Integrative analysis in head and neck cancer reveals distinct role of miRNome and methylome as tumour epigenetic drivers
Abstract Head and neck cancer is the sixth most common malignancy worldwide, with the relatively low 5-year survival rate, mainly because it is diagnosed at a late stage. Infection with HPV is a well known aetiology, which affects the nature of these cancers and patients’ survival. Besides, it is co...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-04-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-024-59312-z |
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| author | Katarina Mandić Nina Milutin Gašperov Ksenija Božinović Emil Dediol Jure Krasić Nino Sinčić Magdalena Grce Ivan Sabol Anja Barešić |
| author_facet | Katarina Mandić Nina Milutin Gašperov Ksenija Božinović Emil Dediol Jure Krasić Nino Sinčić Magdalena Grce Ivan Sabol Anja Barešić |
| author_sort | Katarina Mandić |
| collection | DOAJ |
| description | Abstract Head and neck cancer is the sixth most common malignancy worldwide, with the relatively low 5-year survival rate, mainly because it is diagnosed at a late stage. Infection with HPV is a well known aetiology, which affects the nature of these cancers and patients’ survival. Besides, it is considered that the main driving force for this type of cancer could be epigenetics. In this study we aimed to find potential epigenetic biomarkers, by integrating miRNome, methylome, and transcriptome analyses. From the fresh head and neck cancer tissue samples, we chose a group for miRNome, methylome and transcriptome profiling, in comparison to adequate control samples. Bioinformatics analyses are performed in R v4.2.2. Count normalisation and group differential expression for mRNA and the previously obtained miRNA count data was performed with DESeq2 v1.36. Gene set enrichment analysis was performed and visualised using gProfiler2 v0.2.1 Identification of miRNA targets was performed by querying in miRTarBase using multiMiR v1.18.0. Annotation of CpG sites merging into islands was obtained from RnBeads.hg19 v1.28.0. package. For the integrative analysis we performed kmeans clustering using stats v4.2.2 package, using 8–12 clusters and nstart 100. We found that transcriptome analysis divides samples into cancers and controls clusters, with no relation to HPV status or cancer anatomical location. Differentially expressed genes (n = 2781) were predominantly associated with signalling pathways of tumour progression. We identified a cluster of genes under the control of the transcription factor E2F that are significantly underexpressed in cancer tissue, as well as T cell immunity genes and genes related to regulation of transcription. Among overexpressed genes in tumours we found those that belong to cell cycle regulation and vasculature. A small number of genes were found significantly differentially expressed in HPV-positive versus HPV-negative tumours (for example NEFH, ZFR2, TAF7L, ZNF541, and TYMS). In this comprehensive study on an overlapping set of samples where the integration of miRNome, methylome and transcriptome analysis were performed for head and neck cancer, we demonstrated that the majority of genes were associated exclusively with miRNome or methylome and, to a lesser extent, under the control of both epigenetic mechanisms. |
| first_indexed | 2024-04-24T07:16:35Z |
| format | Article |
| id | doaj.art-aeba350ff6174d6ca201d19bdaac9dae |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-24T07:16:35Z |
| publishDate | 2024-04-01 |
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| spelling | doaj.art-aeba350ff6174d6ca201d19bdaac9dae2024-04-21T11:16:36ZengNature PortfolioScientific Reports2045-23222024-04-0114111210.1038/s41598-024-59312-zIntegrative analysis in head and neck cancer reveals distinct role of miRNome and methylome as tumour epigenetic driversKatarina Mandić0Nina Milutin Gašperov1Ksenija Božinović2Emil Dediol3Jure Krasić4Nino Sinčić5Magdalena Grce6Ivan Sabol7Anja Barešić8Division of Electronics, Ruđer Bošković InstituteDivision of Molecular Medicine, Ruđer Bošković InstituteDivision of Molecular Medicine, Ruđer Bošković InstituteDepartment of Maxillofacial Surgery, Clinical