A protein-based classifier for differentiating follicular thyroid adenoma and carcinoma.

Journal: EMBO molecular medicine
Published Date: May 29, 2025

Abstract

Differentiating follicular thyroid adenoma (FTA) from carcinoma (FTC) remains challenging due to similar histological features separate from invasion. This study developed and validated DNA- and/or protein-based classifiers. A total of 2443 thyroid samples from 1568 patients were obtained from 24 centers in China and Singapore. Next-generation sequencing of a 66-gene panel revealed 41 (62.1%) detectable genes, while 25 were not, showing similar alteration patterns with differing mutation frequencies. Proteomics quantified 10,336 proteins, with 187 dysregulated. A discovery protein-based XGBoost model achieved an AUROC of 0.899 (95% CI, 0.849-0.949), outperforming the gene-based model (AUROC 0.670 [95% CI, 0.612-0.729]). A subsequent 24-protein classifier, developed via targeted mass spectrometry and validated in three independent sets, showed high performance in retrospective cohorts (AUROC 0.871 [95% CI, 0.833-0.910] and 0.853 [95% CI, 0.772-0.934]) and prospective biopsies (AUROC 0.781 [95% CI, 0.563-1.000]). It exhibited a 95.7% negative predictive value for ruling out malignancy. This study presents a promising protein-based approach for the differential diagnosis of FTA and FTC, potentially enhancing diagnostic accuracy and clinical decision-making.

