RT Tumor
STAT1 Subset uveal melanomas
Stratification
Transcriptomic
Tumor
Uveal Melanoma

Semantics

Type Source Name
gene UNIPROT BEST1
gene UNIPROT NBL1
disease MESH monosomy
gene UNIPROT COX5A
gene UNIPROT COX8A
gene UNIPROT CD8A
gene UNIPROT CPOX
gene UNIPROT IRF1
gene UNIPROT STAT1
pathway BSID Gene Expression
disease DOID retinal detachment
disease MESH retinal detachment
gene UNIPROT LARGE1
disease MESH tumor
disease MESH melanomas
drug DRUGBANK Tropicamide
disease DOID uveal melanoma
disease MESH uveal melanoma

Original Article

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