Abstract Objective: Oropharyngeal squamous cell carcinoma (OPSCC) is a subtype of head and neck squamous cell carcinoma (HNSCC). Environmental risk factors such as tobacco, alcohol, and especially, human papillomavirus (HPV) are known to be associated with HNSCC. Also, large-scale sequencing studies identified several HNSCC-associated genes such as TP53, EGFR and PIK3CA. However, still the initiation and progression of OPSCC and mutational profiles of OPSCC in Korean population are unclear. Methods: Frozen non-tumor mucosa, tumor tissues and blood were collected from nine OPSCC patients; 6 HPV positive and 3 negative. Adjacent non-tumor tissues were obtained about 1 cm apart from the tumor tissue and were histologically confirmed as non-neoplastic. We then performed whole exome sequencing with Agilent SureSelect Human All Exon Kit v4+UTR, yielding average on-target coverage of 100X. Results: First, we compared somatic alterations of adjacent non-tumor and tumor tissue to understand the genomic status of non-tumor mucosa. Comparison of genome-wide copy number alterations (CNA) between non-tumor and OPSCCs showed that majority of somatic CNA (SCNA) was occurred after tumor progression. Also, non-tumor mucosa rarely harbored genomic changes, showing average nonsilent mutations rate of 0.07 per Mb. In contrast, OPSCC showed 1.0 mutations per Mb with few shared mutations with non-tumor. These results indicate occurrence of new distinct subclones after tumor progression. Second, somatic mutations and CNA analysis of 9 OPSCC identified two distinct groups divided by the HPV status of tumor. HPV(+) tumors showed lower mutation burden than HPV(-) tumors (0.63 and 1.73 mutations per Mb, respectively). And TP53 and CDKN2A mutations were detected exclusively in HPV(-) group, accounting for 66.6% of HPV(-) tumors. Furthermore, HPV(-) tumors showed greater degree of chromosomal alterations compared to HPV(+) tumors. Conclusions: Although there are many studies to understand the relationships between premalignant and malignant tissue, there is a lack of understanding for genetic changes further from non-neoplastic mucosa. Our data show that genetic profile of normal crypt mucosa rarely changes and tumor develops in distinct subclones. This would provide a glimpse into the fundamental cellular changes of non-tumor cells of tonsillar crypts and oral cavity. Also, we provide a mutational landscape in HNSCC of Korean population. Although our OPSCC showed recurrent mutations and copy number alterations of genes related to RTK/PI(3)K- and differentiation-signaling pathways, similar as western, mutation burden in tumors was relatively lower, and somatic mutations on well-known HNSCC-associated genes such as PIK3CA, FAT1 and HRAS weren’t detected. Further investigation and molecular experiments are required to understand the mechanism of carcinogenesis and to discover early driver mutations of HNSCC. Citation Format: Jeesoo Chae, Weon Seo Park, Dongwan Hong, Jong-Il Kim, Yuh-Seog Jung. Genomic characterization of oropharyngeal squamous cell carcinoma in Korean population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4371. doi:10.1158/1538-7445.AM2017-4371