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Glycosylation in Cancer—Biomarkers and Targeted Therapies

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Biomarkers".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 30167

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Special Issue Editor

Dr. Jennifer Munkley

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Guest Editor

Newcastle University Biosciences Institute, International Centre for Life, Newcastle upon Tyne NE1 3BZ, UK
Interests: glycosylation; glycans; prostate cancer; glycosyltransferases; precision oncology; biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Glycans sugars are attached to proteins and lipids on the cell surface and are a major building block of life essential for virtually every biological process. Glycans play major roles in all of the established cancer hallmarks and hold huge potential for cancer research. Historically, glycans have been difficult to study because of structural complexity and the lack of a clear link to DNA. However, recent advances using new methodologies have fueled a renewed emphasis on exploiting glycans in cancer, positioning glycomics at the forefront of translational developments.

For this Special Issue, we welcome original and review papers focused on exploring the potential to exploit aberrant glycosylation in cancer to improve diagnosis and treatment. We encourage papers that provide insight into the role of glycans in the hallmarks of cancer, glycans as biomarkers for cancer diagnosis, and the potential to target glycans to develop new therapies.

I look forward to receiving your contributions.

Dr. Jennifer Munkley
Guest Editor

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Keywords

glycosylation
glycans
glycoproteins
hallmarks
biomarkers
diagnosis
targeted therapies

Published Papers (12 papers)

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Research

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14 pages, 5307 KiB

Open AccessArticle

A Comprehensive Analysis of Tn and STn Antigen Expression in Esophageal Adenocarcinoma

by Baris Mercanoglu, Karl-Frederick Karstens, Anastasios D. Giannou, Jan Meiners, Jöran Lücke, Philipp Seeger, Vera Brackrock, Cenap Güngör, Jakob R. Izbicki, Maximilian Bockhorn, Thilo Hackert, Nathaniel Melling and Gerrit Wolters-Eisfeld

Cancers 2024, 16(2), 240; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers16020240 - 05 Jan 2024

Viewed by 1014

Abstract

Differential glycosylation, marked by the presence of truncated O-glycans, is a distinctive feature of epithelial-derived cancers. However, there is a notable gap in research regarding the expression of Tn and STn antigens in esophageal adenocarcinoma (EAC). To address this, we employed commercially available antibodies, previously validated for Tn and STn antigens, to analyze two cohorts of EAC tissues. Initially, large-area tissue sections from formalin-fixed paraffin-embedded (FFPE) EAC and corresponding healthy tissues were subjected to immunohistochemistry (IHC) staining and scoring. Subsequently, we evaluated the RNA expression levels of crucial O-glycosylation related genes—C1GALT1 and C1GALT1C1—using a quantitative real-time polymerase chain reaction (qRT-PCR). In a comprehensive analysis, a substantial cohort of EAC tissues (n = 311 for Tn antigen, n = 351 for STn antigen) was investigated and correlated with clinicopathological data. Our findings revealed that Tn and STn antigens are highly expressed (approximately 71% for both) in EAC, with this expression being tumor-specific. Notably, Tn antigen expression correlates significantly with the depth of tumor cell infiltration (p = 0.026). These antigens emerge as valuable markers and potential therapeutic targets for esophageal adenocarcinoma. Full article

(This article belongs to the Special Issue Glycosylation in Cancer—Biomarkers and Targeted Therapies)

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17 pages, 1019 KiB

Open AccessArticle

N-Glycomic Profiling of Microsatellite Unstable Colorectal Cancer

by Iiris Ukkola, Pirjo Nummela, Annamari Heiskanen, Matilda Holm, Sadia Zafar, Mia Kero, Caj Haglund, Tero Satomaa, Soili Kytölä and Ari Ristimäki

Cancers 2023, 15(14), 3571; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15143571 - 11 Jul 2023

