Integrated multi-omics analyses of oral squamous cell carcinoma reveal precision patient stratification and personalized treatment strategies

Chi-Sheng Wu; Hsin-Pai Li; Chia-Hsun Hsieh; Yu-Tsun Lin; Ian Yi-Feng Chang; An-Ko Chung; Yenlin Huang; Shir-Hwa Ueng; Yung-Chin Hsiao; Kun-Yi Chien; Ji-Dung Luo; Chia-Hua Chen; Wei-Chao Liao; Jui-Lung Hung; Sheng-Ning Yuan; Chun-Nan OuYang; Wei-Fan Chiang; Chih-Yen Chien; Hui-Ching Chuang; Lichieh Julie Chu; Hsuan Liu; Chia-Yu Yang; Ana I Robles; Henry Rodriguez; Hsi-Hsien Lin; Huang-Yu Yang; Chuen Hsueh; Kai-Ping Chang; Jau-Song Yu; Yu-Sun Chang

doi:10.1016/j.canlet.2025.217482

Integrated multi-omics analyses of oral squamous cell carcinoma reveal precision patient stratification and personalized treatment strategies

Cancer Lett. 2025 Jan 20:217482. doi: 10.1016/j.canlet.2025.217482. Online ahead of print.

Authors

Chi-Sheng Wu¹, Hsin-Pai Li², Chia-Hsun Hsieh³, Yu-Tsun Lin⁴, Ian Yi-Feng Chang⁵, An-Ko Chung⁴, Yenlin Huang⁶, Shir-Hwa Ueng⁷, Yung-Chin Hsiao⁸, Kun-Yi Chien⁹, Ji-Dung Luo¹⁰, Chia-Hua Chen¹¹, Wei-Chao Liao¹², Jui-Lung Hung⁴, Sheng-Ning Yuan⁴, Chun-Nan OuYang⁴, Wei-Fan Chiang¹³, Chih-Yen Chien¹⁴, Hui-Ching Chuang¹⁴, Lichieh Julie Chu¹⁵, Hsuan Liu¹⁶, Chia-Yu Yang¹⁷, Ana I Robles¹⁸, Henry Rodriguez¹⁸, Hsi-Hsien Lin¹⁹, Huang-Yu Yang²⁰, Chuen Hsueh⁷, Kai-Ping Chang²¹, Jau-Song Yu²², Yu-Sun Chang²³

