Genetic and functional interaction network analysis reveals global enrichment of regulatory T cell genes influencing basal cell carcinoma susceptibility
Abstract Background Basal cell carcinoma (BCC) of the skin is the most common form of human cancer, with more than 90% of tumours presenting with clear genetic activation of the Hedgehog pathway. However, polygenic risk factors affecting mechanisms such as DNA repair and cell cycle checkpoints or wh...
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| Format: | Article |
| Language: | English |
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BMC
2021-02-01
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| Series: | Genome Medicine |
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| Online Access: | https://doi.org/10.1186/s13073-021-00827-9 |
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| author | Christelle Adolphe Angli Xue Atefeh Taherian Fard Laura A. Genovesi Jian Yang Brandon J. Wainwright |
| author_facet | Christelle Adolphe Angli Xue Atefeh Taherian Fard Laura A. Genovesi Jian Yang Brandon J. Wainwright |
| author_sort | Christelle Adolphe |
| collection | DOAJ |
| description | Abstract Background Basal cell carcinoma (BCC) of the skin is the most common form of human cancer, with more than 90% of tumours presenting with clear genetic activation of the Hedgehog pathway. However, polygenic risk factors affecting mechanisms such as DNA repair and cell cycle checkpoints or which modulate the tumour microenvironment or host immune system play significant roles in determining whether genetic mutations culminate in BCC development. We set out to define background genetic factors that play a role in influencing BCC susceptibility via promoting or suppressing the effects of oncogenic drivers of BCC. Methods We performed genome-wide association studies (GWAS) on 17,416 cases and 375,455 controls. We subsequently performed statistical analysis by integrating data from population-based genetic studies of multi-omics data, including blood- and skin-specific expression quantitative trait loci and methylation quantitative trait loci, thereby defining a list of functionally relevant candidate BCC susceptibility genes from our GWAS loci. We also constructed a local GWAS functional interaction network (consisting of GWAS nearest genes) and another functional interaction network, consisting specifically of candidate BCC susceptibility genes. Results A total of 71 GWAS loci and 46 functional candidate BCC susceptibility genes were identified. Increased risk of BCC was associated with the decreased expression of 26 susceptibility genes and increased expression of 20 susceptibility genes. Pathway analysis of the functional candidate gene regulatory network revealed strong enrichment for cell cycle, cell death, and immune regulation processes, with a global enrichment of genes and proteins linked to TReg cell biology. Conclusions Our genome-wide association analyses and functional interaction network analysis reveal an enrichment of risk variants that function in an immunosuppressive regulatory network, likely hindering cancer immune surveillance and effective antitumour immunity. |
| first_indexed | 2024-12-14T04:20:35Z |
| format | Article |
| id | doaj.art-3533f4a98dc442a99f5df1ff653425e8 |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-12-14T04:20:35Z |
| publishDate | 2021-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-3533f4a98dc442a99f5df1ff653425e82022-12-21T23:17:22ZengBMCGenome Medicine1756-994X2021-02-0113111210.1186/s13073-021-00827-9Genetic and functional interaction network analysis reveals global enrichment of regulatory T cell genes influencing basal cell carcinoma susceptibilityChristelle Adolphe0Angli Xue1Atefeh Taherian Fard2Laura A. Genovesi3Jian Yang4Brandon J. Wainwright5Institute for Molecular Bioscience, The University of QueenslandInstitute for Molecular Bioscience, The University of QueenslandAustralian Institute for Bioengineering and Nanotechnology, The University of QueenslandInstitute for Molecular Bioscience, The University of QueenslandInstitute for Molecular Bioscience, The University of QueenslandInstitute for Molecular Bioscience, The University of QueenslandAbstract Background Basal cell carcinoma (BCC) of the skin is the most common form of human cancer, with more than 90% of tumours presenting with clear genetic activation of the Hedgehog pathway. However, polygenic risk factors affecting mechanisms such as DNA repair and cell cycle checkpoints or which modulate the tumour microenvironment or host immune system play significant roles in determining whether genetic mutations culminate in BCC development. We set out to define background genetic factors that play a role in influencing BCC susceptibility via promoting or suppressing the effects of oncogenic drivers of BCC. Methods We performed genome-wide association studies (GWAS) on 17,416 cases and 375,455 controls. We subsequently performed statistical analysis by integrating data from population-based genetic studies of multi-omics data, including blood- and skin-specific expression quantitative trait loci and methylation quantitative trait loci, thereby defining a list of functionally relevant candidate BCC susceptibility genes from our GWAS loci. We also constructed a local GWAS functional interaction network (consisting of GWAS nearest genes) and another functional interaction network, consisting specifically of candidate BCC susceptibility genes. Results A total of 71 GWAS loci and 46 functional candidate BCC susceptibility genes were identified. Increased risk of BCC was associated with the decreased expression of 26 susceptibility genes and increased expression of 20 susceptibility genes. Pathway analysis of the functional candidate gene regulatory network revealed strong enrichment for cell cycle, cell death, and immune regulation processes, with a global enrichment of genes and proteins linked to TReg cell biology. Conclusions Our genome-wide association analyses and functional interaction network analysis reveal an enrichment of risk variants that function in an immunosuppressive regulatory network, likely hindering cancer immune surveillance and effective antitumour immunity.https://doi.org/10.1186/s13073-021-00827-9BCCGWASCancer susceptibilityImmune surveillanceProtein interaction networks |
| spellingShingle | Christelle Adolphe Angli Xue Atefeh Taherian Fard Laura A. Genovesi Jian Yang Brandon J. Wainwright Genetic and functional interaction network analysis reveals global enrichment of regulatory T cell genes influencing basal cell carcinoma susceptibility Genome Medicine BCC GWAS Cancer susceptibility Immune surveillance Protein interaction networks |
| title | Genetic and functional interaction network analysis reveals global enrichment of regulatory T cell genes influencing basal cell carcinoma susceptibility |
| title_full | Genetic and functional interaction network analysis reveals global enrichment of regulatory T cell genes influencing basal cell carcinoma susceptibility |
| title_fullStr | Genetic and functional interaction network analysis reveals global enrichment of regulatory T cell genes influencing basal cell carcinoma susceptibility |
| title_full_unstemmed | Genetic and functional interaction network analysis reveals global enrichment of regulatory T cell genes influencing basal cell carcinoma susceptibility |
| title_short | Genetic and functional interaction network analysis reveals global enrichment of regulatory T cell genes influencing basal cell carcinoma susceptibility |
| title_sort | genetic and functional interaction network analysis reveals global enrichment of regulatory t cell genes influencing basal cell carcinoma susceptibility |
| topic | BCC GWAS Cancer susceptibility Immune surveillance Protein interaction networks |
| url | https://doi.org/10.1186/s13073-021-00827-9 |
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