美国斯坦福大学Christina Curtis小组发现，复杂重排推动ER⁺和HER2⁺乳腺肿瘤。该研究于2025年1月8日在线发表于国际一流学术期刊《自然》。

研究人员表示，乳腺癌是一种高度异质性的疾病，尽管通过三种受体——雌激素受体（ER）、孕激素受体和人类表皮生长因子受体2（HER2；由ERBB2编码）——的表达来定义其预后和治疗，但这种方式不足以全面捕捉临床结果和治疗脆弱性的全貌。此前，研究人员证明了转录和基因组谱系能够定义11种整合亚型，这些亚型具有不同的临床结局，包括四种ER⁺亚型，这些亚型在诊断后几十年内存在较高的复发风险。

为了确定这些亚型是否反映了不同的演变历史、与免疫系统的相互作用以及通路依赖性，研究人员建立了一个包含1828例乳腺肿瘤的元队列，涵盖了预侵袭性、原发侵袭性和转移性疾病，并进行了全基因组和转录组测序。

研究人员证明乳腺肿瘤沿着由三种基因组原型构成的连续谱分布。ER⁺高风险整合亚组的特征是复杂的局部扩增，类似于HER2⁺肿瘤，包括通过R-loop形成和APOBEC3B编辑作用于ER的周期性外染色体DNA扩增，这些扩增在预侵袭性病变中出现。相比之下，三阴性肿瘤表现出全基因组不稳定性和串联重复，且富含同源修复缺陷样特征，而ER⁺典型风险肿瘤则在基因组上基本稳定。

这些基因组原型在肿瘤发生早期就已确立，塑造了肿瘤微环境，并在转移性疾病中得到了保留。这些复杂的结构性改变促进了复制压力和免疫逃逸，并在肿瘤演变过程中持续存在，从而揭示了潜在的脆弱性。

附：英文原文

Title: Complex rearrangements fuel ER+ and HER2+ breast tumours

Author: Houlahan, Kathleen E., Mangiante, Lise, Sotomayor-Vivas, Cristina, Adimoelja, Alvina, Park, Seongyeol, Khan, Aziz, Pribus, Sophia J., Ma, Zhicheng, Caswell-Jin, Jennifer L., Curtis, Christina

Issue&Volume: 2025-01-08

Abstract: Breast cancer is a highly heterogeneous disease whose prognosis and treatment as defined by the expression of three receptors—oestrogen receptor (ER), progesterone receptor and human epidermal growth factor receptor2 (HER2; encoded by ERBB2)—is insufficient to capture the full spectrum of clinical outcomes and therapeutic vulnerabilities. Previously, we demonstrated that transcriptional and genomic profiles define eleven integrative subtypes with distinct clinical outcomes, including four ER+ subtypes with increased risk of relapse decades after diagnosis1,2. Here, to determine whether these subtypes reflect distinct evolutionary histories, interactions with the immune system and pathway dependencies, we established a meta-cohort of 1,828 breast tumours spanning pre-invasive, primary invasive and metastatic disease with whole-genome and transcriptome sequencing. We demonstrate that breast tumours fall along a continuum constrained by three genomic archetypes. The ER+ high-risk integrative subgroup is characterized by complex focal amplifications, similar to HER2+ tumours, including cyclic extrachromosomal DNA amplifications induced by ER through R-loop formation and APOBEC3B-editing, which arise in pre-invasive lesions. By contrast, triple-negative tumours exhibit genome-wide instability and tandem duplications and are enriched for homologous repair deficiency-like signatures, whereas ER+ typical-risk tumours are largely genomically stable. These genomic archetypes, which replicate in an independent cohort of 2,659 primary tumours, are established early during tumorigenesis, sculpt the tumour microenvironment and are conserved in metastatic disease. These complex structural alterations contribute to replication stress and immune evasion, and persist throughout tumour evolution, unveiling potential vulnerabilities.

DOI: 10.1038/s41586-024-08377-x

Source: https://www.nature.com/articles/s41586-024-08377-x