Authors

  • Yaoting Sun
    School of Medicine, School of Life Sciences, Westlake University, Hangzhou, China. sunyaoting@westlake.edu.cn.
  • He Wang
    Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, China International Neuroscience Institute, Beijing, China.
  • Lu Li
    State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei, China.
  • Jianbiao Wang
    Clinical Laboratory, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Wanyuan Chen
  • Li Peng
    School of Internet of Things Engineering, Jiangnan University, Wuxi 214122, China. pengli@jiangnan.edu.cn.
  • Pingping Hu
    Affiliated Hangzhou First People's Hospital, State Key Laboratory of Medical Proteomics, School of Medicine, Westlake University, Hangzhou, Zhejiang 310024, China.
  • Jing Yu
    Department of Ultrasound, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • Xue Cai
    National and Local Joint Engineering Research Center for Biomanufacturing of Chiral Chemicals, Zhejiang University of Technology, Hangzhou, People's Republic of China.
  • Nan Yao
    The Department of Radiology, Jiangmen Central Hospital/Affiliated Jiangmen Hospital of Sun Yat-Sen University, No. 23 Haibang Street, Jiangmen, 529000, Guangdong, China.
  • Yan Zhou
    Department of Computer Science, University of Texas at Dallas, Richardson, Texas 75080, United States.
  • Jiatong Wang
    Key Laboratory of Mechanism Theory and Equipment Design, Ministry of Education, Tianjin, China.
  • Yingrui Wang
    Affiliated Hangzhou First People's Hospital, State Key Laboratory of Medical Proteomics, School of Medicine, Westlake University, No. 18 Shilongshan Road, Hangzhou, 310024, China.
  • Liqin Qian
    Affiliated Hangzhou First People's Hospital, State Key Laboratory of Medical Proteomics, School of Medicine, Westlake University, Hangzhou, Zhejiang Province, China.
  • Weigang Ge
    Westlake Omics (Hangzhou) Biotechnology Co., Ltd., Hangzhou, Zhejiang, China.
  • Mengni Chen
    Westlake Omics (Hangzhou) Biotechnology Co. Ltd, No. 1 Yunmeng Road, Hangzhou, 310024, China.
  • Feng Yang
  • Zhiqiang Gui
    Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang 110001, China.
  • Wei Sun
    Sutra Medical Inc, Lake Forest, CA.
  • Zhihong Wang
    Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • Minghua Ge
    Otolaryngology and Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang 310006, China.
  • Yi He
    National Institutes for Food and Drug Control, 2 Tiantan Xili, Beijing 100050, China.
  • Guangzhi Wang
    Department of Biomedical Engineering, School of Medicine, Tsinghua University, Room C249, Beijing, 100084, China. Electronic address: wgz-dea@tsinghua.edu.cn.
  • Yongfu Zhao
    School of Computer, Qufu Normal University, 276826 Rizhao, People's Republic of China.
  • Huanjie Chen
    Department of Thyroid Surgery, Qingdao Municipal Hospital, No. 1 Jiaozhou Road, Qingdao, 266011, China.
  • Xiaohong Wu
    Department of Oncology, The Fourth People's Hospital of Wuxi, Wuxi, Jiangsu, China.
  • Yuxin Du
    School of Computer Science and Engineering, Beihang University, Beijing, China.
  • Wenjun Wei
    a State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering , Lanzhou University , Lanzhou , People's Republic of China.
  • Fan Wu
    Department of Product Design, Dalian Polytechnic University, Dalian 116034, China.
  • Dingcun Luo
    Department of Oncological Surgery, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, 310006, Zhejiang, China. ldc65@163.com.
  • Xiangfeng Lin
    Department of Thyroid Surgery, The Affiliated Yantai Yuhuangding Hospital, Qingdao University, Qingdao, Shandong Province, China.
  • Haitao Zheng
    Department of Thyroid Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong, 264000, People's Republic of China.
  • Xin Zhu
    Biomedical Information Engineering Lab, The University of Aizu, Fukushima, Japan.
  • Bei Wei
    Key Laboratory of Head and Neck Cancer Translation Research of Zhejiang Province, Zhejiang Cancer Hospital, No. 38 Guangji Road, Hangzhou, 310022, China.
  • Jiafei Shen
    Department of Diagnostic Ultrasound Imaging & Interventional Therapy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China.
  • Jincao Yao
    Department of Diagnostic Ultrasound Imaging & Interventional Therapy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China.
  • Zhennan Yuan
    Department of Oncology Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150081, China.
  • Tong Liu
    Intensive Care Medical Center, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, People's Republic of China.
  • Jun Pan
    Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, College of Bioengineering, Chongqing University, Chongqing, China. Electronic address: panj@cqu.edu.cn.
  • Yifeng Zhang
    Department of Environmental & Resource Engineering, Technical University of Denmark, Kongens Lyngby DK-2800, Denmark.
  • Yangfan Lv
    Department of Pathology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China.
  • Qiaonan Guo
    Department of Breast and Thyroid Surgery, Second Affiliated Hospital of Fujian Medical University, Quanzhou, China.
  • Qijun Wu
    Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China.
  • Tingting Gong
    Department of Gastroenterology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • Ting Chen
    CAS Key Laboratory of Tropical Marine Bio-resources and Ecology (LMB), Guangdong Provincial Key Laboratory of Applied Marine Biology (LAMB), South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, China. chan1010@scsio.ac.cn.
  • Shu Zheng
    Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 68 Jiefang Road, Hangzhou, 310009, China.
  • Jingqiang Zhu
    Department of Thyroid Surgery, West China Hospital, Sichuan University, Chengdu, China.
  • Hanqing Liu
    Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing, 100081, China.
  • Chuang Chen
    College of Electrical Engineering and Control Science, Nanjing Tech University, Nanjing 211816, China.
  • Hong Han
  • Sathiyamoorthy Selvarajan
    Department of Anatomical Pathology, Singapore General Hospital, Singapore 169856, Singapore.
  • Michael Mingzhao Xing
    School of Medicine, Southern University of Science and Technology, 1088 Xueyuan Avenue, Shenzhen, Guangdong, 518055, China.
  • Kennichi Kakudo
    Department of Pathology, Cancer Genome Centre and Thyroid Disease Centre, Izumi City General Hospital, Izumi, Japan.
  • Erik K Alexander
    Thyroid Section, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: ekalexander@bwh.harvard.edu.
  • Yijun Wu
    Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
  • Yu Wang
    Clinical and Technical Support, Philips Healthcare, Shanghai, China.
  • Dong Xu
    Department of Electrical Engineering and Computer Science, University of Missouri, Columbia, MO, USA.
  • Hao Zhang
    College of Mechanical and Electrical Engineering, Henan Agricultural University, Zhengzhou, 450002, China.
  • Xiu Nie
    Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
  • Oi Lian Kon
    Division of Medical Sciences, National Cancer Centre Singapore, 30 Hospital Boulevard, Singapore, 168583, Singapore.
  • N Gopalakrishna Iyer
    National Cancer Centre Singapore, SingHealth, Singapore.
  • Zhiyan Liu
    Department of Computer Science and Technology, Harbin Institute of Technology, Harbin, 150001, People's Republic of China.
  • Yi Zhu
    2State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong China.
  • Haixia Guan
    Department of Endocrinology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China.
  • Tiannan Guo
    Institute of Basic Medical Sciences, School of Life Science, Westlake University, Hangzhou 310024, China.

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