Viewed by 1030

Abstract

Aberrant glycosylation affects cancer progression and immune evasion. Approximately 15% of colorectal cancers (CRCs) demonstrate microsatellite instability (MSI) and display major differences in outcomes and therapeutic responses, as compared to corresponding microsatellite stable (MSS) tumors. We compared the N-glycan profiles of stage II and IV MSI CRC tumors, further subdivided into BRAF^V600E wild-type and mutated subgroups (n = 10 in each subgroup), with each other and with those of paired non-neoplastic mucosal samples using mass spectrometry. Further, the N-glycans of BRAF^V600E wild-type stage II MSI tumors were compared to corresponding MSS tumors (n = 9). Multiple differences in N-glycan profiles were identified between the MSI CRCs and control tissues, as well as between the stage II MSI and MSS samples. The MSI CRC tumors showed a lower relative abundance of high-mannose N-glycans than did the control tissues or the MSS CRCs. Among MSI CRC subgroups, acidic N-glycans showed tumor stage and BRAF mutation status-dependent variation. Specifically, the large, sulfated/phosphorylated, and putative terminal N-acetylhexosamine-containing acidic N-glycans differed between the MSI CRC subgroups, showing opposite changes in stages II and IV, when comparing BRAF mutated and wild-type tumors. Our results show that molecular subgroups of CRC exhibit characteristic glycan profiles that may explain certain carcinogenic properties of MSI tumors. Full article

(This article belongs to the Special Issue Glycosylation in Cancer—Biomarkers and Targeted Therapies)

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16 pages, 3331 KiB

Open AccessArticle

Glycomic, Glycoproteomic, and Proteomic Profiling of Philippine Lung Cancer and Peritumoral Tissues: Case Series Study of Patients Stages I–III

by Michael Russelle Alvarez, Qingwen Zhou, Jennyfer Tena, Mariana Barboza, Maurice Wong, Yixuan Xie, Carlito B. Lebrilla, Michelle Cabanatan, Ma. Teresa Barzaga, Nelia Tan-Liu, Francisco M. Heralde III, Luster Serrano, Ruel C. Nacario and Gladys Cherisse Completo

Cancers 2023, 15(5), 1559; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15051559 - 02 Mar 2023

Cited by 2 | Viewed by 1979

Abstract

Lung cancer is the leading cause of cancer death and non-small cell lung carcinoma (NSCLC) accounting for majority of lung cancers. Thus, it is important to find potential biomarkers, such as glycans and glycoproteins, which can be used as diagnostic tools against NSCLC. Here, the N-glycome, proteome, and N-glycosylation distribution maps of tumor and peritumoral tissues of Filipino lung cancer patients (n = 5) were characterized. We present several case studies with varying stages of cancer development (I−III), mutation status (EGFR, ALK), and biomarker expression based on a three-gene panel (CD133, KRT19, and MUC1). Although the profiles of each patient were unique, specific trends arose that correlated with the role of aberrant glycosylation in cancer progression. Specifically, we observed a general increase in the relative abundance of high-mannose and sialofucosylated N-glycans in tumor samples. Analysis of the glycan distribution per glycosite revealed that these sialofucosylated N-glycans were specifically attached to glycoproteins involved in key cellular processes, including metabolism, cell adhesion, and regulatory pathways. Protein expression profiles showed significant enrichment of dysregulated proteins involved in metabolism, adhesion, cell−ECM interactions, and N-linked glycosylation, supporting the protein glycosylation results. The present case series study provides the first demonstration of a multi-platform mass-spectrometric analysis specifically for Filipino lung cancer patients. Full article

(This article belongs to the Special Issue Glycosylation in Cancer—Biomarkers and Targeted Therapies)

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15 pages, 2048 KiB

Open AccessArticle

Sialyl Lewis^X/A and Cytokeratin Crosstalk in Triple Negative Breast Cancer

by Carlota Pascoal, Mylène A. Carrascal, Daniela F. Barreira, Rita A. Lourenço, Pedro Granjo, Ana R. Grosso, Paula Borralho, Sofia Braga and Paula A. Videira

Cancers 2023, 15(3), 731; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15030731 - 25 Jan 2023

