Department of Breast Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan.
Breast Cancer Res Treat. 2020 Jun;181(2):309-322. doi: 10.1007/s10549-020-05630-5. Epub 2020 Apr 13.
While the prognostic relevance of lymphovascular invasion (LVI) in breast cancer is well known, its molecular biology is poorly understood. We hypothesized that pathologically determined LVI reflects molecular features of tumors and can be discerned from their genomic and transcriptomic profiles.
LVI status and Nottingham histological scores of primary breast tumors of The Cancer Genome Atlas (TCGA) project were assessed from pathology reports; other clinical and molecular data were obtained from TCGA data portals and publications. Two independent datasets (GSE5460 and GSE7849) were combined and used for validation.
LVI status was determinable for 639 and 196 cases of the TCGA and validation cohorts, among whom LVI incidence was 37.8% and 37.2%, respectively. LVI was associated with high tumor Ki67 expression, advanced pathologic stage, and high Nottingham scores. LVI-positive cases had worse overall and progression-free survival regardless of cancer subtype. Surprisingly, in both cohorts, LVI was not associated with lymphangiogenesis or lymphatic vessel density as estimated from tumor expression of lymphatic endothelium-associated genes. LVI-positive tumors had higher genome copy number aberrations, aneuploidy, and homologous recombination defects, but not single-nucleotide variations or intra-tumor genome heterogeneity. Tumor immune cell composition and cytolytic activity was not associated with LVI status. On the other hand, expression of cell proliferation-related genes was significantly increased in LVI-positive tumors.
Our study suggests that breast cancer with LVI is a highly proliferative cancer, and it does not correlate with gene expression markers for lymphangiogenesis or immune response.
虽然淋巴血管侵犯（LVI）在乳腺癌中的预后相关性已得到充分证实，但对其分子生物学仍知之甚少。我们假设病理确定的 LVI 反映了肿瘤的分子特征，可以从其基因组和转录组谱中辨别出来。
从病理学报告中评估了癌症基因组图谱（TCGA）项目中原发性乳腺癌的 LVI 状态和诺丁汉组织学评分；其他临床和分子数据来自 TCGA 数据门户和出版物。两个独立的数据集（GSE5460 和 GSE7849）被合并并用于验证。
TCGA 和验证队列中分别有 639 例和 196 例可确定 LVI 状态，其中 LVI 发生率分别为 37.8%和 37.2%。LVI 与肿瘤 Ki67 表达高、病理分期晚和诺丁汉评分高有关。无论癌症亚型如何，LVI 阳性病例的总生存期和无进展生存期均较差。令人惊讶的是，在两个队列中，LVI 与肿瘤表达的淋巴管内皮相关基因所估计的淋巴管生成或淋巴管密度均无相关性。LVI 阳性肿瘤具有更高的基因组拷贝数异常、非整倍体和同源重组缺陷，但没有单核苷酸变异或肿瘤内基因组异质性。肿瘤免疫细胞组成和细胞溶解活性与 LVI 状态无关。另一方面，LVI 阳性肿瘤中与细胞增殖相关的基因表达显著增加。
我们的研究表明，具有 LVI 的乳腺癌是一种高度增殖性癌症，与淋巴管生成或免疫反应的基因表达标志物无关。
