PMID- 36160735 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220928 IS - 1948-5204 (Print) IS - 1948-5204 (Electronic) VI - 14 IP - 8 DP - 2022 Aug 15 TI - Profiling of gene fusion involving targetable genes in Chinese gastric cancer. PG - 1528-1539 LID - 10.4251/wjgo.v14.i8.1528 [doi] AB - BACKGROUND: Approximately half of all new cases of gastric cancer (GC) and related deaths occur in China. More than 80% of patients with GC are diagnosed at an advanced stage, which results in poor prognosis. Although HER2-directed therapy and immune checkpoint inhibitors have been somewhat successful, new drugs are still needed for the treatment of GC. Notably, several gene fusion-targeted drugs have been approved by the United States Food and Drug Administration for solid tumors, including GC, such as larotrectinib for NTRK fusion-positive cancers and zenocutuzumab for NRG1 fusion-positive cancers. However, gene fusions involving targetable genes have not been well characterized in Chinese patients with GC. AIM: To identify the profile of fusions involving targetable genes in Chinese patients with GC using clinical specimens and determine the distribution of patients with gene fusion variants among the molecular subtypes of GC. METHODS: We retrospectively analyzed gene fusion events in tumor tissue samples from 954 Chinese patients with GC. Clinicopathological characteristics were obtained from their medical records. Genetic alterations, such as single nucleotide variants, indels, amplifications, and gene fusions, were identified using a targeted sequencing panel containing 825 genes. Fusions were validated by fluorescence in situ hybridization (FISH) using break-apart probes. The microsatellite instability (MSI) status was evaluated using MSIsensor from the targeted sequencing panel data. Tumor mutational burden (TMB) was calculated using the total number of nonsynonymous mutations divided by the total genomic targeted region. Chi-square analysis was used to determine the enrichment of gene fusions associated with the molecular subtypes of GC. RESULTS: We found that 1.68% (16/954) of patients harbored 20 fusion events involving targetable genes. RARA fusions (n = 5) were the most common, followed by FGFR2, BRAF, MET, FGFR3, RET, ALK, EGFR, NTRK2, and NRG1 fusions. Two of the RARA fusions, EML4-ALK (E6:E20) and EGFR-SEPTIN14 (E7:E10), have been identified in other tumors but not in GC. Surprisingly, 18 gene fusion events were previously not reported in any cancer types. Twelve of the eighteen novel gene fusions included complete exons encoding functional domains of targetable genes, such as the tyrosine kinase domain of receptor tyrosine kinases and the DNA- and ligand-binding domains of RARA. Consistent with the results of detection using the targeted sequencing fusion panel, the results of FISH (fluorescence in situ hybridization) confirmed the rearrangement of FGFR2 and BRAF in tumors from patients 04 and 09, respectively. Genetic analysis indicated that the fusion genes were significantly enriched in patients with ERBB2 amplification (P = 0.02); however, there were no significant differences between fusion-positive and fusion-negative patients in age, sex, MSI status, and TMB. CONCLUSION: We characterized the landscape of fusions involving targetable genes in a Chinese GC cohort and found that 1.68% of patients with GC harbor potential targetable gene fusions, which were enriched in patients with ERBB2 amplification. Gene fusion detection may provide a potential treatment strategy for patients with GC with disease progression following standard therapy. CI - (c)The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved. FAU - Liu, Zhen-Hua AU - Liu ZH AD - Department of Medical Oncology, Fujian Medical University, Fuzhou 350001, Fujian Province, China. FAU - Zhu, Bo-Wen AU - Zhu BW AD - Medical Center, Genetron Health (Beijing) Technology, Co. Ltd., Beijing 102200, China. FAU - Shi, Min AU - Shi M AD - Medical Center, Genetron Health (Beijing) Technology, Co. Ltd., Beijing 102200, China. FAU - Qu, Yu-Rong AU - Qu YR AD - Medical Center, Genetron Health (Beijing) Technology, Co. Ltd., Beijing 102200, China. FAU - He, Xun-Jun AU - He XJ AD - Department of Genetics and Genomic Medicine, Zhejiang Provincial People's Hospital, Hangzhou 310000, Zhejiang Province, China. AD - Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Hangzhou 310000, Zhejiang Province, China. FAU - Yuan, Hong-Ling AU - Yuan HL AD - Medical Center, Genetron Health (Beijing) Technology, Co. Ltd., Beijing 102200, China. FAU - Ma, Jie AU - Ma J AD - Department of Pathology, Zhejiang Provincial People's Hospital, Hangzhou 310000, Zhejiang Province, China. FAU - Li, Wei AU - Li W AD - Medical Center, Genetron Health (Beijing) Technology, Co. Ltd., Beijing 102200, China. FAU - Zhao, Dan-Dan AU - Zhao DD AD - Medical Center, Genetron Health (Beijing) Technology, Co. Ltd., Beijing 102200, China. FAU - Liu, Zheng-Chuang AU - Liu ZC AD - Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Hangzhou 310000, Zhejiang Province, China. AD - Department of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Hangzhou 310000, Zhejiang Province, China. FAU - Wang, Bao-Ming AU - Wang BM AD - Medical Center, Genetron Health (Beijing) Technology, Co. Ltd., Beijing 102200, China. FAU - Wang, Chun-Yang AU - Wang CY AD - Medical Center, Genetron Health (Beijing) Technology, Co. Ltd., Beijing 102200, China. FAU - Tao, Hou-Quan AU - Tao HQ AD - Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Hangzhou 310000, Zhejiang Province, China. AD - Department of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Hangzhou 310000, Zhejiang Province, China. FAU - Ma, Tong-Hui AU - Ma TH AD - Department of Translational Medicine, Genetron Health (Beijing) Technology, Co. Ltd., Beijing 102200, China. tonghuima0818@sina.com. LA - eng PT - Journal Article PL - China TA - World J Gastrointest Oncol JT - World journal of gastrointestinal oncology JID - 101532470 PMC - PMC9412921 OTO - NOTNLM OT - Chinese population OT - ERBB2 amplification OT - Gastric cancer OT - Gene fusion OT - Targetable genes COIS- Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article. EDAT- 2022/09/27 06:00 MHDA- 2022/09/27 06:01 PMCR- 2022/08/15 CRDT- 2022/09/26 17:55 PHST- 2022/03/30 00:00 [received] PHST- 2022/06/14 00:00 [revised] PHST- 2022/07/19 00:00 [accepted] PHST- 2022/09/26 17:55 [entrez] PHST- 2022/09/27 06:00 [pubmed] PHST- 2022/09/27 06:01 [medline] PHST- 2022/08/15 00:00 [pmc-release] AID - 10.4251/wjgo.v14.i8.1528 [doi] PST - ppublish SO - World J Gastrointest Oncol. 2022 Aug 15;14(8):1528-1539. doi: 10.4251/wjgo.v14.i8.1528.