Background: Effective targeted therapy sorely depends on comprehensive and precise genomic profiling. Besides, single nucleotide variations (SNVs) and InDels, gene fusions, as drivers and therapeutic targets of great importance, are not yet well characterized in Chinese patients. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor tissues from 1,384 pan-cancer patients were collected and sequenced using next-generation sequencing (NGS) targeting 40 cancer genes including SNV, fusion and assessing copy number variation (CNV) (AmoyDx HANDLE Classic Panel). qPCR and fluorescence in situ hybridization (FISH) were further applied to verify NGS detected fusion genes. Results: 1,384 patients were recruited including 890 lung cancers, 272 colorectal cancers, 174 gastric cancers, and 48 endometrial cancers. The prevalence of fusion genes (5.49%), including ALK-fusion (2.67%), ROS1-fusion (0.94%), RET-fusion (0.72%), NRG1-fusion (0.29%), and NTRK-fusion (0.07%), was nearly double the frequency of previously reported data from East Asians. Prevalence of fusion genes varied in different types of cancers. For instance, ALK (3.7%), ROS1 (1.5%), RET (1.0%) and NRG1 (0.2%) fusions were largely found in patients with non-small cell lung cancer (NSCLC), and were rarely detected in other cancer types. Further analysis of genomic alterations in fusion-positive patients revealed that, TP53 (21%) was the most frequently co-occurred mutated gene with ALK fusion, while RET fusions and ROS1 fusions were rarely accompanied by other mutated genes. In addition, two patients with RBPMS-NRG1 fusion were accompanied by BRAF and RB1 mutations, whereas no co-occurred mutation was found in patients with other partners of NRG1. Patients with inconsistent results of RNA-based NGS and FISH validation fusions are still being followed for treatment and survival, updated data will be available at the time of the presentation. Conclusions: Genomic alterations in real-world Chinese populations have specific characteristics, especially fusion genes. Further characterization of these variants is essential for clinics to guide appropriate targeted therapies.