背景:患有乳腺导管原位癌(DCIS)的年轻患者通常预后较差。年轻发病的DCIS的基因组复杂性,然而,保持未充分开发。
方法:为了解决这个问题,我们进行了包括外显子组的全面研究,转录组,和vmethylome分析。我们的调查包括20个DCIS样本(包括15个年轻发病的DCIS)和配对的正常乳腺组织和血液样本。
结果:通过RNA测序,我们确定了两个不同的DCIS亚组:“免疫热”和“免疫感冒”。“免疫热”亚组的特点是淋巴细胞和巨噬细胞浸润增加,PDCD1和CTLA4的表达升高,GATA3表达降低。该组还表现出活性的免疫相关转录调节因子。突变分析显示TP53改变(38%),GATA3(25%),和TTN(19%),有两个病例显示APC突变,ERBB2和SMARCC1。常见的基因组改变,不管免疫状态如何,包括1q时拷贝数的增加,8q,17q,20q,和11季度的损失,17p,22q特征分析突出了特征2和1的优势,其中“免疫感冒”样品显示显著存在特征8。我们对13个DCIS样本的甲基化组研究确定了328个高差异甲基化区域(DMRs)和521个hypo-DMRs,“免疫感冒”病例通常显示较低的甲基化水平。
结论:总之,年轻发病的DCIS的分子特征与浸润性乳腺癌(IBC)相似,可能表明预后不良。了解这些特点,尤其是DCIS的免疫微环境,可能是确定乳腺癌新的治疗靶点和预防策略的关键。
BACKGROUND: Young patients with breast ductal carcinoma in situ (DCIS) often face a poorer prognosis. The genomic intricacies in young-onset DCIS, however, remain underexplored.
METHODS: To address this gap, we undertook a comprehensive study encompassing
exome, transcriptome, and vmethylome analyses. Our investigation included 20 DCIS samples (including 15 young-onset DCIS) and paired samples of normal breast tissue and blood.
RESULTS: Through RNA sequencing, we identified two distinct DCIS subgroups: \"immune hot\" and \"immune cold\". The \"immune hot\" subgroup was characterized by increased infiltration of lymphocytes and macrophages, elevated expression of PDCD1 and CTLA4, and reduced GATA3 expression. This group also exhibited active immunerelated transcriptional regulators. Mutational analysis revealed alterations in TP53 (38%), GATA3 (25%), and TTN (19%), with two cases showing mutations in APC, ERBB2, and SMARCC1. Common genomic alterations, irrespective of immune status, included gains in copy numbers at 1q, 8q, 17q, and 20q, and losses at 11q, 17p, and 22q. Signature analysis highlighted the predominance of signatures 2 and 1, with \"immune cold\" samples showing a significant presence of signature 8. Our methylome study on 13 DCIS samples identified 328 hyperdifferentially methylated regions (DMRs) and 521 hypo-DMRs, with \"immune cold\" cases generally showing lower levels of methylation.
CONCLUSIONS: In summary, the molecular characteristics of young-onset DCIS share similarities with invasive breast cancer (IBC), potentially indicating a poor prognosis. Understanding these characteristics, especially the immune microenvironment of DCIS, could be pivotal in identifying new therapeutic targets and preventive strategies for breast cancer.