Kim Do Hyun, Binder Alexandra M, Zhou Hua, Jung Su Yon
Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, United States.
Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, United States.
Front Genet. 2023 Mar 2;14:1133443. doi: 10.3389/fgene.2023.1133443. eCollection 2023.
Tumor subtype and menopausal status are strong predictors of breast cancer (BC) prognosis. We aimed to find and validate subtype- or menopausal-status-specific changes in tumor DNA methylation (DNAm) associated with all-cause mortality or BC progression. Associations between site-specific tumor DNAm and BC prognosis were estimated among The Cancer Genome Atlas participants ( = 692) with Illumina Infinium HumanMethylation450 BeadChip array data. All-cause mortality and BC progression were modeled using Cox proportional hazards models stratified by tumor subtypes, adjusting for age, race, stage, menopausal status, tumor purity, and cell type proportion. Effect measure modification by subtype and menopausal status were evaluated by incorporating a product term with DNAm. Site-specific inference was used to identify subtype- or menopausal-status-specific differentially methylated regions (DMRs) and functional pathways. The validation of the results was carried out on an independent dataset (GSE72308; = 180). We identified a total of fifteen unique CpG probes that were significantly associated ( with survival outcomes in subtype- or menopausal-status-specific manner. Seven probes were associated with overall survival (OS) or progression-free interval (PFI) for women with luminal A subtype, and four probes were associated with PFI for women with luminal B subtype. Five probes were associated with PFI for post-menopausal women. A majority of significant probes showed a lower risk of OS or BC progression with higher DNAm. We identified subtype- or menopausal-status-specific DMRs and functional pathways of which top associated pathways differed across subtypes or menopausal status. None of significant probes from site-specific analyses met genome-wide significant level in validation analyses while directions and magnitudes of coefficients showed consistent pattern. We have identified subtype- or menopausal-status-specific DNAm biomarkers, DMRs and functional pathways associated with all-cause mortality or BC progression, albeit with limited validation. Future studies with larger independent cohort of non-post-menopausal women with non-luminal A subtypes are warranted for identifying subtype- and menopausal-status-specific DNAm biomarkers for BC prognosis.
肿瘤亚型和绝经状态是乳腺癌（BC）预后的有力预测指标。我们旨在寻找并验证与全因死亡率或BC进展相关的肿瘤DNA甲基化（DNAm）中特定于亚型或绝经状态的变化。在拥有Illumina Infinium HumanMethylation450 BeadChip阵列数据的癌症基因组图谱参与者（n = 692）中，估计了位点特异性肿瘤DNAm与BC预后之间的关联。使用按肿瘤亚型分层的Cox比例风险模型对全因死亡率和BC进展进行建模，并对年龄、种族、分期、绝经状态、肿瘤纯度和细胞类型比例进行调整。通过纳入DNAm的乘积项来评估亚型和绝经状态对效应量的修正。使用位点特异性推断来识别特定于亚型或绝经状态的差异甲基化区域（DMR）和功能途径。在一个独立数据集（GSE72308；n = 180）上对结果进行验证。我们总共鉴定出15个独特的CpG探针，它们以特定于亚型或绝经状态的方式与生存结果显著相关（P < 0.05）。七个探针与管腔A型女性的总生存期（OS）或无进展生存期（PFI）相关，四个探针与管腔B型女性的PFI相关。五个探针与绝经后女性的PFI相关。大多数显著探针显示，DNAm水平越高，OS或BC进展的风险越低。我们鉴定出特定于亚型或绝经状态的DMR和功能途径，其中顶级相关途径在不同亚型或绝经状态之间有所不同。位点特异性分析中的显著探针在验证分析中均未达到全基因组显著水平，但其系数的方向和大小显示出一致的模式。我们已经鉴定出与全因死亡率或BC进展相关的特定于亚型或绝经状态的DNAm生物标志物、DMR和功能途径，尽管验证有限。未来有必要对更大规模的非管腔A型非绝经女性独立队列进行研究，以确定用于BC预后的特定于亚型和绝经状态的DNAm生物标志物。