Affiliations

¹ Molecular Medicine Research Center, Chang Gung University, Taoyuan City 33302, Taiwan; Department of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan City 33305, Taiwan.
² Molecular Medicine Research Center, Chang Gung University, Taoyuan City 33302, Taiwan; Department of Microbiology and Immunology, Chang Gung University, Taoyuan City 33302, Taiwan; Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, at Linkou, Taoyuan City 33305, Taiwan. Electronic address: [email protected].
³ Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, at Linkou, Taoyuan City 33305, Taiwan; Division of Hematology-Oncology, Department of Internal Medicine, New Taipei Municipal City TuCheng Hospital, New Taipei City, Taiwan; College of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan.
⁴ Molecular Medicine Research Center, Chang Gung University, Taoyuan City 33302, Taiwan.
⁵ Molecular Medicine Research Center, Chang Gung University, Taoyuan City 33302, Taiwan; Department of Neurosurgery, Chang Gung Memorial Hospital at Linkou, Taoyuan City 33305, Taiwan; Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Taoyuan City 33305, Taiwan.
⁶ Department of Pathology, Chang Gung Memorial Hospital at Linkou, Taoyuan City 33305, Taiwan; School of Medicine, National Tsing-Hua University, Hsinchu 300044, Taiwan; Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan City 33302, Taiwan.
⁷ Molecular Medicine Research Center, Chang Gung University, Taoyuan City 33302, Taiwan; Department of Pathology, Chang Gung Memorial Hospital at Linkou, Taoyuan City 33305, Taiwan.
⁸ Molecular Medicine Research Center, Chang Gung University, Taoyuan City 33302, Taiwan; Department of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan City 33305, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.
⁹ Molecular Medicine Research Center, Chang Gung University, Taoyuan City 33302, Taiwan; Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan.
¹⁰ Molecular Medicine Research Center, Chang Gung University, Taoyuan City 33302, Taiwan; Bioinformatics Resource Center, The Rockefeller University 1230 York Avenue, New York City, NY, USA 10065.
¹¹ Molecular Medicine Research Center, Chang Gung University, Taoyuan City 33302, Taiwan; Department of Anatomy, School of Medicine, Chang Gung University, Taoyuan, Taiwan.
¹² Molecular Medicine Research Center, Chang Gung University, Taoyuan City 33302, Taiwan; Department of Nephrology, Chang Gung Memorial Hospital at Linkou, Taoyuan City 33305, Taiwan.
¹³ Department of Dentistry, Chi-Mei Medical Center, Liouying, Taiwan; School of Dentistry, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan.
¹⁴ Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
¹⁵ Molecular Medicine Research Center, Chang Gung University, Taoyuan City 33302, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Liver Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan City 33305, Taiwan.
¹⁶ Molecular Medicine Research Center, Chang Gung University, Taoyuan City 33302, Taiwan; Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan; Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan City 33305, Taiwan.
¹⁷ Molecular Medicine Research Center, Chang Gung University, Taoyuan City 33302, Taiwan; Department of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan City 33305, Taiwan; Department of Microbiology and Immunology, Chang Gung University, Taoyuan City 33302, Taiwan.
¹⁸ Office of Cancer Clinical Proteomics Research, National Cancer Institute, National Institutes of Health, Rockville, Maryland, 20850, USA.
¹⁹ Department of Microbiology and Immunology, Chang Gung University, Taoyuan City 33302, Taiwan; Department of Pathology, Chang Gung Memorial Hospital at Linkou, Taoyuan City 33305, Taiwan; Division of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital at Keelung, Keelung 20401, Taiwan.
²⁰ College of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan; Department of Nephrology, Chang Gung Memorial Hospital at Linkou, Taoyuan City 33305, Taiwan.
²¹ Molecular Medicine Research Center, Chang Gung University, Taoyuan City 33302, Taiwan; Department of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan City 33305, Taiwan; College of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan. Electronic address: [email protected].
²² Molecular Medicine Research Center, Chang Gung University, Taoyuan City 33302, Taiwan; Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan; Liver Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan City 33305, Taiwan. Electronic address: [email protected].
²³ Molecular Medicine Research Center, Chang Gung University, Taoyuan City 33302, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.

PMID: 39842500
DOI: 10.1016/j.canlet.2025.217482

Abstract

Oral cavity squamous cell carcinoma (OSCC), a leading subtype of head and neck cancer, exhibits high global incidence and mortality rates. Despite advancements in surgery and radiochemotherapy, approximately one-third of patients experience relapse. To improve current targeted and immunotherapy strategies for recurrent OSCC, we conducted multi-omics analyses on pretreatment OSCC samples (cohorts 1 and 2, n=137) and identified A3A and EGFR, both at the RNA and protein levels, as inversely expressed markers for patient stratification and response prediction. Survival analysis demonstrated that elevated A3A or PD-L1 expression levels correlated to improved responses to anti-PD-1 therapy in patients (cohort 3a, n=50, IHC). In contrast, high RRAS expression (cohort 4, n=252, qRT-PCR) was significantly associated with OSCC recurrence. Cell-based experiments revealed that RRAS was involved in radiotherapy and cisplatin resistance through the EGFR/RRAS/AKT/ERK signaling pathway. In OSCC patient-derived xenograft (PDX) mouse models, treatments with cisplatin and cetuximab (anti-EGFR) effectively reduced tumor size in EGFR-high-derived (#34) but not A3A-high-derived (#22) PDX tumors. Our study demonstrated that A3A-high tumors were immune-hot and responsive to anti-PD-1 therapy, whereas EGFR-high tumors exhibited chr.7p11.2 gains and DNA repair alterations. Additionally, RRAS-high tumors were associated with OSCC recurrence via AKT and ERK phosphorylation and demonstrate improved clinical outcomes with cetuximab therapy (cohort 3b, n=49, IHC). This study emphasizes the significance of A3A and EGFR expression levels in OSCC patient stratification and precision therapy, suggesting the use of anti-PD-1 or anti-EGFR treatments, respectively based on these biomarkers. Furthermore, RRAS emerges as a novel prognostic marker for local recurrence.

Keywords: APOBEC3A; EGFR; OSCC proteogenomic study; PD-L1; RRAS.