Genomic characterization of clonal evolution during oropharyngeal carcinogenesis driven by human papillomavirus 16
2018
Chae, J., Seoul National University Graduate School, Seoul, Republic of Korea | Park, W.S., National Cancer Center, Goyang, Republic of Korea | Kim, M.J., Seoul National University College of Medicine, Seoul, Republic of Korea | Jang, S.S., Seoul National University Graduate School, Seoul, Republic of Korea | Hong, D., National Cancer Center, Goyang, Republic of Korea | Ryu, J., National Cancer Center, Goyang, Republic of Korea | Ryu, C.H., National Cancer Center, Goyang, Republic of Korea | Kim, J.H., National Cancer Center, Goyang, Republic of Korea | Choi, M.K., National Cancer Center, Goyang, Republic of Korea | Cho, K.H., National Cancer Center, Goyang, Republic of Korea | Moon, S.H., National Cancer Center, Goyang, Republic of Korea | Yun, T., National Cancer Center, Goyang, Republic of Korea | Kim, J.I., Seoul National University Graduate School, Seoul, Republic of Korea | Jung, Y.S., National Cancer Center, Goyang, Republic of Korea
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.
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