miRNA transcriptome profiling in early-stage luminal breast cancer. miRNA transcriptome profiling in early-stage luminal breast cancer

Oxysterols, oxidized derivatives of cholesterol, act in breast cancer (BC) as selective estrogen receptor modulators and affect cholesterol homeostasis, drug transport, nuclear and cell receptors, and other signaling proteins. Using overlapping data from patients with early-stage estrogen receptor-positive BC—high-coverage targeted DNA sequencing (99 patients, 113 genes), mRNA sequencing (67 patients), and full miRNome by microarrays (123 patients)—we describe complex mRNA-miRNA and miRNA-miRNA interaction (correlation) networks, with validation in two carefully curated public datasets (n=538 in total) and 11 databases. The ESR1-CH25H-INSIG1-ABCA9 axis was the most prominent, being interconnected through hsa-miR-125b-5p, but also hsa-miR-99a-5p, hsa-miR-100-5p, hsa miR 143 3p, hsa-199b-5p, hsa-miR-376a-3p, and hsa-miR-376c-3p. Mutations in SC5D, CYP46A1, and its functionally linked gene set were associated with multiple differentially expressed genes. STARD5 was upregulated in patients with positive lymph node status. High expression of miR-19b-3p was weakly associated with poor survival in multiple datasets. This is the first detailed dedicated study of interactions between DNA variation and mRNA expression of oxysterol-related genes, the miRNA transcriptome, and clinical factors in BC. Overall design: Tumor samples, 1 each for every patient (125 in total). Measured in two batches - 101 and 24. No replicates. No control samples. The purpose was to assess overall miRNome trends of the cohort.

氧甾醇（oxysterols）是胆固醇的氧化衍生物，在乳腺癌（breast cancer, BC）中可作为选择性雌激素受体调节剂，并可影响胆固醇稳态、药物转运、核受体与细胞受体及其他信号蛋白。本研究针对早期雌激素受体阳性乳腺癌患者的多组学重叠数据展开分析：涵盖高覆盖度靶向DNA测序（99例患者，113个基因）、信使RNA（mRNA）测序（67例患者）以及基于微阵列的全微小RNA组（miRNome）检测（123例患者），构建了复杂的mRNA-微小RNA（miRNA）及miRNA-miRNA相互作用（关联）网络，并通过两个经过严格质控筛选的公共数据集（总计538例样本）与11个数据库完成验证。其中ESR1-CH25H-INSIG1-ABCA9信号轴最为显著，该轴通过hsa-miR-125b-5p，同时还涉及hsa-miR-99a-5p、hsa-miR-100-5p、hsa-miR-143-3p、hsa-miR-199b-5p、hsa-miR-376a-3p及hsa-miR-376c-3p实现相互连接。SC5D、CYP46A1及其功能关联基因集的突变与多个差异表达基因显著相关。STARD5在淋巴结阳性患者中呈上调表达。miR-19b-3p的高表达在多个数据集中与不良预后呈弱相关性。本研究是首个针对乳腺癌中氧甾醇相关基因的DNA变异与mRNA表达、miRNA转录组及临床因素之间相互作用的系统性专项研究。研究整体设计：所有样本均为患者肿瘤组织样本，每名患者1份，总计125例；分两批完成检测，分别为101例与24例；无生物学重复，未设置对照样本，本研究旨在评估该队列的全miRNome表达趋势。