Systems analysis of barrier molecule and ARNT-related gene expression regulation in melanoma

Background: We have identified, in melanomas, a set of genes encoding proteins that mediate mechanical barrier function in normal skin (barrier molecule genes, BMGs) and whose overexpression is associated with decreased immune signatures and shorter patient survival. The most overexpressed of these,...

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Main Authors: Katie M. Leick, Joseph M. Obeid, Stefan Bekiranov, Craig L. Slingluff
Format: Article
Language:English
Published: Taylor & Francis Group 2019-12-01
Series:OncoImmunology
Subjects:
Online Access:http://dx.doi.org/10.1080/2162402X.2019.1665978
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spelling doaj-7cf98e6ff74946888f5c4f92f62188eb2020-11-25T03:28:12ZengTaylor & Francis GroupOncoImmunology2162-402X2019-12-0181210.1080/2162402X.2019.16659781665978Systems analysis of barrier molecule and ARNT-related gene expression regulation in melanomaKatie M. Leick0Joseph M. Obeid1Stefan Bekiranov2Craig L. Slingluff3University of VirginiaUniversity of VirginiaUniversity of VirginiaUniversity of VirginiaBackground: We have identified, in melanomas, a set of genes encoding proteins that mediate mechanical barrier function in normal skin (barrier molecule genes, BMGs) and whose overexpression is associated with decreased immune signatures and shorter patient survival. The most overexpressed of these, filaggrin (FLG), is expressed on chromosome 1q21.3, which also encodes genes of the epidermal differentiation complex (EDC). EDC genes may be regulated by the transcription factors (TFs) AHR and ARNT. We hypothesized that ARNT-related genes would be expressed concordantly with BMG and EDC genes, inversely associated with immune signatures, and enhanced by 1q21.3 copy gain. Methods: Gene expression data from human melanomas in the Cancer Genome Atlas (TCGA), and a validation GEO dataset were evaluated, with copy number profiles from TCGA. Expression of Th1 immune genes and BMG/EDCs at 1q21.3 was visualized using clustered copy number and mRNA profiles. Associations of clusters and 1q21.3 copy number with patient survival and mRNA expression were assessed using Kaplan Meier curves, log-rank tests, and Wilcoxon rank sum tests. Results: BMGs are concordantly expressed with EDC genes. Clustering divided tumors into 4 categories: (1) ImmuneHI, (2) BMG/EDCHI, (3) ARNTHI, (4) Mixed. Both ARNTHI and BMG/EDCHI tumors had low immune signatures and significantly shortened survival. KLF4 and FOXF2 are putative TFs that may regulate these genes. Conclusions: ARNTHI tumors may represent another subset of tumors, in addition to BMG/EDCHI tumors, with barriers to immune infiltrates, likely with different mechanisms. These genes have prognostic significance and may be relevant targets for future therapy.http://dx.doi.org/10.1080/2162402X.2019.1665978barrier molecule genesepidermal differentiation complexmelanomaaryl hydrocarbon receptoraryl hydrocarbon receptor nuclear translocatorchromosome 1q21.3 copy number gain
collection DOAJ
language English
format Article
sources DOAJ
author Katie M. Leick
Joseph M. Obeid
Stefan Bekiranov
Craig L. Slingluff
spellingShingle Katie M. Leick
Joseph M. Obeid
Stefan Bekiranov
Craig L. Slingluff
Systems analysis of barrier molecule and ARNT-related gene expression regulation in melanoma
OncoImmunology
barrier molecule genes
epidermal differentiation complex
melanoma
aryl hydrocarbon receptor
aryl hydrocarbon receptor nuclear translocator
chromosome 1q21.3 copy number gain
author_facet Katie M. Leick
Joseph M. Obeid
Stefan Bekiranov
Craig L. Slingluff
author_sort Katie M. Leick
title Systems analysis of barrier molecule and ARNT-related gene expression regulation in melanoma
title_short Systems analysis of barrier molecule and ARNT-related gene expression regulation in melanoma
title_full Systems analysis of barrier molecule and ARNT-related gene expression regulation in melanoma
title_fullStr Systems analysis of barrier molecule and ARNT-related gene expression regulation in melanoma
title_full_unstemmed Systems analysis of barrier molecule and ARNT-related gene expression regulation in melanoma
title_sort systems analysis of barrier molecule and arnt-related gene expression regulation in melanoma
publisher Taylor & Francis Group
series OncoImmunology
issn 2162-402X
publishDate 2019-12-01
description Background: We have identified, in melanomas, a set of genes encoding proteins that mediate mechanical barrier function in normal skin (barrier molecule genes, BMGs) and whose overexpression is associated with decreased immune signatures and shorter patient survival. The most overexpressed of these, filaggrin (FLG), is expressed on chromosome 1q21.3, which also encodes genes of the epidermal differentiation complex (EDC). EDC genes may be regulated by the transcription factors (TFs) AHR and ARNT. We hypothesized that ARNT-related genes would be expressed concordantly with BMG and EDC genes, inversely associated with immune signatures, and enhanced by 1q21.3 copy gain. Methods: Gene expression data from human melanomas in the Cancer Genome Atlas (TCGA), and a validation GEO dataset were evaluated, with copy number profiles from TCGA. Expression of Th1 immune genes and BMG/EDCs at 1q21.3 was visualized using clustered copy number and mRNA profiles. Associations of clusters and 1q21.3 copy number with patient survival and mRNA expression were assessed using Kaplan Meier curves, log-rank tests, and Wilcoxon rank sum tests. Results: BMGs are concordantly expressed with EDC genes. Clustering divided tumors into 4 categories: (1) ImmuneHI, (2) BMG/EDCHI, (3) ARNTHI, (4) Mixed. Both ARNTHI and BMG/EDCHI tumors had low immune signatures and significantly shortened survival. KLF4 and FOXF2 are putative TFs that may regulate these genes. Conclusions: ARNTHI tumors may represent another subset of tumors, in addition to BMG/EDCHI tumors, with barriers to immune infiltrates, likely with different mechanisms. These genes have prognostic significance and may be relevant targets for future therapy.
topic barrier molecule genes
epidermal differentiation complex
melanoma
aryl hydrocarbon receptor
aryl hydrocarbon receptor nuclear translocator
chromosome 1q21.3 copy number gain
url http://dx.doi.org/10.1080/2162402X.2019.1665978
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