Open Access

ARTICLE

Integrative Analysis of Glycosylation-Related Genes Reveals Prognostic Subtypes, Immune Evasion, and Therapeutic Vulnerabilities in Lung Adenocarcinoma

Yu-Wei Liu^1,#, Yung-Kuo Lee^2,3,4,#, Kai-Fu Chang^2,3, Chung-Bao Hsieh⁵, Chih-Hsuan Chang^2,4, Ching-Chung Ko^6,7,8, Hui-Ru Lin^4,9, Chi-Jen Wu^9,10, Chien-Han Yuan^2,4,11,12, Sachin Kumar^13,14,15, Dahlak Daniel Solomon¹³, Do Thi Minh Xuan¹⁶, Neethu Palekkode¹⁷, Ayman Fathima¹⁸, Hung-Yun Lin^{5,19,20,21,22}, Chih-Yang Wang^13,14,19, Chih-Jen Yang^23,24,*, Yuen-Jung Wu^25,*
1 Division of Thoracic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
2 Medical Laboratory, Medical Education and Research Center, Kaohsiung Armed Forces General Hospital, National Defense Medical University, Kaohsiung, Taiwan
3 Division of Experimental Surgery Center, Department of Surgery, Tri-Service General Hospital, National Defense Medical University, Taipei City, Taiwan
4 Institute of Medical Science and Technology, National Sun Yat-Sen University, Kaohsiung, Taiwan
5 Department of General Surgery, Taipei City Hospital Zhongxing Branch, Taipei City, Taiwan
6 Department of Medical Imaging, Chi-Mei Medical Center, Tainan, Taiwan
7 Department of Health and Nutrition, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
8 School of Medicine, College of Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan
9 Nursing Department, Kaohsiung Armed Forces General Hospital, National Defense Medical University, Kaohsiung, Taiwan
10 College of Nursing, Kaohsiung Medical University, Kaohsiung, Taiwan
11 Department of Otolaryngology, Kaohsiung Armed Forces General Hospital, National Defense Medical University, Kaohsiung, Taiwan
12 Department of Otolaryngology, National Defense Medical University, Taipei City, Taiwan
13 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei City, Taiwan
14 Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei City, Taiwan
15 Faculty of Applied Sciences and Biotechnology, Shoolini University of Biotechnology and Management Sciences, Bajhol, Himachal Pradesh, India
16 Faculty of Pharmacy, Van Lang University, 69/68 Dang Thuy Tram Street, Ward 13, Binh Thanh District, Ho Chi Minh City, Vietnam
17 Department of Biotechnology, Mother Teresa Women’s University, Kodaikanal, Tamil Nadu, India
18 Computer Engineering with specialization in Artificial Intelligence and Machine Learning, Presidency University, Yelahanka, Bengaluru, Karnataka, India
19 TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei City, Taiwan
20 Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei Medical University, Taipei City, Taiwan
21 Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USA
22 Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan
23 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
24 School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, No. 100, Tzyou 1st Road, Kaohsiung, Taiwan
25 Department of Surgery, Kaohsiung Armed Forces General Hospital, National Defense Medical University, Kaohsiung, Taiwan
* Corresponding Author: Chih-Jen Yang. Email: ; Yuen-Jung Wu. Email: ,
# These authors contributed equally to this work
(This article belongs to the Special Issue: Tumor Biomarkers for Diagnosis, Prognosis and Targeted Therapy)

Oncology Research https://doi.org/10.32604/or.2026.074013

Received 30 September 2025; Accepted 08 April 2026; Published online 24 April 2026

Abstract

Background: Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer (NSCLC) and remains a leading cause of cancer-related mortality worldwide. Aberrant glycosylation contributes to tumor progression by regulating receptor signalling, immune evasion, and metastatic. However, the prognostic and therapeutic relevance of glycosylation-related genes (GRGs) in LUAD has not been comprehensively defined. Therefore, this study aimed to comprehensively evaluate GRG-associated molecular subtypes and their clinical and therapeutic relevance in LUAD. Methods: GRGs were curated from multiple public databases and integrated with transcriptomic and clinical data from The Cancer Genome Atlas LUAD cohort (TCGA-LUAD) with validation in Gene Expression Omnibus (GEO) datasets. Consensus clustering, pathway enrichment, and immune profiling were used to identify glycosylation-associated subtypes. A glycosylation activity scoring (Glyco. marker) was developed to quantify glycosylation features. Drug response prediction was analyzed using OncoPredict and the Genomics of Drug Sensitivity in Cancer (GDSC) database. Single-cell RNA sequencing (scRNA-seq) was analyzed to evaluate cell-type-specific GRG expression. Selected proteins were by immunohistochemistry (IHC) in LUAD tissue microarrays. Results: GRG expression stratified 513 LUAD patients into four molecular clusters with distinct clinical and immune characteristics. The Glyco.High group showed elevated expression of MGAT5 (mannosyl (α-1,6)-glycoprotein β-1,6-N-acetylglucosaminyltransferase), ST6GAL1 (β-galactoside α-2,6-sialyltransferase 1), GALNT7 (polypeptide N-acetylgalactosaminyltransferase 7), and FUT8 (fucosyltransferase 8), frequent tumor protein p53 (TP53) mutations, increased immune checkpoint expression, and enrichment of regulatory T cells. The Glyco. marker score predicted overall survival and was associated with stemness signatures. Drug response prediction suggested reduced sensitivity to platinum chemotherapy and epidermal growth factor receptor (EGFR) inhibitors but increased sensitivity to phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) inhibitors. Conclusion: GRG-based molecular stratification identifies clinically distinct LUAD subtypes associated with immune regulation, tumor stemness, and therapeutic response. The Glyco. marker system provides a potential framework for prognostic assessment and precision oncology strategies in LUAD.

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Keywords

Lung adenocarcinoma; glycosylation; prognostic biomarker; tumor microenvironment; immune evasion; single-cell RNA sequencing; immunohistochemistry; precision oncology

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