PO.BCS01.02 · 生物信息与计算
同源重组的转录沉默定义了浸润性小叶癌中一种功能性HRD
Transcriptional silencing of homologous recombination defines a functional HRD in invasive lobular carcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：同源重组缺陷（HRD）是基因组不稳定性的关键决定因素，也是乳腺癌中PARP抑制剂（PARPi）敏感性的主要预测指标。虽然浸润性导管癌（IDC）常表现出由BRCA1/2缺失和特征性基因组瘢痕驱动的经典HRD，但浸润性小叶癌（ILC）的HR状态仍未得到充分表征。近期证据表明，一部分ILC表现出常规基因组HRD评分无法检出的BRCA样表型，提示存在一种转录驱动的功能性HRD机制。
方法：通过将基因组HRDsum评分与针对精选HR基因集的基于ssGSEA的通路评分相整合，分析来自TCGA-BRCA的RNA测序数据。样本按组织学亚型（IDC vs. ILC）分层，并按PARPi7排序，PARPi7是一个预测PARPi应答的七基因转录组特征。应用相关性分析和线性交互模型来考察PARPi7、基因组HRDsum与HR通路活性之间的亚型特异性关系。进行差异表达和上游调控因子分析，以识别与ILC功能性HRD相关的转录组特征和调控因子。
结果：在IDC中，PARPi7与HRDsum呈正相关（R = 0.34），与雌激素受体表达呈负相关，这与经典的三阴性乳腺癌样基因组HRD表型一致。HR通路活性显示出极小的关联（R = -0.07），支持一种基因组驱动的HRD。在ILC中，这一模式则相反：PARPi7与HRDsum呈负相关（R = -0.20），与HR通路抑制强烈相关（R = -0.48），提示HR基因的转录沉默是ILC中功能性HRD表型的基础。PARPi7高表达的ILC肿瘤表现出DNA修复和细胞周期程序的协同下调，同时伴有炎症与免疫激活。BRCA1表达在两种亚型中均下降，但在IDC中更为显著（校正P = 9.29×10⁻⁸¹ vs 1.47×10⁻¹⁸）。上游调控因子分析在PARPi7高表达的ILC中识别出NUPR1的选择性激活——这是一种应激反应性转录调控因子，与PARP活性和对DNA损伤的耐受相关。
结论：虽然PARPi7高表达的IDC反映了具有BRCA1型生物学特征的经典、基因组驱动的HRD，但ILC则表现出一种转录定义的、缺乏基因组瘢痕的功能性HRD，提示PARPi7高表达行为甚至可以在基因组HRD低的肿瘤中出现。这一表型涉及HR基因和DNA修复机器的转录抑制、低HRDsum、炎症激活以及NUPR1介导的应激适应。这些发现定义了ILC中功能性HRD的一个转录组轴，提示可将PARPi策略扩展至基因组HRD之外，把HR通路沉默和NUPR1激活纳入作为治疗敏感性的生物标志物。
查看英文原文 English abstract
Background: Homologous recombination deficiency (HRD) is a key determinant of genomic instability and a major predictor of PARP inhibitor (PARPi) sensitivity in breast cancer. While invasive ductal carcinoma (IDC) commonly exhibits canonical HRD driven by BRCA1/2 loss and characteristic genomic scars, the HR status of invasive lobular carcinoma (ILC) remains poorly characterized. Recent evidence suggests that a subset of ILC displays a BRCAness-like phenotype undetected by conventional genomic HRD scores, implying a transcriptionally driven functional HRD mechanism.
Methods: RNA-sequencing data from TCGA-BRCA were analyzed by integrating genomic HRDsum scores with ssGSEA-based pathway scores for a curated HR gene set. Samples were stratified by histological subtype (IDC vs. ILC) and ranked by PARPi7, a seven-gene transcriptomic signature predictive of PARPi response. Correlation analyses and linear interaction models were applied to examine subtype-specific relationships among PARPi7, genomic HRDsum, and HR pathway activity. Differential expression and upstream regulator analyses were performed to identify transcriptomic features and regulators associated with functional HRD in ILC.
Results: In IDC, PARPi7 correlated positively with HRDsum (R = 0.34) and negatively with estrogen receptor expression, consistent with the classical triple-negative breast cancer-like genomic HRD phenotype. HR pathway activity showed minimal association (R = -0.07), supporting a genomically driven HRD. In ILC, this pattern was reversed: PARPi7 correlated negatively with HRDsum (R = -0.20) and strongly with HR pathway suppression (R = -0.48), suggesting that transcriptional silencing of HR genes underlies a functional HRD phenotype in ILC. PARPi7-high ILC tumors exhibited coordinated downregulation of DNA repair and cell-cycle programs with concurrent inflammatory and immune activation. BRCA1 expression was reduced in both subtypes but more markedly in IDC (adj.P = 9.29×10⁻⁸¹ vs 1.47×10⁻¹⁸). Upstream regulator analysis identified selective activation of NUPR1 in PARPi7-high ILC - a stress-responsive transcriptional regulator linked to PARP activity and tolerance to DNA damage.
Conclusion: While PARPi7-high IDC reflects canonical, genomically driven HRD with BRCA1-type biology, ILC demonstrates a transcriptionally defined functional HRD lacking genomic scars, implying that PARPi7-high behavior can emerge even in genomically HRD-low tumors. This phenotype involves transcriptional suppression of HR genes and DNA repair machinery, low HRDsum, inflammatory activation, and NUPR1-mediated stress adaptation. These findings define a transcriptomic axis of functional HRD in ILC, suggesting expansion of PARPi strategies beyond genomic HRD to include HR pathway silencing and NUPR1 activation as biomarkers of therapeutic sensitivity.
利益披露 Disclosure
Y. Kim, None..
Y. Kim, None..
H. Oh, None..
S. Ahn, None..
Y. Sung, None.