Cited by 3 | Viewed by 2137

Abstract

Triple-negative breast cancer (TNBC) encompasses multiple entities and is generally highly aggressive and metastatic. We aimed to determine the clinical and biological relevance of Sialyl-Lewis X and A (sLe^X/A)—a fucosylated glycan involved in metastasis—in TNBC. Here, we studied tissues from 50 TNBC patients, transcripts from a TNBC dataset from The Cancer Genome Atlas (TCGA) database, and a primary breast cancer cell line. All 50 TNBC tissue samples analysed expressed sLe^X/A. Patients with high expression of sLe^X/A had 3 years less disease-free survival than patients with lower expression. In tissue, sLe^X/A negatively correlated with cytokeratins 5/6 (CK5/6, which was corroborated by the inverse correlation between fucosyltransferases and CK5/6 genes. Our observations were confirmed in vitro when inhibition of sLe^X/A remarkably increased expression of CK5/6, followed by a decreased proliferation and invasion capacity. Among the reported glycoproteins bearing sLe^X/A and based on the STRING tool, α6 integrin showed the highest interaction score with CK5/6. This is the first report on the sLe^X/A expression in TNBC, highlighting its association with lower disease-free survival and its inverse crosstalk with CK5/6 with α6 integrin as a mediator. All in all, sLe^X/A is critical for TNBC malignancy and a potential prognosis biomarker and therapeutic target. Full article

(This article belongs to the Special Issue Glycosylation in Cancer—Biomarkers and Targeted Therapies)

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17 pages, 2582 KiB

Open AccessArticle

Sialyltransferase Inhibitor Ac₅3F_axNeu5Ac Reverts the Malignant Phenotype of Pancreatic Cancer Cells, and Reduces Tumor Volume and Favors T-Cell Infiltrates in Mice

by Laura Miró, Júlia López, Pedro E. Guerrero, Neus Martínez-Bosch, Noemí Manero-Rupérez, Mireia Moreno, M. Rosa Ortiz, Esther Llop, Pilar Navarro and Rosa Peracaula

Cancers 2022, 14(24), 6133; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14246133 - 12 Dec 2022

Cited by 2 | Viewed by 1866

Abstract

Hypersialylation is a feature of pancreatic ductal adenocarcinoma (PDA) and it has been related to tumor malignancy and immune suppression. In this work, we have evaluated the potential of the sialyltransferase inhibitor, Ac₅3F_axNeu5Ac, to decrease tumor sialoglycans in PDA and to revert its malignant phenotype. Sialoglycans on PDA cells were evaluated by flow cytometry, and the functional impact of Ac₅3F_axNeu5Ac was assessed using E-selectin adhesion, migration, and invasion assays. PDA tumors were generated in syngeneic mice from KC cells and treated with Ac₅3F_axNeu5Ac to evaluate tumor growth, mice survival, and its impact on blocking sialic acid (SA) and on the tumor immune component. Ac₅3F_axNeu5Ac treatment on human PDA cells decreased α2,3-SA and sialyl-Lewis^x, which resulted in a reduction in their E-selectin adhesion, and in their migratory and invasive capabilities. Subcutaneous murine tumors treated with Ac₅3F_axNeu5Ac reduced their volume, their SA expression, and modified their immune component, with an increase in CD8⁺ T-lymphocytes and NK cells. In conclusion, Ac₅3F_axNeu5Ac treatment weakened PDA cells’ malignant phenotype, thereby reducing tumor growth while favoring anti-tumor immune surveillance. Altogether, these results show the positive impact of reducing SA expression by inhibiting cell sialyltransferases and open the way to use sialyltransferase inhibitors to target this dismal disease. Full article

(This article belongs to the Special Issue Glycosylation in Cancer—Biomarkers and Targeted Therapies)

