The clinicomolecular landscape of de novo versus relapsed stage IV metastatic breast cancer
The clinicomolecular landscape of de novo versus relapsed stage IV metastatic breast cancer
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DOI：
10.1016/j.yexmp.2020.104404
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发表时间：
2020-06-01
影响因子：
3.6
通讯作者：
O'Reilly, Seamus
中科院分区：
文献类型：
--
作者：
Seltzer, Sean;Corrigan, Mark;O'Reilly, Seamus
背景：初发转移性乳腺癌(DnMBC)占乳腺癌发病的6-10%，发病率呈上升趋势，且对钼靶X线筛查仍有抵抗力。最近的文献推测，除了筛选摄取不佳外，dnMBC的出现可能是由于其在分子水平上尚不清楚的不利生物学作用。在这里，我们从临床病理、基因组改变和差异基因表达的形式研究dnMBC的肿瘤生物学，以创建初发和复发转移性乳腺癌(RMBC)的比较图景。此外，为了解决目前筛查的局限性，我们进行了一项早期dnMBC检测的初步生物标志物调查。方法：在这项回顾性病例对照研究中，从癌症基因组图谱(TCGA)获取了治疗未获治疗的dnMBC患者(n=17)、RMBC(n=49)和正常组织(n=113)的原发肿瘤的基因表达和临床数据。临床和组织学数据采用Fisher的精确显著性检验(p<；0.05)进行分类评估，或在适当的情况下继续使用Mann-Whitney检验(p&t；0.05)。差异基因表达分析采用Edger负二项分布模型，假发现率(FDR)为0.05。结果：与RMBC相比，DNMBCs的中位生存期(36个月)明显提高(12个月)。DNMBCs激素受体阳性的可能性较大，组织学淋巴细胞浸润率较低，三重阴性的可能性较小。在基因组改变方面，dnMBCs的PTEN突变增加了4倍，ABL2和GATA3改变的存活率很低。在表达方面，dnMBCs下调TNFa、IL-17信号和趋化作用，而上调类固醇生物合成、细胞迁移和细胞黏附。结论：dnMBC和RMBC在临床、病理和分子水平上存在显著差异，提示dnMBC可能是RMBC在原发水平上的独立生物实体，其转移途径不同。此外，我们提供了一个潜在的血清生物标志物列表，如果存在这样的窗口，可能有助于检测dnMBC的转移前窗口。
Background: de novo metastatic breast cancer (dnMBC) is responsible for 6-10% of breast cancer presentations with increasing incidence and has remained resistant to detection by mammography screening. Recent publications hypothesized that in addition to poor screening uptake, the presentation of dnMBC may be due to its unfavourable biology which remains unknown at the molecular level. Here we investigated the tumour biology of dnMBC in the form of clinicopathology, genomic alterations and differential gene expression to create a comparative landscape of de novo versus relapsed metastatic breast cancer (rMBC). Additionally, to address the current screening limitations, we conducted a preliminary biomarker investigation for early dnMBC detection.Methods: In this retrospective case-control study, gene expression and clinical data were accessed from the Cancer Genome Atlas (TCGA) for primary tumours of treatment-naive patients with dnMBC (n = 17), rMBC (n = 49), and normal tissue (n = 113). The clinical and histological data were assessed categorically using Fisher's Exact-Test for significance (p < .05), or continuously using the Mann-Whitney Test (p < .05) where appropriate. The differential gene expression analysis was performed using EdgeR's negative binomial distribution model with a false discovery rate (FDR) < 0.05. The resulting gene list was analysed manually for roles in metastasis as well as ontologically using STRING-DB with FDR < 0.05.Results: dnMBCs showed improved median survival vs rMBC (36 vs. 12 months). dnMBCs were more likely to be hormone receptor positive, less likely to be triple negative with lower histological lymphocytic infiltrate. In terms of genome alterations, dnMBCs had 4-fold increased PTEN mutations and poor survival with ABL2 and GATA3 alterations. Expression-wise, dnMBCs down-regulated TNFa, IL-17 signalling, and chemotaxis, while up-regulating steroid biosynthesis, cell migration, and cell adhesion. Biomarker analysis detected pre-existing and novel breast cancer biomarkers.Conclusion: The comparative tumour landscape revealed significant clinical, pathological and molecular differences between dnMBC and rMBC, indicating that dnMBC may be a separate biological entity to rMBC at the primary level with differing paths to metastasis. Additionally, we provided a list of potential serum biomarkers that may be useful in detecting dnMBC in its pre-metastatic window if such a window exists.