Background Recently, HER2-negative breast cancers have been reclassified by protein expression into 'HER2-low' and 'HER2-zero' subgroups, but the consideration of HER2-low breast cancer as a distinct biological subtype with differing prognoses remains controversial. By contrast, non-neutral ERBB2 copy number alteration (CNA) status is associated with inferior survival outcomes compared to ERBB2 CNA-neutral breast cancer, providing an alternative approach to classification. Methods Here, we investigated the molecular landscape of non-metastatic HER2-negative BCs in relation to ERBB2 CNA status to elucidate biological differences. Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA) TCGA-BRCA datasets (n = 1875) were analyzed. Results Nearly two-fifths of the cohort harbored ERBB2 CNAs (39.4%), which were significantly enriched within hormone receptor-negative (56.1%) than within hormone receptor-positive BCs (35.5%; p < 0.0001). Globally, CNAs across the genome were significantly higher in ERBB2 non-neutral compared to neutral cohorts (p < 0.0001). Notably, genetic aberrations on chromosome 17 - BRCA1, NF1, TP53, MAP2K4, and NCOR1 - were widespread in the ERBB2 non-neutral cases. While chromosome 17q arm-level alterations were largely in tandem with ERBB2 CNA status, arm-level loss in chromosome 17p was prevalent regardless of ERBB2 gain, amplification, or loss. Differential gene expression analysis demonstrated that pathways involved in the cell cycle, proteasome, and DNA replication were upregulated in ERBB2 non-neutral cases. Conclusion Classification of HER2-negative BCs according to ERBB2 CNA status reveals differences in the genomic landscape. The implications of concurrent aberrations in other genes on chromosome 17 merit further research in ERBB2 non-neutral BCs.

中文翻译：

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通过 ERBB2 拷贝数改变状态对 HER2 阴性乳腺癌进行分类揭示了与 17 号染色体基因畸变相关的分子差异。

背景 最近，HER2 阴性乳腺癌已根据蛋白表达重新分类为“HER2 低”和“HER2 零”亚组，但将 HER2 低乳腺癌视为具有不同预后的独特生物亚型仍存在争议。相比之下，与 ERBB2 CNA 中性乳腺癌相比，非中性 ERBB2 拷贝数改变 (CNA) 状态与较差的生存结果相关，这提供了另一种分类方法。方法在这里，我们研究了非转移性 HER2 阴性 BC 与 ERBB2 CNA 状态相关的分子图谱，以阐明生物学差异。对乳腺癌国际联盟 (METABRIC) 的分子分类学和癌症基因组图谱 (TCGA) TCGA-BRCA 数据集 (n = 1875) 进行了分析。结果 近五分之二的队列拥有 ERBB2 CNA (39.4%)，其在激素受体阴性 (56.1%) 中显着富集于激素受体阳性 BC 中 (35.5%；p < 0.0001)。在全球范围内，与中性队列相比，ERBB2 非中性队列中整个基因组的 CNA 显着更高 (p < 0.0001)。值得注意的是，17号染色​​体上的遗传畸变——BRCA1、NF1、TP53、MAP2K4和NCOR1——在ERBB2非中性病例中普遍存在。虽然染色体 17q 臂水平的改变很大程度上与 ERBB2 CNA 状态相关，但无论 ERBB2 增益、扩增或丢失如何，染色体 17p 的臂水平丢失都很普遍。差异基因表达分析表明，在 ERBB2 非中性病例中，涉及细胞周期、蛋白酶体和 DNA 复制的通路上调。结论 根据 ERBB2 CNA 状态对 HER2 阴性 BC 进行分类揭示了基因组景观的差异。17 号染色体上其他基因并发畸变的影响值得在 ERBB2 非中性 BC 中进一步研究。