Prognostic Gene Expression, Stemness and Immune Microenvironment in Pediatric Tumors.

David Stahl,Ines Gütgemann,Rainer Knoll,Andrew J Gentles,Christian Vokuhl,Andreas Buness

doi:10.3390/cancers13040854

Abstract

Simple SummaryTumors in children and young adults are rare and diagnostically distinct from those occurring in older patients. They frequently arise from developing cells, resembling stem cells, which may explain some of the clinical and biologic differences observed. The aim of this retrospective transcriptome study was to investigate the prognostic landscape, immune tumor microenvironment (TME) and stemness in a cohort of 4068 transcriptomes of such tumors. We find that patients’ prognosis correlates with distinct gene expression patterns similar to adult tumor types. Stemness defined by a computational stemness score (mRNAsi) correlates with clinical and molecular parameters that is distinct for each tumor type. In Wilms tumors that recapitulate normal kidney development microscopically, stemness correlates with distinct patterns of immune cell infiltration by transcriptome analysis and by cell localization in tumor tissue.Pediatric tumors frequently arise from embryonal cells, often displaying a stem cell-like (“small round blue”) morphology in tissue sections. Because recently “stemness” has been associated with a poor immune response in tumors, we investigated the association of prognostic gene expression, stemness and the immune microenvironment systematically using transcriptomes of 4068 tumors occurring mostly at the pediatric and young adult age. While the prognostic landscape of gene expression (PRECOG) and infiltrating immune cell types (CIBERSORT) is similar to that of tumor entities occurring mainly in adults, the patterns are distinct for each diagnostic entity. A high stemness score (mRNAsi) correlates with clinical and morphologic subtype in Wilms tumors, neuroblastomas, synovial sarcomas, atypical teratoid rhabdoid tumors and germ cell tumors. In neuroblastomas, a high mRNAsi is associated with shortened overall survival. In Wilms tumors a high mRNAsi correlates with blastemal morphology, whereas tumors with predominant epithelial or stromal differentiation have a low mRNAsi and a high percentage of M2 type macrophages. This could be validated in Wilms tumor tissue (n = 78). Here, blastemal areas are low in M2 macrophage infiltrates, while nearby stromal differentiated areas contain abundant M2 macrophages, suggesting local microanatomic regulation of the immune response.

Highlights

Stemness, defined as the potential to self-renew and differentiate from a cell of origin, is a feature of precursor cells in the developing embryo [1]
Shared genes by all cancers (Figure 1b) with an adverse prognosis, such as MAD2L1, CCNB1, NUF2 and UBE2C, were associated with gene ontology (GO) enrichment analysis terms related to proliferation, replication and mitosis, similar to adult tumors [27] (Figure 1c)
Differences were observed in top adverse and favorable genes expressed per tumor entity

Summary

Introduction

Stemness, defined as the potential to self-renew and differentiate from a cell of origin, is a feature of precursor cells in the developing embryo [1]. Mesenchymal and induced pluripotent stem cells possess immune modulatory properties, while resistance to immune-mediated destruction is an intrinsic feature of quiescent adult tissue stem cells [8] and cancer stem cells [9,10,11]. As these findings imply that immune control may be improved in tumors by targeting the stemness phenotype, we were interested to examine the relation of stemness and immune tumor microenvironment (immune TME) in pediatric tumors in a more systematic fashion

Methods

Results

Discussion

Conclusion