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Epigenetic imprinting alterations as effective diagnostic biomarkers for early-stage lung cancer and small pulmonary nodules

  • Zhou, Jian1, 2
  • Cheng, Tong3
  • Li, Xing3
  • Hu, Jie1
  • Li, Encheng4
  • Ding, Ming5
  • Shen, Rulong6
  • Pineda, John P.3
  • Li, Chun1
  • Lu, Shaohua1
  • Yu, Hongyu7
  • Sun, Jiayuan8
  • Huang, Wenbin9
  • Wang, Xiaonan3
  • Si, Han3
  • Shi, Panying3
  • Liu, Jing10
  • Chang, Meijia1
  • Dou, Maosen1
  • Shi, Meng11
  • And 5 more
  • 1 Fudan University, Shanghai, 200032, China , Shanghai (China)
  • 2 Shanghai Engineering Research Center of Internet of Things for Respiratory Medicine, Shanghai, 200032, China , Shanghai (China)
  • 3 Chinese Alliance Against Lung Cancer, 6th Floor, Building 5, No.66, Jinghuidongdao Road, Wuxi, Jiangsu, 214135, China , Wuxi (China)
  • 4 The Second Hospital Affiliated to Dalian Medical University, Dalian, Liaoning, 116044, China , Dalian (China)
  • 5 The Affiliated Zhongda Hospital of Southeast University, Nanjing, Jiangsu, 210009, China , Nanjing (China)
  • 6 Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA , Columbus (United States)
  • 7 Changzheng Hospital, Navy Medical University, Shanghai, 200003, China , Shanghai (China)
  • 8 Shanghai Jiao Tong University, Shanghai, 200030, China , Shanghai (China)
  • 9 Nanjing First Hospital, Nanjing, Jiangsu, 210006, China , Nanjing (China)
  • 10 Qingdao University, Yantai, Shandong, 264000, China , Yantai (China)
  • 11 Fudan University, Shanghai, 200040, China , Shanghai (China)
  • 12 Johns Hopkins University School of Medicine, Baltimore, MD, 21207, USA , Baltimore (United States)
Published Article
Clinical Epigenetics
Publication Date
Dec 14, 2021
DOI: 10.1186/s13148-021-01203-5
Springer Nature
  • Epigenetic Biomarkers


BackgroundEarly lung cancer detection remains a clinical challenge for standard diagnostic biopsies due to insufficient tumor morphological evidence. As epigenetic alterations precede morphological changes, expression alterations of certain imprinted genes could serve as actionable diagnostic biomarkers for malignant lung lesions.ResultsUsing the previously established quantitative chromogenic imprinted gene in situ hybridization (QCIGISH) method, elevated aberrant allelic expression of imprinted genes GNAS, GRB10, SNRPN and HM13 was observed in lung cancers over benign lesions and normal controls, which were pathologically confirmed among histologically stained normal, paracancerous and malignant tissue sections. Based on the differential imprinting signatures, a diagnostic grading model was built on 246 formalin-fixed and paraffin-embedded (FFPE) surgically resected lung tissue specimens, tested against 30 lung cytology and small biopsy specimens, and blindly validated in an independent cohort of 155 patients. The QCIGISH diagnostic model demonstrated 99.1% sensitivity (95% CI 97.5–100.0%) and 92.1% specificity (95% CI 83.5–100.0%) in the blinded validation set. Of particular importance, QCIGISH achieved 97.1% sensitivity (95% CI 91.6–100.0%) for carcinoma in situ to stage IB cancers with 100% sensitivity and 91.7% specificity (95% CI 76.0–100.0%) noted for pulmonary nodules with diameters ≤ 2 cm.ConclusionsOur findings demonstrated the diagnostic value of epigenetic imprinting alterations as highly accurate translational biomarkers for a more definitive diagnosis of suspicious lung lesions.

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