BMB Reports 2018; 51(11): 584-589
Genomic characterization of clonal evolution during oropharyngeal carcinogenesis driven by human papillomavirus 16
Jeesoo Chae1,2, Weon Seo Park3, Min Jung Kim2, Se Song Jang1,2, Dongwan Hong4, Junsun Ryu5, Chang Hwan Ryu5, Ji-Hyun Kim5, Moon-Kyung Choi3, Kwan Ho Cho6, Sung Ho Moon6, Tak Yun7, Jong-Il Kim1,8,9,* & Yuh-Seog Jung5,*
1Department of Biomedical Science, Seoul National University Graduate School, Seoul 03080, 2Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 03080, 3Department of Pathology, Center for Specific Organs Cancer, Hematologic Malignancy Branch, National Cancer Center, Goyang 10408, 4Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Goyang 10408, 5Department of Otorhinolaryngology, Graduate School of Cancer Science and Policy, Department of Immunotherapeutics, National Cancer Center, Goyang 10408, 6Center for Proton Therapy, Center for Specific Organs Cancer, National Cancer Center, Goyang 10408, 7Hematologic Oncology Clinic, Center for Specific Organs Cancer, National Cancer Center, Goyang 10408, 8Cancer Research Institute, Seoul National University, Seoul 03080, 9Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 03080, Korea
Correspondence to: Jong-Il Kim, Tel: +82-2-740-8421; Fax: +82-2-741-5423; E-mail:; Yuh-Seog Jung, Tel: +82-31-920-1685; Fax: +82-31-920-2799; E-mail:
Received: April 24, 2018; Revised: May 21, 2018; Accepted: June 25, 2018; Published online: November 30, 2018.
© Korean Society for Biochemistry and Molecular Biology. All rights reserved.

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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× for WES and 35.3× 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.
Keywords: Carcinogenesis, Clonal evolution, Human papillomavirus 16, Oropharynx, Precancerous conditions

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