Attenuated sex-related DNA methylation differences in cancer highlight the magnitude bias mediating existing disparities

	Attenuated sex-related DNA methylation differences in cancer highlight the magnitude bias mediating existing disparities
	Zhou, JQ; Li, M; Chen, Y; Wang, SZ; Wang, DK; Suo, C; Chen, XD
	2024
发表期刊	BIOL SEX DIFFER
卷号	15 期号:1
摘要	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.
收录类别	SCI
语种	英语
文献类型	期刊论文
条目标识符	http://ir.kiz.ac.cn/handle/152453/14621
专题	科研部门_东南亚野生动物多样性（陈小勇）
推荐引用方式 GB/T 7714	Zhou, JQ,Li, M,Chen, Y,et al. Attenuated sex-related DNA methylation differences in cancer highlight the magnitude bias mediating existing disparities[J]. BIOL SEX DIFFER,2024,15(1).
APA	Zhou, JQ.,Li, M.,Chen, Y.,Wang, SZ.,Wang, DK.,...&Chen, XD.(2024).Attenuated sex-related DNA methylation differences in cancer highlight the magnitude bias mediating existing disparities.BIOL SEX DIFFER,15(1).
MLA	Zhou, JQ,et al."Attenuated sex-related DNA methylation differences in cancer highlight the magnitude bias mediating existing disparities".BIOL SEX DIFFER 15.1(2024).

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