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Graphical abstract

13 pages, 2095 KiB

Open AccessArticle

A Biomarker Panel Based upon AFP, Fucosylated Kininogen and PEG-Precipitated IgG Is Highly Accurate for the Early Detection Hepatocellular Carcinoma in Patients with Cirrhosis in Phase II and Phase III Biomarker Evaluation

by Mengjun Wang, Amit G. Singal, Neehar Parikh, Yuko Kono, Jorge Marrero and Anand Mehta

Cancers 2022, 14(23), 5970; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14235970 - 02 Dec 2022

Cited by 1 | Viewed by 1322

Abstract

We have previously identified alterations in glycosylation on serum proteins from patients with HCC and developed plate-based assays using lectins to detect the change in glycosylation. However, heterophilic antibodies, which increase with non-malignant liver disease, compromised these assays. To address this, we developed a method of polyethylene glycol (PEG) precipitation that removed the contaminating IgG and IgM but allowed for the lectin detection of the relevant glycoprotein. We found that this PEG-precipitated material itself could differentiate between cirrhosis and HCC. In the analysis of three training cohorts and one validation cohort, consisting of 571 patients, PEG-IgG had AUC values that ranged from 0.713 to 0.810. In the validation cohort, which contained samples from patients at a time of 1–6 months prior to HCC detection or 7+ months prior to detection, the AUC of this marker remained consistent (0.813 and 0.846, respectively). When this marker was incorporated into a biomarker algorithm that also consisted of AFP and fucosylated kininogen, the AUROC increased to 0.816–0.883 in the training cohort and was 0.909 in the external validation cohort. Biomarker performance was also examined though the analysis of partial ROC curves, at false positive values less than 10% (90-ROC), ≤20% (80-ROC) or ≤30% (70-ROC), which highlighted the algorithm’s improvement over the individual markers at clinically relevant specificity values. Full article

(This article belongs to the Special Issue Glycosylation in Cancer—Biomarkers and Targeted Therapies)

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16 pages, 2699 KiB

Open AccessArticle

The B-Cell-Specific Ablation of B4GALT1 Reduces Cancer Formation and Reverses the Changes in Serum IgG Glycans during the Induction of Mouse Hepatocellular Carcinoma

by Jichen Sha, Rongrong Zhang, Jiteng Fan, Yong Gu, Yiqing Pan, Jing Han, Xiaoyan Xu, Shifang Ren and Jianxin Gu

Cancers 2022, 14(5), 1333; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14051333 - 04 Mar 2022

Cited by 2 | Viewed by 2410

Abstract

Serum immunoglobulin G (IgG) glycosylation, especially galactosylation, has been found to be related to a variety of tumors, including hepatocellular carcinoma (HCC). However, whether IgG glycan changes occur in the early stages of HCC formation remains unclear. We found that the galactosylation level increased and that the related individual glycans showed regular changes over the course of HCC induction. Then, the effect of the B-cell-specific ablation of β1,4galactosyltransferase 1 (CKO B4GALT1) and B4GALT1 defects on the IgG glycans that were modified during the model induction process and HCC formation is investigated in this study. CKO B4GALT1 reduces serum IgG galactosylation levels and reduces cancer formation. Furthermore, insignificant changes in the B-cell B4GALT1 and unchanged serum IgG galactosylation levels were found during cancer induction in female mice, which might contribute to the lower cancer incidence in female mice than in male mice. The gender differences observed during glycan and B4GALT1 modification also add more evidence that the B4GALT1 in B cells and in serum IgG galactosylation may play an important role in HCC. Therefore, the findings of the present research can be used to determine the methods for the early detection of HCC as well as for prevention. Full article

(This article belongs to the Special Issue Glycosylation in Cancer—Biomarkers and Targeted Therapies)

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Review

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27 pages, 2198 KiB

Open AccessReview

Aberrant Glycosylation as Immune Therapeutic Targets for Solid Tumors

by Yasuyuki Matsumoto and Tongzhong Ju

Cancers 2023, 15(14), 3536; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15143536 - 08 Jul 2023

