Changes in glycosylation patterns have been associated with malignant transformation and clinical outcome in several types of cancer, although no comprehensive analysis has been performed in a pan-cancer setting. Here, we performed an extensive transcriptomic analysis of glycosylation related genes (such as enzymes involved in synthesis and degradation of glycoconjugates, transporters, mucins and galectins), using publicly available bulk and single cell transcriptomic data sets from tumor samples and cancer cell lines. We identified genes and pathways associated with different tumor types, which may represent novel diagnostic biomarkers as α2-3 sialylation for Melanoma, MUC21 for Lung adenocarcinoma and Galectin-7 for Squamous cell carcinomas (SCC). Accordingly, serum levels of Galectin-7 in patients with lung cancer were elevated in SCC respect to adenocarcinomas, supporting its biomarker potential. Moreover, we characterized the contribution of different cell types to the overall glycosylation profiles observed by performing the integration and analysis of 14 single cell RNA-seq datasets. This led us to identify that cancer cells are responsible for the specific tumor glyco-codes identified in bulk transcriptomics, while stromal and immune cells contribute in a conserved manner across various malignancies. Furthermore, our results suggest that the glycosylation-related genes and pathways expressed by cancer cells are influenced by the cell of origin and the oncogenic pathways that led to malignant transformation. Lastly, we described the association of different glycosylation-related genes and pathways with the clinical outcome of patients. Interestingly, while the expression of genes associated to some pathways (as proteoglycan biosynthesis) are consistently associated with a more aggressive disease, the correlation of others pathways with the survival of patients depends on the particular tumor type. Remarkably, the expression of genes associated with the synthesis of CMP-sialic acid was correlated with lower survival of patients in Uveal Melanoma and PDAC, while the opposite was observed for colorectal cancer. The extensive transcriptomic analysis of glycosylation pathways in cancer that we report here can serve as a resource for future research aimed to unravel the glyco-code in cancer related to clinical outcome or biomarker development.

中文翻译：

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癌症中糖基化相关基因的转录景观

尽管尚未在泛癌环境中进行全面分析，但糖基化模式的变化与几种癌症的恶性转化和临床结果有关。在这里，我们使用来自肿瘤样本和癌细胞系的公开可用的大量和单细胞转录组数据集，对糖基化相关基因（例如参与糖缀合物、转运蛋白、粘蛋白和半乳凝素的合成和降解的酶）进行了广泛的转录组分析。我们确定了与不同肿瘤类型相关的基因和通路，它们可能代表新的诊断生物标志物，如黑色素瘤的 α2-3 唾液酸化、肺腺癌的 MUC21 和鳞状细胞癌 (SCC) 的 Galectin-7。因此，肺癌患者的血清 Galectin-7 水平在 SCC 中相对于腺癌升高，这支持了其生物标志物的潜力。此外，我们通过对 14 个单细胞 RNA-seq 数据集进行整合和分析，表征了不同细胞类型对观察到的整体糖基化谱的贡献。这使我们确定癌细胞负责大量转录组学中确定的特定肿瘤糖码，而基质和免疫细胞在各种恶性肿瘤中以保守的方式起作用。此外，我们的研究结果表明，癌细胞表达的糖基化相关基因和途径受到起源细胞和导致恶性转化的致癌途径的影响。最后，我们描述了不同糖基化相关基因和通路与患者临床结果的关联。有趣的是，虽然与某些途径（如蛋白聚糖生物合成）相关的基因表达始终与更具侵袭性的疾病相关，但其他途径与患者存活率的相关性取决于特定的肿瘤类型。值得注意的是，与 CMP-唾液酸合成相关的基因表达与葡萄膜黑色素瘤和 PDAC 患者的较低存活率相关，而在结直肠癌中观察到相反的情况。我们在此报告的癌症糖基化途径的广泛转录组学分析可以作为未来研究的资源，旨在解开癌症中与临床结果或生物标志物开发相关的糖码。