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Abstract：
BACKGROUND: Inflammatory breast cancer (IBC) is a rare disease characterized by rapid progression, early metastasis, and a high mortality rate.
METHODS: Genome-wide DNA methylation analysis (EPIC BeadChip platform, Illumina) and somatic gene variants (105 cancer-related genes) were performed in 24 IBCs selected from a cohort of 140 cases.
RESULTS: We identified 46,908 DMPs (differentially methylated positions) (66% hypomethylated); CpG islands were predominantly hypermethylated (39.9%). Unsupervised clustering analysis revealed three clusters of DMPs characterized by an enrichment of specific gene mutations and hormone receptor status. The comparison among DNA methylation findings and external datasets (TCGA-BRCA stages III-IV) resulted in 385 shared DMPs mapped in 333 genes (264 hypermethylated). 151 DMPs were associated with 110 genes previously detected as differentially expressed in IBC (GSE45581), and 68 DMPs were negatively correlated with gene expression. We also identified 4369 DMRs (differentially methylated regions) mapped on known genes (2392 hypomethylated). BCAT1, CXCL12, and TBX15 loci were selected and evaluated by bisulfite pyrosequencing in 31 IBC samples. BCAT1 and TBX15 had higher methylation levels in triple-negative compared to non-triple-negative, while CXCL12 had lower methylation levels in triple-negative than non-triple-negative IBC cases. TBX15 methylation level was associated with obesity.
CONCLUSIONS: Our findings revealed a heterogeneous DNA methylation profile with potentially functional DMPs and DMRs. The DNA methylation data provided valuable insights for prognostic stratification and therapy selection to improve patient outcomes.
METHODS: Genome-wide DNA methylation analysis (EPIC BeadChip platform, Illumina) and somatic gene variants (105 cancer-related genes) were performed in 24 IBCs selected from a cohort of 140 cases.
RESULTS: We identified 46,908 DMPs (differentially methylated positions) (66% hypomethylated); CpG islands were predominantly hypermethylated (39.9%). Unsupervised clustering analysis revealed three clusters of DMPs characterized by an enrichment of specific gene mutations and hormone receptor status. The comparison among DNA methylation findings and external datasets (TCGA-BRCA stages III-IV) resulted in 385 shared DMPs mapped in 333 genes (264 hypermethylated). 151 DMPs were associated with 110 genes previously detected as differentially expressed in IBC (GSE45581), and 68 DMPs were negatively correlated with gene expression. We also identified 4369 DMRs (differentially methylated regions) mapped on known genes (2392 hypomethylated). BCAT1, CXCL12, and TBX15 loci were selected and evaluated by bisulfite pyrosequencing in 31 IBC samples. BCAT1 and TBX15 had higher methylation levels in triple-negative compared to non-triple-negative, while CXCL12 had lower methylation levels in triple-negative than non-triple-negative IBC cases. TBX15 methylation level was associated with obesity.
CONCLUSIONS: Our findings revealed a heterogeneous DNA methylation profile with potentially functional DMPs and DMRs. The DNA methylation data provided valuable insights for prognostic stratification and therapy selection to improve patient outcomes.
摘要：
背景：炎症性乳腺癌（IBC）是一种罕见的疾病，其特征是进展迅速，早期转移,和高死亡率。
方法：全基因组DNA甲基化分析（EPICBeadChip平台，Illumina）和体细胞基因变体（105个癌症相关基因）在从140例病例组中选择的24个IBC中进行。
结果：我们确定了46,908个DMP（差异甲基化位置）（66％低甲基化）；CpG岛主要是高甲基化（39.9％）。无监督聚类分析显示了三簇DMP，其特征是特定基因突变和激素受体状态的富集。DNA甲基化发现和外部数据集（TCGA-BRCAIII-IV期）之间的比较导致385个共享DMP映射在333个基因（264个高甲基化）中。151个DMP与先前在IBC中检测到差异表达的110个基因相关（GSE45581），68例DMPs与基因表达呈负相关。我们还鉴定了定位在已知基因(2392次甲基化)上的4369个DMRs(差异甲基化区域)。选择BCATl、CXCL12和TBX15基因座,并在31个IBC样品中通过亚硫酸氢盐焦磷酸测序进行评估。与非三阴性相比，三阴性BCAT1和TBX15的甲基化水平更高，而CXCL12在三阴性IBC中的甲基化水平低于非三阴性IBC。TBX15甲基化水平与肥胖相关。
结论：我们的发现揭示了具有潜在功能性DMPs和DMRs的异质性DNA甲基化谱。DNA甲基化数据为预后分层和治疗选择提供了有价值的见解，以改善患者的预后。
方法：全基因组DNA甲基化分析（EPICBeadChip平台，Illumina）和体细胞基因变体（105个癌症相关基因）在从140例病例组中选择的24个IBC中进行。
结果：我们确定了46,908个DMP（差异甲基化位置）（66％低甲基化）；CpG岛主要是高甲基化（39.9％）。无监督聚类分析显示了三簇DMP，其特征是特定基因突变和激素受体状态的富集。DNA甲基化发现和外部数据集（TCGA-BRCAIII-IV期）之间的比较导致385个共享DMP映射在333个基因（264个高甲基化）中。151个DMP与先前在IBC中检测到差异表达的110个基因相关（GSE45581），68例DMPs与基因表达呈负相关。我们还鉴定了定位在已知基因(2392次甲基化)上的4369个DMRs(差异甲基化区域)。选择BCATl、CXCL12和TBX15基因座,并在31个IBC样品中通过亚硫酸氢盐焦磷酸测序进行评估。与非三阴性相比，三阴性BCAT1和TBX15的甲基化水平更高，而CXCL12在三阴性IBC中的甲基化水平低于非三阴性IBC。TBX15甲基化水平与肥胖相关。
结论：我们的发现揭示了具有潜在功能性DMPs和DMRs的异质性DNA甲基化谱。DNA甲基化数据为预后分层和治疗选择提供了有价值的见解，以改善患者的预后。
