三阴性乳腺癌（TNBC）异质性高、预后差、治疗成功率有限。最近，基于免疫组化的“复旦大学上海肿瘤中心（FUSCC）亚型分型”替代分类已被开发出来，并被认为更适合临床应用。使用基于 IHC 的替代分类，将手术切除的 TNBC 的 71 个石蜡包埋切片分为四种分子亚型。通过靶向二代测序进行基因组分析，并通过生物信息学探索亚型的特异性，包括生存分析、多元Cox回归、通路富集、Pyclone分析、突变特征分析和PHIAL分析。 AKT1 和 BRCA1 突变被确定为 TNBC 的独立预后因素。 TNBC 分子亚型包含表现出特定异质性的不同基因组景观。管腔雄激素受体 (LAR) 亚型与 PIK3CA 和 PI3K 通路突变相关，这些通路可能对 PI3K 通路抑制剂敏感。基底样免疫抑制 (BLIS) 亚型的特点是基因组高度不稳定性和特征 19 的特异性，而免疫调节 (IM) 亚型患者属于 PD-L1 ≥ 1% 亚组，Notch 信号传导丰富，这表明免疫检查点抑制剂和 Notch 抑制剂可能带来的好处。此外，间充质样（MES）肿瘤表现出受体酪氨酸激酶（RTK）-RAS通路的富集以及对RTK通路抑制剂的潜在敏感性。研究结果提出了潜在的治疗目标和预后因素，表明未来 TNBC 分层治疗的可能性。© 2024。作者。

Triple-negative breast cancer (TNBC) has high heterogeneity, poor prognosis, and limited treatment success. Recently, an immunohistochemistry-based surrogate classification for the "Fudan University Shanghai Cancer Center (FUSCC) subtyping" has been developed and is considered more suitable for clinical application. Seventy-one paraffin-embedded sections of surgically resected TNBC were classified into four molecular subtypes using the IHC-based surrogate classification. Genomic analysis was performed by targeted next-generation sequencing and the specificity of the subtypes was explored by bioinformatics, including survival analysis, multivariate Cox regression, pathway enrichment, Pyclone analysis, mutational signature analysis and PHIAL analysis. AKT1 and BRCA1 mutations were identified as independent prognostic factors in TNBC. TNBC molecular subtypes encompass distinct genomic landscapes that show specific heterogeneities. The luminal androgen receptor (LAR) subtype was associated with mutations in PIK3CA and PI3K pathways, which are potentially sensitive to PI3K pathway inhibitors. The basal-like immune-suppressed (BLIS) subtype was characterized by high genomic instability and the specific possession of signature 19 while patients in the immunomodulatory (IM) subtype belonged to the PD-L1 ≥ 1% subgroup with enrichment in Notch signaling, suggesting a possible benefit of immune checkpoint inhibitors and Notch inhibitors. Moreover, mesenchymal-like (MES) tumors displayed enrichment in the receptor tyrosine kinase (RTK)-RAS pathway and potential sensitivity to RTK pathway inhibitors. The findings suggest potential treatment targets and prognostic factors, indicating the possibility of TNBC stratified therapy in the future.© 2024. The Author(s).