Multimodal profiling of oral squamous cell carcinoma - identifies genomic alterations and expression programs associated with betel quid chewing

Sep 23, 2026

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Betel quid (BQ) chewing is a major risk factor for oral squamous cell carcinoma (OSCC) in Southeast Asia, but the mechanisms linking BQ exposure to genome damage and a distinct tumor niche remain unclear. A multi-omics study combined exome sequencing of tumor-normal pairs from 261 male OSCC patients (129 habitual BQ chewers, 132 non-BQ users) with integrated single-cell and spatial transcriptomics. Genomic analyses revealed BQ-associated enrichment of altered genes, including TP53 and CHUK mutations and MAP3K13/FADD copy gains with CDKN2A loss, together with frequently changed oncogenic pathways such as Hippo and p53 signaling and potential combination therapy opportunities. Tissue-level program shifts indicated tumor microenvironment remodeling, featuring induced hypoxia in tumor epithelium, altered dendritic-cell immunosuppression, and increased sprouting angiogenesis. Quantitative intercellular communication inference showed more heterogeneous cell-cell crosstalk in BQ-related OSCC, especially between fibroblasts and dendritic cells with other non-epithelial populations via extracellular matrix-receptor signaling. Overall, BQ-driven genomic landscapes suggest an etiological OSCC subtype distinct from BQ-negative counterparts.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Introduction

Carcinogenic causes of OSCC and lifestyle associations

Role of betel quid exposure in oral tumorigenesis

Carcinogen-mediated mechanisms (areca nut, arecoline, ROS and cytokines)

Neoplasia 68 (2025) 101218 Contents lists available at ScienceDirect Neoplasia journal [homepage:](homepage: www.elsevier.com/locate/neo)[ www.elsevier.com/locate/neo](homepage: www.elsevier.com/locate/neo) | Original Research
Multimodal profiling of oral squamous cell carcinoma identifies genomic alterations and expression programs associated with betel quid chewing
Shih-Chi Sua,b , Chiao-Wen Linc,d, Mu-Kuan Chene, Yi-Chan Lee f,g, Chun-Wen Suh,i, Shi Baij, Hansraj Jangirj, Chun-Yi Chuang k,l, Wen-Hung Chung a,m, Lun-Ching Chang j,* ,
Shun-Fa Yangh,i,**
a Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, 204, Taiwan b Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan c Institute of Oral Sciences, Chung Shan Medical University, Taichung, 402 Taiwan
d Department of Dentistry, Chung Shan Medical University Hospital, Taichung, 402, Taiwan
e Department of Otorhinolaryngology-Head and Neck Surgery, Changhua Christian Hospital, Changhua, 500, Taiwan f Department of Otolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Keelung, 204, Taiwan g College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan
h Institute of Medicine, Chung Shan Medical University, Taichung, 402, Taiwan
i Department of Medical Research, Chung Shan Medical University Hospital, Taichung, 402, Taiwan j Department of Mathematics and Statistics, Florida Atlantic University, Florida, FL33431, USA k Department of Otolaryngology, Chung Shan Medical University Hospital, Taichung, 402, Taiwan l School of Medicine, Chung Shan Medical University, Taichung, 402, Taiwan
m Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Linkou, 333, Taiwan | | | | | --- | --- | --- | --- | | A R T I C L E I N F O | | A B S T R A C T | | | Keywords:
oral squamous cell carcinoma betel quid
actionable alteration mutational signature expression program
cell-cell communication | | Betel quid (BQ) chewing is a profound risk for oral squamous cell carcinoma (OSCC) in Southeast Asia. Yet, the detailed mechanisms by which BQ chewing damages the genome and creates a unique tumor niche that ultimately cause OSCC are still not fully understood. To address this, we conducted a multi-omics survey, including exome sequencing of tumor-normal pairs from 261 male patients with OSCC (129 habitual BQ chewers and 132 non-BQ users), alone with integrated single-cell and spatial transcriptomics of a set of tumors. Comparative analyses of the mutational catalog identified enrichment of significantly altered genes (e.g. mutations of TP53 and CHUK, copy gains of MAP3K13 and FADD, copy losses of CDKN2A) associated with BQ chewing. Assessment of oncogenic and co-occurring actionable alterations demonstrated frequently altered oncogenic pathways (Hippo and p53 signaling) and potential combination therapy opportunities linked to BQ use. In addition, evaluation of epithelial, immune, stromal expression programs in the corresponding tissue compartments revealed a shift of tumor microenvironment in BQ-related OSCC, characterized by induced hypoxia of tumor epithelium, altered immunosuppression of dendritic cells, and raised sprouting angiogenesis of tumor endothelium. Quantitative predictions of intercellular communications inferred a more heterogeneous cell-cell crosstalk among BQ-related OSCC, highlighted by extensive interactions of fibroblasts and dendritic cells with other non-epithelial cell types via mostly extracellular matrix-receptor signaling pathways. Collectively, these differences in genomic landscape and tumor niche suggest that OSCC caused by BQ chewing could be an etiological subtype different from their BQ-negative counterparts. | | Abbreviations: BQ, betel quid; OSCC, oral squamous cell carcinoma; scRNA-seq, single-cell RNA-sequencing; ST, spatial transcriptomics. * Corresponding author at: Departme

FAQs

What was the study design used to connect betel quid chewing to OSCC?

The research used multi-omics profiling, including exome sequencing of tumor-normal pairs from 261 male OSCC patients and integrated single-cell and spatial transcriptomics on selected tumors.

Which genomic changes were enriched in BQ-related OSCC?

Comparative mutational analyses identified enrichment of significantly altered genes, including TP53 and CHUK mutations, MAP3K13 and FADD copy gains, and CDKN2A copy losses.

How does BQ-related OSCC differ in the tumor microenvironment?

The study reported epithelial hypoxia, altered immunosuppression of dendritic cells, and increased sprouting angiogenesis of tumor endothelium, indicating microenvironment remodeling.

Sep 23, 2026

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