Computational Biology Laboratory, Danish Cancer Society Research Center, Copenhagen, Denmark.
Department of Cancer Genetics, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Norway.
Mol Oncol. 2018 Jun;12(6):972-990. doi: 10.1002/1878-0261.12312. Epub 2018 May 14.
Particular N-glycan structures are known to be associated with breast malignancies by coordinating various regulatory events within the tumor and corresponding microenvironment, thus implying that N-glycan patterns may be used for cancer stratification and as predictive or prognostic biomarkers. However, the association between N-glycans secreted by breast tumor and corresponding clinical relevance remain to be elucidated. We profiled N-glycans by HILIC UPLC across a discovery dataset composed of tumor interstitial fluids (TIF, n = 85), paired normal interstitial fluids (NIF, n = 54) and serum samples (n = 28) followed by independent evaluation, with the ultimate goal of identifying tumor-related N-glycan patterns in blood of patients with breast cancer. The segregation of N-linked oligosaccharides revealed 33 compositions, which exhibited differential abundances between TIF and NIF. TIFs were depleted of bisecting N-glycans, which are known to play essential roles in tumor suppression. An increased level of simple high mannose N-glycans in TIF strongly correlated with the presence of tumor infiltrating lymphocytes within tumor. At the same time, a low level of highly complex N-glycans in TIF inversely correlated with the presence of infiltrating lymphocytes within tumor. Survival analysis showed that patients exhibiting increased TIF abundance of GP24 had better outcomes, whereas low levels of GP10, GP23, GP38, and coreF were associated with poor prognosis. Levels of GP1, GP8, GP9, GP14, GP23, GP28, GP37, GP38, and coreF were significantly correlated between TIF and paired serum samples. Cross-validation analysis using an independent serum dataset supported the observed correlation between TIF and serum, for five of nine N-glycan groups: GP8, GP9, GP14, GP23, and coreF. Collectively, our results imply that profiling of N-glycans from proximal breast tumor fluids is a promising strategy for determining tumor-derived glyco-signature(s) in the blood. N-glycans structures validated in our study may serve as novel biomarkers to improve the diagnostic and prognostic stratification of patients with breast cancer.
特定的 N-糖链结构已知通过协调肿瘤内和相应的微环境中的各种调节事件与乳腺癌有关，因此意味着 N-糖链模式可用于癌症分层以及作为预测或预后生物标志物。然而，乳腺癌肿瘤分泌的 N-聚糖与相应的临床相关性之间的关联仍有待阐明。我们通过 HILIC UPLC 对一组发现数据集进行了 N-聚糖分析，该数据集由肿瘤间质液（TIF，n=85）、配对的正常间质液（NIF，n=54）和血清样本（n=28）组成，然后进行了独立评估，最终目的是鉴定乳腺癌患者血液中的肿瘤相关 N-聚糖模式。N-连接寡糖的分离显示出 33 种组成，它们在 TIF 和 NIF 之间表现出不同的丰度。TIF 中缺乏双分支 N-聚糖，双分支 N-聚糖已知在肿瘤抑制中发挥重要作用。TIF 中简单高甘露糖 N-聚糖水平升高与肿瘤内浸润淋巴细胞的存在强烈相关。同时，TIF 中高度复杂 N-聚糖水平低与肿瘤内浸润淋巴细胞的存在呈负相关。生存分析表明，表现出 TIF 中 GP24 丰度增加的患者预后更好，而 TIF 中 GP10、GP23、GP38 和核心 F 的低水平与预后不良相关。TIF 和配对血清样本之间 GP1、GP8、GP9、GP14、GP23、GP28、GP37、GP38 和核心 F 的水平显著相关。使用独立的血清数据集进行的交叉验证分析支持了 TIF 和血清之间观察到的相关性，在九个 N-聚糖组中的五个中：GP8、GP9、GP14、GP23 和核心 F。总的来说，我们的结果表明，从近端乳腺肿瘤液中对 N-聚糖进行分析是确定血液中肿瘤衍生糖谱的有前途的策略。我们研究中验证的 N-聚糖结构可作为新型生物标志物，用于改善乳腺癌患者的诊断和预后分层。
