Background and Aim: DNA methylation may contribute to a worsening in breast cancer (BC). Methods: We conducted a matched case–control study to investigate the contribution of DNA methylation (DNAm) in breast cancer recurrence risk. Genome-wide DNAm profiles were generated from peripheral white blood cells (WBC) collected post-surgery from women with primary breast cancerBRCAwild-type, using Illumina Infinium HumanMethylationEPIC array. Cases had to experience recurrence of breast cancer or death and were matched to controls (subjects without recurrence, ratio 1:2) by age at diagnosis (+/− 5 years) and follow-up duration. Results: We identified three differentially methylated regions between the groups. Cases showed two hypomethylated regions, one upstream of thevtRNA2–1gene (estimate −0.30,p-value < 0.005), and one in the 5′ UTR region of theFGFR2gene (estimate −0.34,p-value < 0.028), whereas one, upstream of theRUFY1gene (estimate 0.32,p-value < 0.015), was hypermethylated. Additionally, we identified two methylation signals, recognised as predictors of biochemical traits. The chemokine ligand 21 (unadjustedp-value < 0.03) and insulin receptor expression (unadjustedp-value < 0.04) were higher in cases than in controls. Conclusions: Our exploratory study suggests that specific DNA methylation patterns in WBCs, particularly in genes related to cellular proliferation, invasion, and glucose homeostasis, may be associated with the risk of breast cancer recurrence inBRCAwild-type women. If validated in larger cohorts, these circulating signatures may serve as blood-based biomarkers to improve risk stratification and guide tailored treatment strategies.
背景与目的：DNA甲基化可能加剧乳腺癌（BC）的进展。方法：我们开展了一项匹配的病例对照研究，以探讨DNA甲基化（DNAm）对乳腺癌复发风险的影响。研究使用Illumina Infinium HumanMethylationEPIC芯片，对原发性乳腺癌且BRCA野生型女性术后采集的外周血白细胞（WBC）进行了全基因组DNA甲基化谱分析。病例组需出现乳腺癌复发或死亡，并按确诊年龄（±5岁）和随访时长与对照组（未复发受试者，比例1:2）进行匹配。结果：我们在两组间识别出三个差异甲基化区域。病例组呈现两个低甲基化区域：一个位于vtRNA2–1基因上游（估计值−0.30，p值<0.005），另一个位于FGFR2基因的5′非翻译区（估计值−0.34，p值<0.028）；同时发现RUFY1基因上游存在一个高甲基化区域（估计值0.32，p值<0.015）。此外，我们鉴定出两个可作为生化特征预测指标的甲基化信号：病例组的趋化因子配体21（未校正p值<0.03）和胰岛素受体表达水平（未校正p值<0.04）均高于对照组。结论：本探索性研究表明，白细胞中特定的DNA甲基化模式（尤其涉及细胞增殖、侵袭和葡萄糖稳态相关基因）可能与BRCA野生型女性的乳腺癌复发风险相关。若在更大规模队列中得到验证，这些循环标志物或可作为血液生物标志物，用于改善风险分层并指导个体化治疗策略。
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