Abstract Introduction: Lung cancer is the leading cause of death from cancer in Hong Kong and worldwide. Nearly 80-85% of lung cancers are diagnosed with non-small cell lung cancer (NSCLC). Treatment strategies can be refined according to the distinct difference of NSCLC molecular profiling among different ethnic populations. Moreover, oncogenic driver mutations are closely linked to NSCLC in non-smokers and young people. Therefore, the urge of finding pathogenic mutations is inevitable. This study aims to discover novel mutations in NSCLC patients in Hong Kong by next-generation sequencing and characterize the clinical significance of these mutations. Methods: In order to identify mutations, DNA was purified from 6 pairs of lung tumor-normal tissues from 2 stage I adenocarcinoma (LUAD), 2 stage III LUAD and 2 stage I squamous cell carcinoma (LUSC) patients. Samples were sequenced by targeted sequencing with the TOMA OS-Seq 130 cancer gene panel. Sequence alignment and variant calling were performed by combining TOMA Stratus and in-house pipelines. Results: The mean aligned reads exceeded 14 million and the mean coverage of target region was over 1000X. MUTYH deletion was found in 66.7% (4/6) of the patients. Data from The Cancer Genome Atlas (TCGA) revealed that MUTYH deletion is significantly associated with poorer disease-free survival (DFS) (p=0.0063) and overall survival (p=0.022) in LUAD patients. TCGA data also showed that MUTYH copy number correlates with gene expression (r=0.473) and LUAD patients with MUTYH mRNA overexpression have better DFS (p=0.0205). However, such correlations were not observed in LUSC patients. MUTYH is a DNA glycosylase which involves in the base excision repair and it repairs oxidative DNA damage by preventing G:C to T:A transversion. Numerous studies indicated that biallelic mutations in MUTYH cause MUTYH-associated polyposis and increase the lifetime risk of colorectal cancer. MUTYH mutations could be associated with increased risk of endometrial and breast cancer. Conclusion: To elucidate the clinical significance of MUTYH in LUAD, an independent cohort will be sequenced to validate the primary result. Immunohistochemistry, RT-qPCR and functional assays will be performed to examine the protein expression, the gene expression and the functional role. All these findings suggested that MUTYH deletion may play a crucial role in LUAD and potentially lead to the development of biomarker and therapeutic target. Citation Format: Alvin Hong-Wai Fong, Eunice Yuen-Ting Lau, William Ka-Chun Cheung, William Chi-Shing Cho. Identification of a novel MUTYH mutation in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 560.