Hospital DubravaDepartment of Medical Biology, University of Zagreb School of MedicineDepartment of Medical Biology, University of Zagreb School of MedicineDivision of Molecular Medicine, Ruđer Bošković InstituteDivision of Molecular Medicine, Ruđer Bošković InstituteDivision of Electronics, Ruđer Bošković InstituteAbstract Head and neck cancer is the sixth most common malignancy worldwide, with the relatively low 5-year survival rate, mainly because it is diagnosed at a late stage. Infection with HPV is a well known aetiology, which affects the nature of these cancers and patients’ survival. Besides, it is considered that the main driving force for this type of cancer could be epigenetics. In this study we aimed to find potential epigenetic biomarkers, by integrating miRNome, methylome, and transcriptome analyses. From the fresh head and neck cancer tissue samples, we chose a group for miRNome, methylome and transcriptome profiling, in comparison to adequate control samples. Bioinformatics analyses are performed in R v4.2.2. Count normalisation and group differential expression for mRNA and the previously obtained miRNA count data was performed with DESeq2 v1.36. Gene set enrichment analysis was performed and visualised using gProfiler2 v0.2.1 Identification of miRNA targets was performed by querying in miRTarBase using multiMiR v1.18.0. Annotation of CpG sites merging into islands was obtained from RnBeads.hg19 v1.28.0. package. For the integrative analysis we performed kmeans clustering using stats v4.2.2 package, using 8–12 clusters and nstart 100. We found that transcriptome analysis divides samples into cancers and controls clusters, with no relation to HPV status or cancer anatomical location. Differentially expressed genes (n = 2781) were predominantly associated with signalling pathways of tumour progression. We identified a cluster of genes under the control of the transcription factor E2F that are significantly underexpressed in cancer tissue, as well as T cell immunity genes and genes related to regulation of transcription. Among overexpressed genes in tumours we found those that belong to cell cycle regulation and vasculature. A small number of genes were found significantly differentially expressed in HPV-positive versus HPV-negative tumours (for example NEFH, ZFR2, TAF7L, ZNF541, and TYMS). In this comprehensive study on an overlapping set of samples where the integration of miRNome, methylome and transcriptome analysis were performed for head and neck cancer, we demonstrated that the majority of genes were associated exclusively with miRNome or methylome and, to a lesser extent, under the control of both epigenetic mechanisms.https://doi.org/10.1038/s41598-024-59312-zHead and neck cancerHPVmiRNomeMethylomeTranscriptomeIntegrative analysis |
| spellingShingle | Katarina Mandić Nina Milutin Gašperov Ksenija Božinović Emil Dediol Jure Krasić Nino Sinčić Magdalena Grce Ivan Sabol Anja Barešić Integrative analysis in head and neck cancer reveals distinct role of miRNome and methylome as tumour epigenetic drivers Scientific Reports Head and neck cancer HPV miRNome Methylome Transcriptome Integrative analysis |
| title | Integrative analysis in head and neck cancer reveals distinct role of miRNome and methylome as tumour epigenetic drivers |
| title_full | Integrative analysis in head and neck cancer reveals distinct role of miRNome and methylome as tumour epigenetic drivers |
| title_fullStr | Integrative analysis in head and neck cancer reveals distinct role of miRNome and methylome as tumour epigenetic drivers |
| title_full_unstemmed | Integrative analysis in head and neck cancer reveals distinct role of miRNome and methylome as tumour epigenetic drivers |
| title_short | Integrative analysis in head and neck cancer reveals distinct role of miRNome and methylome as tumour epigenetic drivers |
| title_sort | integrative analysis in head and neck cancer reveals distinct role of mirnome and methylome as tumour epigenetic drivers |
| topic | Head and neck cancer HPV miRNome Methylome Transcriptome Integrative analysis |
| url | https://doi.org/10.1038/s41598-024-59312-z |
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