Cited by 6 | Viewed by 4582

Abstract

Glycosylation occurs at all major types of biomolecules, including proteins, lipids, and RNAs to form glycoproteins, glycolipids, and glycoRNAs in mammalian cells, respectively. The carbohydrate moiety, known as glycans on glycoproteins and glycolipids, is diverse in their compositions and structures. Normal cells have their unique array of glycans or glycome which play pivotal roles in many biological processes. The glycan structures in cancer cells, however, are often altered, some having unique structures which are termed as tumor-associated carbohydrate antigens (TACAs). TACAs as tumor biomarkers are glycan epitopes themselves, or glycoconjugates. Some of those TACAs serve as tumor glyco-biomarkers in clinical practice, while others are the immune therapeutic targets for treatment of cancers. A monoclonal antibody (mAb) to GD2, an intermediate of sialic-acid containing glycosphingolipids, is an example of FDA-approved immune therapy for neuroblastoma indication in young adults and many others. Strategies for targeting the aberrant glycans are currently under development, and some have proceeded to clinical trials. In this review, we summarize the currently established and most promising aberrant glycosylation as therapeutic targets for solid tumors. Full article

(This article belongs to the Special Issue Glycosylation in Cancer—Biomarkers and Targeted Therapies)

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14 pages, 3549 KiB

Open AccessReview

Role of Truncated O-GalNAc Glycans in Cancer Progression and Metastasis in Endocrine Cancers

by Diluka Pinto and Rajeev Parameswaran

Cancers 2023, 15(13), 3266; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15133266 - 21 Jun 2023

Cited by 1 | Viewed by 1535

Abstract

Glycans are an essential part of cells, playing a fundamental role in many pathophysiological processes such as cell differentiation, adhesion, motility, signal transduction, host–pathogen interactions, tumour cell invasion, and metastasis development. These glycans are also able to exert control over the changes in tumour immunogenicity, interfering with tumour-editing events and leading to immune-resistant cancer cells. The incomplete synthesis of O-glycans or the formation of truncated glycans such as the Tn-antigen (Thomsen nouveau; GalNAcα- Ser/Thr), its sialylated version the STn-antigen (sialyl-Tn; Neu5Acα2–6GalNAcα-Ser/Thr) and the elongated T-antigen (Thomsen–Friedenreich; Galβ1-3GalNAcα-Ser/Thr) has been shown to be associated with tumour progression and metastatic state in many human cancers. Prognosis in various human cancers is significantly poor when they dedifferentiate or metastasise. Recent studies in glycobiology have shown truncated O-glycans to be a hallmark of cancer cells, and when expressed, increase the oncogenicity by promoting dedifferentiation, risk of metastasis by impaired adhesion (mediated by selectins and integrins), and resistance to immunological killing by NK cells. Insight into these truncated glycans provides a complimentary and attractive route for cancer antigen discovery. The recent emergence of immunotherapies against cancers is predicted to harness the potential of using such agents against cancer-associated truncated glycans. In this review, we explore the role of truncated O-glycans in cancer progression and metastasis along with some recent studies on the role of O-glycans in endocrine cancers affecting the thyroid and adrenal gland. Full article

(This article belongs to the Special Issue Glycosylation in Cancer—Biomarkers and Targeted Therapies)

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18 pages, 1736 KiB

Open AccessReview

The Emerging Roles of Protein Interactions with O-GlcNAc Cycling Enzymes in Cancer

by Chia-Wei Hu, Jinshan Xie and Jiaoyang Jiang

Cancers 2022, 14(20), 5135; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14205135 - 20 Oct 2022

