Attenuated sex-related DNA methylation differences in cancer highlight the magnitude bias mediating existing disparities
Abstract Background DNA methylation (DNAm) influences both sex differences and cancer development, yet the mechanisms connecting these factors remain unclear. Methods Utilizing data from The Cancer Genome Atlas, we conducted a comprehensive analysis of sex-related DNAm effects in nine non-reproducti...
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BMC
2024-12-01
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| Series: | Biology of Sex Differences |
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| Online Access: | https://doi.org/10.1186/s13293-024-00682-4 |
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| author | Jiaqi Zhou Miao Li Yu Chen Shangzi Wang Danke Wang Chen Suo Xingdong Chen |
| author_facet | Jiaqi Zhou Miao Li Yu Chen Shangzi Wang Danke Wang Chen Suo Xingdong Chen |
| author_sort | Jiaqi Zhou |
| collection | DOAJ |
| description | Abstract Background DNA methylation (DNAm) influences both sex differences and cancer development, yet the mechanisms connecting these factors remain unclear. Methods Utilizing data from The Cancer Genome Atlas, we conducted a comprehensive analysis of sex-related DNAm effects in nine non-reproductive cancers, compared to paired normal adjacent tissues (NATs), and validated the results using independent datasets. First, we assessed the extent of sex differential DNAm between cancers and NATs to explore how sex-related DNAm differences change in cancerous tissues. Next, we employed a multivariate adaptive shrinkage approach to model the covariance of cancer-related DNAm effects between sexes, aiming to elucidate how sex impacts aberrant DNAm patterns in cancers. Finally, we investigated correlations between the methylome and transcriptome to identify key signals driving sex-biased DNAm regulation in cancers. Results Our analysis revealed a significant attenuation of sex differences in DNAm within cancerous tissues compared to baseline differences in normal tissues. We identified 3,452 CpGs (P bonf < 0.05) associated with this reduction, with 72% of the linked genes involved in X chromosome inactivation. Through covariance analysis, we demonstrated that sex differences in cancer are predominantly driven by variations in the magnitude of shared DNAm signals, referred to as “amplification.” Based on these patterns, we classified cancers into female- and male-biased groups and identified key CpGs exhibiting sex-specific amplification. These CpGs were enriched in binding sites of critical transcription factors, including P53, SOX2, and CTCF. Integrative multi-omics analyses uncovered 48 CpG-gene-cancer trios for females and 380 for males, showing similar magnitude differences in DNAm and gene expression, pointing to a sex-specific regulatory role of DNAm in cancer risk. Notably, several genes regulated by these trios were previously identified as drug targets for cancers, highlighting their potential as sex-specific therapeutic targets. Conclusions These findings advance our understanding of how sex, DNAm, and gene expression interact in cancer, offering insights into the development of sex-specific biomarkers and precision medicine. |
| format | Article |
| id | doaj-art-daff4b72390f43e9bdc9ae2d3514a82e |
| institution | DOAJ |
| issn | 2042-6410 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Biology of Sex Differences |
| spelling | doaj-art-daff4b72390f43e9bdc9ae2d3514a82e2025-08-20T02:43:24ZengBMCBiology of Sex Differences2042-64102024-12-0115112110.1186/s13293-024-00682-4Attenuated sex-related DNA methylation differences in cancer highlight the magnitude bias mediating existing disparitiesJiaqi Zhou0Miao Li1Yu Chen2Shangzi Wang3Danke Wang4Chen Suo5Xingdong Chen6State Key Laboratory of Genetic Engineering, School of Life Sciences, Human Phenome Institute, Fudan UniversityKey Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of SciencesDepartment of Psychiatry, Massachusetts General Hospital, Harvard Medical SchoolState Key Laboratory of Genetic Engineering, School of Life Sciences, Human Phenome Institute, Fudan UniversityState Key Laboratory of Genetic Engineering, School of Life Sciences, Human Phenome Institute, Fudan UniversityFudan University Taizhou Institute of Health SciencesState Key Laboratory of Genetic Engineering, School of Life Sciences, Human Phenome Institute, Fudan UniversityAbstract Background DNA methylation (DNAm) influences both sex differences and cancer development, yet the mechanisms connecting these factors remain unclear. Methods Utilizing data from The Cancer Genome Atlas, we conducted a comprehensive analysis of sex-related DNAm effects in nine non-reproductive cancers, compared to paired normal adjacent tissues (NATs), and validated the results using independent datasets. First, we assessed the extent of sex differential DNAm between cancers and NATs to explore how sex-related DNAm differences change in cancerous tissues. Next, we employed a multivariate adaptive shrinkage approach to model the covariance of cancer-related DNAm effects between sexes, aiming to elucidate how sex impacts aberrant DNAm patterns in cancers. Finally, we investigated correlations between the methylome and transcriptome to identify key signals driving sex-biased DNAm regulation in cancers. Results Our analysis revealed a significant attenuation of sex differences in DNAm within cancerous tissues compared to baseline differences in normal tissues. We identified 3,452 CpGs (P bonf < 0.05) associated with this reduction, with 72% of the linked genes involved in X chromosome inactivation. Through covariance analysis, we demonstrated that sex differences in cancer are predominantly driven by variations in the magnitude of shared DNAm signals, referred to as “amplification.” Based on these patterns, we classified cancers into female- and male-biased groups and identified key CpGs exhibiting sex-specific amplification. These CpGs were enriched in binding sites of critical transcription factors, including P53, SOX2, and CTCF. Integrative multi-omics analyses uncovered 48 CpG-gene-cancer trios for females and 380 for males, showing similar magnitude differences in DNAm and gene expression, pointing to a sex-specific regulatory role of DNAm in cancer risk. Notably, several genes regulated by these trios were previously identified as drug targets for cancers, highlighting their potential as sex-specific therapeutic targets. Conclusions These findings advance our understanding of how sex, DNAm, and gene expression interact in cancer, offering insights into the development of sex-specific biomarkers and precision medicine.https://doi.org/10.1186/s13293-024-00682-4Sex differencesDNA methylationCancerGene expressionRNA-seq |
| spellingShingle | Jiaqi Zhou Miao Li Yu Chen Shangzi Wang Danke Wang Chen Suo Xingdong Chen Attenuated sex-related DNA methylation differences in cancer highlight the magnitude bias mediating existing disparities Biology of Sex Differences Sex differences DNA methylation Cancer Gene expression RNA-seq |
| title | Attenuated sex-related DNA methylation differences in cancer highlight the magnitude bias mediating existing disparities |
| title_full | Attenuated sex-related DNA methylation differences in cancer highlight the magnitude bias mediating existing disparities |
| title_fullStr | Attenuated sex-related DNA methylation differences in cancer highlight the magnitude bias mediating existing disparities |
| title_full_unstemmed | Attenuated sex-related DNA methylation differences in cancer highlight the magnitude bias mediating existing disparities |
| title_short | Attenuated sex-related DNA methylation differences in cancer highlight the magnitude bias mediating existing disparities |
| title_sort | attenuated sex related dna methylation differences in cancer highlight the magnitude bias mediating existing disparities |
| topic | Sex differences DNA methylation Cancer Gene expression RNA-seq |
| url | https://doi.org/10.1186/s13293-024-00682-4 |
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