PO.CL01.16 · 临床研究
血清检测MUC1和肾素可识别乳腺癌预后的循环生物标志物
Serum detection of MUC1 and renin identifies circulating biomarkers for breast cancer prognosis
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摘要 Abstract
中文摘要
背景：涉及1号染色体长臂多个位点的细胞遗传学异常是人类乳腺癌中最常见的改变之一。为界定其生物学和临床意义，我们在多样化的乳腺癌数据集中进行了大规模整合基因组分析。
方法：使用cBioPortal（包括癌症基因组图谱TCGA）分析了来自超过13,000例乳腺肿瘤的数据（n = 13,146份样本；30项研究中的12,229名患者）。评估了拷贝数改变、mRNA/蛋白表达和临床结局。通过与35种其他癌症中超过100,000份样本（n = 105,424）的比较分析确定了特异性。互斥性和共现分析识别了与肿瘤进展相关的遗传相互作用模式。评估了顶级候选物的血清可检测性。
结果：来自1q染色体不同位点的八个基因，尤其是TRIM67、DISC1、REN、DNM3、ATP1B1、VSIG8、SPTA1和MUC1，在乳腺肿瘤中显示出反复扩增（12-15%），显著超过泛癌数据集中的频率（约3%）。这些基因在正常乳腺组织中基线表达低，但在肿瘤中高表达。共现分析揭示了显著的遗传相互作用，包括TP53与MUC1/SPTA1/VSIG8以及PIK3CA与TRIM67/DISC1/REN，提示协同的功能获得性驱动侵袭性表型。在八个扩增的1q基因中，MUC1和REN显示出最强的临床相关性，因为两者均编码分泌型或脱落型蛋白，可在血清中轻易检测到，且与侵袭性乳腺癌生物学有既定关联。相比之下，DNM3和ATP1B1在血清来源的细胞外囊泡中以较低丰度可检测，支持其作为新兴但尚不确立的循环标志物的潜力。
结论：多位点扩增通过不同的基因相互作用网络共同促成乳腺癌进展。本研究识别出一组功能相关、可在血清中检测的核心基因产物，它们可能作为侵袭性乳腺癌预后、复发监测和治疗靶向的生物标志物。
查看英文原文 English abstract
Background: Cytogenetic abnormalities involving multiple loci on the long arm of chromosome 1 are among the most frequent alterations in human breast carcinoma. To define their biological and clinical significance, we conducted a large-scale integrative genomic analysis across diverse breast cancer datasets.
Methods: Data from over 13,000 breast tumors (n = 13,146 samples; 12,229 patients across 30 studies) were analyzed using cBioPortal, including The Cancer Genome Atlas (TCGA). Copy number alterations, mRNA/protein expression, and clinical outcomes were evaluated. Comparative analyses with >100,000 samples across 35 other cancers (n = 105,424) determined specificity. Mutual exclusivity and co-occurrence analyses identified genetic interaction patterns relevant to tumor progression. Serum detectability of top candidates was evaluated.
Results: Eight genes particularly TRIM67, DISC1, REN, DNM3, ATP1B1, VSIG8, SPTA1, and MUC1 from different loci of 1q chromosome showed recurrent amplifications (12-15%) in breast tumors, significantly exceeding frequencies in pan-cancer datasets (~3%). These genes displayed low baseline expression in normal breast tissue but were highly expressed in tumors. Co-occurrence analyses revealed significant genetic interplay, including TP53 with MUC1/SPTA1/VSIG8 and PIK3CA with TRIM67/DISC1/REN, suggesting cooperative gain-of-function driving aggressive phenotypes. Among the eight amplified 1q genes, MUC1 and REN showed the strongest clinical relevance, as both encode secreted or shed proteins that were readily detectable in serum and have established associations with aggressive breast cancer biology. In contrast, DNM3 and ATP1B1 were detectable at lower abundance in serum-derived extracellular vesicles, supporting their potential as emerging but less established circulating markers.
Conclusions: Multi-locus amplifications contribute collectively to breast cancer progression through distinct gene interaction networks. This study identifies a core set of functionally relevant, serum-detectable gene products that may serve as biomarkers for prognosis, recurrence monitoring, and therapeutic targeting in aggressive breast cancer.
利益披露 Disclosure
A. Bera, None..
C. D. Shriver, None..
M. Srivastava, None.