Cited by 7 | Viewed by 3152

Abstract

The dynamic O-GlcNAc modification of intracellular proteins is an important nutrient sensor for integrating metabolic signals into vast networks of highly coordinated cellular activities. Dysregulation of the sole enzymes responsible for O-GlcNAc cycling, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), and the associated cellular O-GlcNAc profile is a common feature across nearly every cancer type. Many studies have investigated the effects of aberrant OGT/OGA expression on global O-GlcNAcylation activity in cancer cells. However, recent studies have begun to elucidate the roles of protein–protein interactions (PPIs), potentially through regions outside of the immediate catalytic site of OGT/OGA, that regulate greater protein networks to facilitate substrate-specific modification, protein translocalization, and the assembly of larger biomolecular complexes. Perturbation of OGT/OGA PPI networks makes profound changes in the cell and may directly contribute to cancer malignancies. Herein, we highlight recent studies on the structural features of OGT and OGA, as well as the emerging roles and molecular mechanisms of their aberrant PPIs in rewiring cancer networks. By integrating complementary approaches, the research in this area will aid in the identification of key protein contacts and functional modules derived from OGT/OGA that drive oncogenesis and will illuminate new directions for anti-cancer drug development. Full article

(This article belongs to the Special Issue Glycosylation in Cancer—Biomarkers and Targeted Therapies)

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23 pages, 1216 KiB

Open AccessReview

Aberrant Sialylation in Cancer: Therapeutic Opportunities

by Jennifer Munkley

Cancers 2022, 14(17), 4248; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14174248 - 31 Aug 2022

Cited by 32 | Viewed by 4216

Abstract

The surface of every eukaryotic cell is coated in a thick layer of glycans that acts as a key interface with the extracellular environment. Cancer cells have a different ‘glycan coat’ to healthy cells and aberrant glycosylation is a universal feature of cancer cells linked to all of the cancer hallmarks. This means glycans hold huge potential for the development of new diagnostic and therapeutic strategies. One key change in tumour glycosylation is increased sialylation, both on N-glycans and O-glycans, which leads to a dense forest of sialylated structures covering the cell surface. This hypersialylation has far-reaching consequences for cancer cells, and sialylated glycans are fundamental in tumour growth, metastasis, immune evasion and drug resistance. The development of strategies to inhibit aberrant sialylation in cancer represents an important opportunity to develop new therapeutics. Here, I summarise recent advances to target aberrant sialylation in cancer, including the development of sialyltransferase inhibitors and strategies to inhibit Siglecs and Selectins, and discuss opportunities for the future. Full article

(This article belongs to the Special Issue Glycosylation in Cancer—Biomarkers and Targeted Therapies)

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Graphical abstract

19 pages, 2420 KiB

Open AccessReview

Glycosyltransferases in Cancer: Prognostic Biomarkers of Survival in Patient Cohorts and Impact on Malignancy in Experimental Models

by Michela Pucci, Martina Duca, Nadia Malagolini and Fabio Dall’Olio

Cancers 2022, 14(9), 2128; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14092128 - 24 Apr 2022

Cited by 9 | Viewed by 3681

Abstract

Background: Glycosylation changes are a main feature of cancer. Some carbohydrate epitopes and expression levels of glycosyltransferases have been used or proposed as prognostic markers, while many experimental works have investigated the role of glycosyltransferases in malignancy. Using the transcriptomic data of the 21 TCGA cohorts, we correlated the expression level of 114 glycosyltransferases with the overall survival of patients. Methods: Using the Oncolnc website, we determined the Kaplan–Meier survival curves for the patients falling in the 15% upper or lower percentile of mRNA expression of each glycosyltransferase. Results: Seventeen glycosyltransferases involved in initial steps of N- or O-glycosylation and of glycolipid biosynthesis, in chain extension and sialylation were unequivocally associated with bad prognosis in a majority of cohorts. Four glycosyltransferases were associated with good prognosis. Other glycosyltransferases displayed an extremely high predictive value in only one or a few cohorts. The top were GALNT3, ALG6 and B3GNT7, which displayed a p < 1 × 10⁻⁹ in the low-grade glioma (LGG) cohort. Comparison with published experimental data points to ALG3, GALNT2, B4GALNT1, POFUT1, B4GALT5, B3GNT5 and ST3GAL2 as the most consistently malignancy-associated enzymes. Conclusions: We identified several cancer-associated glycosyltransferases as potential prognostic markers and therapeutic targets. Full article

(This article belongs to the Special Issue Glycosylation in Cancer—Biomarkers and Targeted Therapies)

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