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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Genomic characterization of clonal evolution during oropharyngeal carcinogenesis driven by human papillomavirus 16

  • Chae, Jeesoo (Department of Biomedical Science, Seoul National University Graduate School) ;
  • Park, Weon Seo (Department of Pathology, Center for Specific Organs Cancer, Hematologic Malignancy Branch, National Cancer Center) ;
  • Kim, Min Jung (Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine) ;
  • Jang, Se Song (Department of Biomedical Science, Seoul National University Graduate School) ;
  • Hong, Dongwan (Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center) ;
  • Ryu, Junsun (Department of Otorhinolaryngology, Graduate School of Cancer Science and Policy, Department of Immunotherapeutics, National Cancer Center) ;
  • Ryu, Chang Hwan (Department of Otorhinolaryngology, Graduate School of Cancer Science and Policy, Department of Immunotherapeutics, National Cancer Center) ;
  • Kim, Ji-Hyun (Department of Otorhinolaryngology, Graduate School of Cancer Science and Policy, Department of Immunotherapeutics, National Cancer Center) ;
  • Choi, Moon-Kyung (Department of Pathology, Center for Specific Organs Cancer, Hematologic Malignancy Branch, National Cancer Center) ;
  • Cho, Kwan Ho (Center for Proton Therapy, Center for Specific Organs Cancer, National Cancer Center) ;
  • Moon, Sung Ho (Center for Proton Therapy, Center for Specific Organs Cancer, National Cancer Center) ;
  • Yun, Tak (Hematologic Oncology Clinic, Center for Specific Organs Cancer, National Cancer Center) ;
  • Kim, Jong-Il (Department of Biomedical Science, Seoul National University Graduate School) ;
  • Jung, Yuh-Seog (Department of Otorhinolaryngology, Graduate School of Cancer Science and Policy, Department of Immunotherapeutics, National Cancer Center)
  • Received : 2018.04.24
  • Accepted : 2018.06.25
  • Published : 2018.11.30
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Abstract

Secondary prevention via earlier detection would afford the greatest chance for a cure in premalignant lesions. We investigated the exomic profiles of non-malignant and malignant changes in head and neck squamous cell carcinoma (HNSCC) and the genomic blueprint of human papillomavirus (HPV)-driven carcinogenesis in oropharyngeal squamous cell carcinoma (OPSCC). Whole-exome (WES) and whole-genome (WGS) sequencing were performed on peripheral blood and adjacent non-tumor and tumor specimens obtained from eight Korean HNSCC patients from 2013 to 2015. Next-generation sequencing yielded an average coverage of $94.3{\times}$ for WES and $35.3{\times}$ for WGS. In comparative genomic analysis of non-tumor and tumor tissue pairs, we were unable to identify common cancer-associated early mutations and copy number alterations (CNA) except in one pair. Interestingly, in this case, we observed that non-tumor tonsillar crypts adjacent to HPV-positive OPSCC appeared normal under a microscope; however, this tissue also showed weak p16 expression. WGS revealed the infection and integration of high-risk type HPV16 in this tissue as well as in the matched tumor. Furthermore, WES identified shared and tumor-specific genomic alterations for this pair. Clonal analysis enabled us to infer the process by which this transitional crypt epithelium (TrCE) evolved into a tumor; this evolution was accompanied by the subsequent accumulation of genomic alterations, including an ERBB3 mutation and large-scale CNAs, such as 3q27-qter amplification and 9p deletion. We suggest that HPV16-driven OPSCC carcinogenesis is a stepwise evolutionary process that is consistent with a multistep carcinogenesis model. Our results highlight the carcinogenic changes driven by HPV16 infection and provide a basis for the secondary prevention of OPSCC.

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References

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