Abstract Background: Alterations in MET exon 14 (METex14) and its flanking intronic regions have been identified in a variety of cancers, and suggested to cause enhanced MET activity and oncogenesis. Clinical evidences suggested that patients with METex14 alterations often benefit from MET inhibitors such as crizotinib. Given the unique mutation profiles of Chinese lung cancer patients, it is necessary to investigate the prevalence of METex14 alterations in a large cohort of cancer patients. Patients and methods: Cases carrying METex14 alterations were screened from 26,391 Chinese cancer patients, and the clinicopathologic and molecular characteristics of the cohort were reviewed. PD-L1 immunohistochemistry and the treatment response to MET inhibitors were also analyzed for cases with such information available. Results: Compared to Western cancer population (3~7%), the frequency of METex14 alterations is much lower in Chinese cancer patients (0.7%, n=184) and in Chinese lung cancer patients (1.1%, n=175). Seventy-eight distinct METex14 alterations were detected, with majority of alterations are base substitutions at splice donor site (42%) and insertion/deletions (indels) in intron 13 (28%). Concurrent MET copy gain and non-exon14 MET mutations were found in 4% and 11% of cases, respectively. Other driver alterations, such as EGFR copy gain (11%) and mutations (8%), KRAS (5%) and PIK3CA (5%), appeared in a mutually exclusive pattern. In 71 patients sequenced by 425-gene panel, gene copy gains were prevalent in MDM2 (24%), CDK4 (14%), MCL1 (13%), TERT (13%), MYC (11%), CD274 (7%) and CDK6 (6%). Female patients contain much less TP53 mutations than male patients (65% vs. 24%, FDR = 0.01). Of 9 tissue specimens having PD-L1 immunohistochemistry (IHC) results, 5 of them (55.5%) were found PD-L1 positive, indicating the option for immunotherapy. In 14 patients who received crizotinib-treatment, the median progression free survival (mPFS) was 7 months with the longest PFS of 17 months. Upon resistance to crizotinib, two patients acquired secondary mutations in MET and one patient acquired BRAF p.K601E that can be a novel resistance mechanism to crizotinib treatment. Conclusion: Chinese cancer patients have a relatively lower frequency of METex14 alterations compared to Western patients, and these patients can be potentially treated by immunotherapy and crizotinib. Citation Format: Sisi Liu, Danni Song, Xiaoling Tong, Xue Wu, Xiaonan Wang, Yang Washington Shao. Genomic and clinical characteristics of MET exon14 alterations in 26,391 Chinese cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1324.