Genome-wide DNA methylation profiling of HPV-negative leukoplakia and gingivobuccal complex cancers
Abstract Background Gingivobuccal complex oral squamous cell carcinoma (GBC-OSCC) is an aggressive malignancy with high mortality often preceded by premalignant lesions, including leukoplakia. Previous studies have reported genomic drivers in OSCC, but much remains to be elucidated about DNA methyla...
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| Format: | Article |
| Language: | English |
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BMC
2023-05-01
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| Series: | Clinical Epigenetics |
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| Online Access: | https://doi.org/10.1186/s13148-023-01510-z |
| _version_ | 1797817914610417664 |
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| author | Mayuri Inchanalkar Sumana Srivatsa Srikant Ambatipudi Priyanka G. Bhosale Asawari Patil Alejandro A. Schäffer Niko Beerenwinkel Manoj B. Mahimkar |
| author_facet | Mayuri Inchanalkar Sumana Srivatsa Srikant Ambatipudi Priyanka G. Bhosale Asawari Patil Alejandro A. Schäffer Niko Beerenwinkel Manoj B. Mahimkar |
| author_sort | Mayuri Inchanalkar |
| collection | DOAJ |
| description | Abstract Background Gingivobuccal complex oral squamous cell carcinoma (GBC-OSCC) is an aggressive malignancy with high mortality often preceded by premalignant lesions, including leukoplakia. Previous studies have reported genomic drivers in OSCC, but much remains to be elucidated about DNA methylation patterns across different stages of oral carcinogenesis. Results There is a serious lack of biomarkers and clinical application of biomarkers for early detection and prognosis of gingivobuccal complex cancers. Hence, in search of novel biomarkers, we measured genome-wide DNA methylation in 22 normal oral tissues, 22 leukoplakia, and 74 GBC-OSCC tissue samples. Both leukoplakia and GBC-OSCC had distinct methylation profiles as compared to normal oral tissue samples. Aberrant DNA methylation increases during the different stages of oral carcinogenesis, from premalignant lesions to carcinoma. We identified 846 and 5111 differentially methylated promoters in leukoplakia and GBC-OSCC, respectively, with a sizable fraction shared between the two sets. Further, we identified potential biomarkers from integrative analysis in gingivobuccal complex cancers and validated them in an independent cohort. Integration of genome, epigenome, and transcriptome data revealed candidate genes with gene expression synergistically regulated by copy number and DNA methylation changes. Regularised Cox regression identified 32 genes associated with patient survival. In an independent set of samples, we validated eight genes (FAT1, GLDC, HOXB13, CST7, CYB5A, MLLT11, GHR, LY75) from the integrative analysis and 30 genes from previously published reports. Bisulfite pyrosequencing validated GLDC (P = 0.036), HOXB13 (P < 0.0001) promoter hypermethylation, and FAT1 (P < 0.0001) hypomethylation in GBC-OSCC compared to normal controls. Conclusions Our findings identified methylation signatures associated with leukoplakia and gingivobuccal complex cancers. The integrative analysis in GBC-OSCC identified putative biomarkers that enhance existing knowledge of oral carcinogenesis and may potentially help in risk stratification and prognosis of GBC-OSCC. Graphical abstract |
| first_indexed | 2024-03-13T09:00:30Z |
| format | Article |
| id | doaj.art-68e3d9c0391a4ad49e33391560a83b9e |
| institution | Directory Open Access Journal |
| issn | 1868-7083 |
| language | English |
| last_indexed | 2024-03-13T09:00:30Z |
| publishDate | 2023-05-01 |
| publisher | BMC |
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| series | Clinical Epigenetics |
