Center for Endocrine Tumors and Disorders, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA.
Ann Surg Oncol. 2018 Oct;25(10):3082-3087. doi: 10.1245/s10434-018-6582-7. Epub 2018 Jun 28.
Molecular alterations impact tumor prognosis and response to treatment. This study was designed to identify transcriptomic and epigenomic signatures of breast cancer (BC) tumors from patients with any prior malignancy.
RNA-sequencing and genome-wide DNA methylation profiles from BCs were generated in the Cancer Genome Atlas project. Patients with secondary breast cancer (SBC) were separated by histological subtype and matched to primary breast cancer controls to create two independent cohorts of invasive ductal (IDC, n = 36) and invasive lobular (ILC, n = 40) carcinoma. Differentially expressed genes, as well as differentially methylated genomic regions, were integrated to identify epigenetically regulated abnormal gene pathways in SBCs.
Differentially expressed genes were identified in IDC SBCs (n = 727) and in ILC SBCs (n = 261; Wilcoxon's test; P < 0.05). In IDC SBCs, 105 genes were upregulated and hypomethylated, including an estrogen receptor gene, and 73 genes were downregulated and hypermethylated, including genes involved in antigen presentation and interferon response pathways (HLA-E, IRF8, and RELA). In ILC SBCs, however, only 17 genes were synchronously hypomethylated and upregulated, whereas 46 genes hypermethylated and downregulated. Interestingly, the SBC gene expression signatures closely corresponded with each histological subtype with only 1.51% of genes overlapping between the two histological subtypes.
Differential gene expression and DNA methylation signatures are seen in both IDC and ILC SBCs, including genes that are relevant to tumor growth and proliferation. Differences in gene expression signatures corresponding with each histological subtype emphasize the importance of disease subtype-specific evaluations of molecular alterations.
分子改变会影响肿瘤的预后和对治疗的反应。本研究旨在鉴定来自有既往恶性肿瘤史的患者的乳腺癌（BC）肿瘤的转录组和表观基因组特征。
在癌症基因组图谱项目中生成了来自 BC 的 RNA-seq 和全基因组 DNA 甲基化谱。通过组织学亚型将继发性乳腺癌（SBC）患者分开，并与原发性乳腺癌对照匹配，创建了两个独立的浸润性导管（IDC，n=36）和浸润性小叶（ILC，n=40）癌队列。整合差异表达基因以及差异甲基化基因组区域，以鉴定 SBC 中受表观遗传调控的异常基因途径。
在 IDC SBC（n=727）和 ILC SBC（n=261）中鉴定到差异表达基因（Wilcoxon 检验；P<0.05）。在 IDC SBC 中，有 105 个基因上调且低甲基化，包括雌激素受体基因，73 个基因下调且高甲基化，包括参与抗原呈递和干扰素反应途径的基因（HLA-E、IRF8 和 RELA）。然而，在 ILC SBC 中，仅有 17 个基因同步低甲基化和上调，而 46 个基因高甲基化和下调。有趣的是，SBC 基因表达谱与每种组织学亚型密切对应，仅有 1.51%的基因在两种组织学亚型之间重叠。
在 IDC 和 ILC SBC 中都观察到差异基因表达和 DNA 甲基化特征，包括与肿瘤生长和增殖相关的基因。与每个组织学亚型相对应的基因表达谱的差异强调了对疾病亚型特异性分子改变进行评估的重要性。
