中国肿瘤生物治疗杂志2026，Vol.33Issue(8)：876-885,10.DOI:10.3872/j.issn.1007-385X.2026.08.008
基于多区域甲基化特征的年轻乳腺癌预后模型构建与验证
Development and validation of a multi-region DNA methylation signature-based prognostic model for breast cancer in young women
摘要
Abstract
Objective:This study aims to systematically characterize the unique DNA methylation landscape of breast cancer in young women(BCYW),identify prognosis-associated methylation loci,develop and externally validate a robust prognostic prediction model,and further elucidate its clinical utility via multi-omics integration analysis and protein-level validation of a pivotal candidate gene.Methods:DNA methylation and clinical data were obtained from The Cancer Genome Atlas(TCGA).BCYW-specific methylation loci were identified.A prognostic prediction model was developed using random forest,LASSO regression,and univariate and multivariate Cox regression analyses.The predictive performance of the constructed model was comprehensively evaluated using receiver operating characteristic(ROC)curves,calibration plots,and the concordance index(C-index).Multi-omics characteristics were compared between high-risk and low-risk subgroups.In an independent cohort,immunohistochemistry was performed to assess the association between LAMA5 protein expression and clinical outcomes.Results:Compared with their older counterparts with breast cancer,young patients exhibited prominent hypomethylation in promoter regions,which was particularly pronounced within CpG islands.Through a multi-step differential methylation analysis,a total of 3 489 BCYW-specific methylation loci were identified.Subsequent univariate and multivariate Cox regression analyses further screened out 12 loci that were independently correlated with overall survival(OS),among which 4 were located in promoter regions,4 in gene body regions,and the remaining 4 in intergenic regions.The prognostic prediction model constructed based on these 12 methylation loci exhibited satisfactory discriminative performance in the TCGA training cohort,where patients assigned to the high-risk subgroup presented significantly worse overall survival outcomes(P=0.002 5).The areas under the curve(AUCs)for 5-,8-,and 10-year OS prediction ranged from 0.88 to 0.94.Multi-omics analysis revealed that the high-risk subgroup exhibited the activation of the mitogen-activated protein kinase(MAPK)signaling pathway,higher frequency of TP53 mutations,and lower expression of estrogen receptor alpha protein.Incorporating key multi-omics indicators,including TP53 mutation status and estrogen receptor 1(ESR1)mRNA expression level,into the comprehensive nomogram further significantly improved the model's predictive performance.Tissue microarray-based immunohistochemical validation demonstrated that young breast cancer patients with negative LAMA5 protein expression exhibited significantly shorter OS(P=0.046),and this phenotype was enriched in triple-negative breast cancer,consistent with the clinicopathological features of the high-risk group defined by the methylation model.Conclusion:The 12-methylation-site model integrating promoter and non-promoter region information shows potential for prognostic stratification in young patients with breast cancer.The multi-omics nomogram constructed by combining age,TP53 mutations and ESR1 mRNA expression level demonstrated superior predictive performance over the methylation-only model.关键词
DNA甲基化/年轻乳腺癌/表观遗传学/预后标志物/预测模型Key words
DNA methylation/breast cancer in young women(BCYW)/epigenetics/prognostic biomarker/prediction model分类
医药卫生引用本文复制引用
孙礼峰,韩雷,陈桂冬,程亚楠,于津浦..基于多区域甲基化特征的年轻乳腺癌预后模型构建与验证[J].中国肿瘤生物治疗杂志,2026,33(8):876-885,10.基金项目
天津市医学重点学科建设项目(TJYXZDXK-3-003A) （TJYXZDXK-3-003A）