| spelling | doaj.art-68e3d9c0391a4ad49e33391560a83b9e2023-05-28T11:20:09ZengBMCClinical Epigenetics1868-70832023-05-0115111610.1186/s13148-023-01510-zGenome-wide DNA methylation profiling of HPV-negative leukoplakia and gingivobuccal complex cancersMayuri Inchanalkar0Sumana Srivatsa1Srikant Ambatipudi2Priyanka G. Bhosale3Asawari Patil4Alejandro A. Schäffer5Niko Beerenwinkel6Manoj B. Mahimkar7Mahimkar Lab, Cancer Research Institute (CRI), Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial CenterDepartment of Biosystems Science and Engineering, ETH ZurichMahimkar Lab, Cancer Research Institute (CRI), Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial CenterMahimkar Lab, Cancer Research Institute (CRI), Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial CenterHomi Bhabha National InstituteCancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, and National Center for Biotechnology Information, National Institutes of HealthDepartment of Biosystems Science and Engineering, ETH ZurichMahimkar Lab, Cancer Research Institute (CRI), Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial CenterAbstract Background Gingivobuccal complex oral squamous cell carcinoma (GBC-OSCC) is an aggressive malignancy with high mortality often preceded by premalignant lesions, including leukoplakia. Previous studies have reported genomic drivers in OSCC, but much remains to be elucidated about DNA methylation patterns across different stages of oral carcinogenesis. Results There is a serious lack of biomarkers and clinical application of biomarkers for early detection and prognosis of gingivobuccal complex cancers. Hence, in search of novel biomarkers, we measured genome-wide DNA methylation in 22 normal oral tissues, 22 leukoplakia, and 74 GBC-OSCC tissue samples. Both leukoplakia and GBC-OSCC had distinct methylation profiles as compared to normal oral tissue samples. Aberrant DNA methylation increases during the different stages of oral carcinogenesis, from premalignant lesions to carcinoma. We identified 846 and 5111 differentially methylated promoters in leukoplakia and GBC-OSCC, respectively, with a sizable fraction shared between the two sets. Further, we identified potential biomarkers from integrative analysis in gingivobuccal complex cancers and validated them in an independent cohort. Integration of genome, epigenome, and transcriptome data revealed candidate genes with gene expression synergistically regulated by copy number and DNA methylation changes. Regularised Cox regression identified 32 genes associated with patient survival. In an independent set of samples, we validated eight genes (FAT1, GLDC, HOXB13, CST7, CYB5A, MLLT11, GHR, LY75) from the integrative analysis and 30 genes from previously published reports. Bisulfite pyrosequencing validated GLDC (P = 0.036), HOXB13 (P < 0.0001) promoter hypermethylation, and FAT1 (P < 0.0001) hypomethylation in GBC-OSCC compared to normal controls. Conclusions Our findings identified methylation signatures associated with leukoplakia and gingivobuccal complex cancers. The integrative analysis in GBC-OSCC identified putative biomarkers that enhance existing knowledge of oral carcinogenesis and may potentially help in risk stratification and prognosis of GBC-OSCC. Graphical abstracthttps://doi.org/10.1186/s13148-023-01510-zLeukoplakiaGingivobuccal complex cancersOSCCDNA methylationIntegrative analysisPrognosis |
| spellingShingle | Mayuri Inchanalkar Sumana Srivatsa Srikant Ambatipudi Priyanka G. Bhosale Asawari Patil Alejandro A. Schäffer Niko Beerenwinkel Manoj B. Mahimkar Genome-wide DNA methylation profiling of HPV-negative leukoplakia and gingivobuccal complex cancers Clinical Epigenetics Leukoplakia Gingivobuccal complex cancers OSCC DNA methylation Integrative analysis Prognosis |
| title | Genome-wide DNA methylation profiling of HPV-negative leukoplakia and gingivobuccal complex cancers |
| title_full | Genome-wide DNA methylation profiling of HPV-negative leukoplakia and gingivobuccal complex cancers |
| title_fullStr | Genome-wide DNA methylation profiling of HPV-negative leukoplakia and gingivobuccal complex cancers |
| title_full_unstemmed | Genome-wide DNA methylation profiling of HPV-negative leukoplakia and gingivobuccal complex cancers |
| title_short | Genome-wide DNA methylation profiling of HPV-negative leukoplakia and gingivobuccal complex cancers |
| title_sort | genome wide dna methylation profiling of hpv negative leukoplakia and gingivobuccal complex cancers |
| topic | Leukoplakia Gingivobuccal complex cancers OSCC DNA methylation Integrative analysis Prognosis |
| url | https://doi.org/10.1186/s13148-023-01510-z |
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