Analysis of MET genetic aberrations in Chinese solid tumor patients.

Abstract

e15031 Background: Mesenchymal-epithelial transition (MET) gene encodes a member of the receptor tyrosine kinase family of proteins and is a proto-oncogene. MET gene takes part in various signaling pathways such as PI3K/AKT, Ras/MAPK, and JAK/STAT which are associated with tumor development and progression. This study aimed to reveal MET aberrated characteristics in Chinese solid tumor patients and explore the occurrence of MET oncogenic variants in solid tumors. Methods: This study retrospectively analyzed MET alterations in 1856 solid tumor patients in China from laboratory of Simcere Diagnosis (Nanjing, China) during 2019-2021. Next-generation sequencing (NGS) was performed to detect gene mutations in tumor or blood samples of the patients. Results: We screened out 1856 patients with MET gene alterations from 45717 patients with solid tumor. The high frequency of MET gene alterations was lung cancer (72.8%), colorectal cancer (10.7%), gastric cancer (4.9%), and liver cancer (2.7%). MET gene variants included missense (61.7%), copy number variation (copy number≥5) (15.4%), truncation (7.9%), splicing site variant (7.2%),fusion (1.7%),and in-frame insertion/deletions (0.9%). Among them, MET amplification was detected in 285 patients, and 93 patients carried high-level MET amplification (copy number≥10). High-level MET amplification was most frequently detected in lung cancer (41, 44.1%), gastric cancer (17, 18.3%) and liver cancer (14, 15.1%). MET exon 14 skipping was detected in 287 solid tumor patients (15.5%), of which 277 patients were lung cancer, the remaining were liver cancer, colorectal cancer, gastric cancer, osteosarcoma, melanoma, bladder cancer and glioma. We analyzed MET exon 14 alterations and classified them into 4 subgroups according to the alteration types and locations. The most common alterations were at splice donor sites (215, 74.91%), followed by the splice acceptor sites (35, 12.20%), Y1003 site (5, 1.74%), and other types (32, 11.15%). Other types included insertion or deletion in MET intron 13 or 14, for example, c.3028+21_3028+65del, c.2888-20_2888-11del, c.2888-27_2888-9del, etc. 7 lung cancer patients carried MET exon 14 skipping and MET amplification simultaneously. 36 patients carried MET gene fusions, and mostly were lung cancer (22, 61.1%). The breakpoints often located in exon 2 of MET (4, 11.1%). Conclusions: We discovered MET alterations in multiple types of solid tumors in this study. We found classic MET exon 14 skipping and MET high-level amplification in solid tumors except for lung cancer. It suggested that the activation of MET-driven signaling pathway was ubiquitous in pan-cancer, which might benefit from MET inhibitors.