Yan Li1, Lianju Gao2, Di Ma3, Tian Qiu1, Wenbin Li1, Weihua Li1, Lei Guo1, Puyuan Xing3, Bing Liu2, Lamei Deng2, Jake Fu4, Junling Li5, Yang Yu6, Jianming Ying7. 1. Departments of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 2. Novogene Co., Ltd, Beijing, China. 3. Departments of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 4. Pfizer China Medical, Beijing, China. 5. Departments of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: drlijunling@vip.163.com. 6. Novogene Co., Ltd, Beijing, China. Electronic address: yuyang@novogene.com. 7. Departments of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: jmying@cicams.ac.cn.
Abstract
BACKGROUND: Pulmonary sarcomatoid carcinomas (PSCs) constitutes a heterogeneous group of NSCLCs, which show poor prognosis even with aggressive surgical treatment and postoperative chemotherapy. The detection MET exon14 skipping (METex14 skipping) in PSCs suggests the targeted therapeutic opportunities with MET TKIs. PATIENTS AND METHODS: We detected MET exon14 alterations using both targeted DNA- and RNA-based Next Generation Sequencing (NGS) and elucidated the driver mutation profile of 77 Chinese PSC patients. We also collected and analyzed the demographic features and clinical outcomes of patients harboring METex14 skipping mutation. RESULTS: METex14 skipping was detected in 20.8% of PSCs. A concordance of 96.1% was observed for DNA- and RNA-based NGS. 13 different genomic variants were revealed to induce METex14 skipping, including indels (N = 1) at splice acceptor sites, base substitutions (N = 4) and indels (N = 5) at splice donor sites, indels (N = 2) in the ∼20bp intronic noncoding region adjacent to the splice acceptor site, and indels (N = 1) in the exonic region. Patients harboring METex14 skipping tended to be older than others. In most cases, METex14 skipping were exclusive to other tumor driver alterations, however, we detected one case with METex14 skipping and a concurrent KRAS mutation. In survival analysis, we identified METex14 skipping as an unfavorable factor for Disease Free Survival (DFS) of PSCs. CONCLUSION: Although a high concordance of 96.1% was observed for DNA- and RNA-based NGS in detecting METex14 skipping, RNA-based sequencing appears the most accurate method, because some somatic variants not covering METex14 splices sites might also induce skipping. Without targeted treatment, patients with METex14 skipping had a shorter DFS. Because of the clinical significance of METex14 skipping and emerging effective treatment with MET TKI, the clinical screening for METex14 skipping should be encouraged, particularly in PSC patients who have poor prognosis with no effective treatments.
BACKGROUND:Pulmonary sarcomatoid carcinomas (PSCs) constitutes a heterogeneous group of NSCLCs, which show poor prognosis even with aggressive surgical treatment and postoperative chemotherapy. The detection MET exon14 skipping (METex14 skipping) in PSCs suggests the targeted therapeutic opportunities with MET TKIs. PATIENTS AND METHODS: We detected MET exon14 alterations using both targeted DNA- and RNA-based Next Generation Sequencing (NGS) and elucidated the driver mutation profile of 77 Chinese PSCpatients. We also collected and analyzed the demographic features and clinical outcomes of patients harboring METex14 skipping mutation. RESULTS: METex14 skipping was detected in 20.8% of PSCs. A concordance of 96.1% was observed for DNA- and RNA-based NGS. 13 different genomic variants were revealed to induce METex14 skipping, including indels (N = 1) at splice acceptor sites, base substitutions (N = 4) and indels (N = 5) at splice donor sites, indels (N = 2) in the ∼20bp intronic noncoding region adjacent to the splice acceptor site, and indels (N = 1) in the exonic region. Patients harboring METex14 skipping tended to be older than others. In most cases, METex14 skipping were exclusive to other tumor driver alterations, however, we detected one case with METex14 skipping and a concurrent KRAS mutation. In survival analysis, we identified METex14 skipping as an unfavorable factor for Disease Free Survival (DFS) of PSCs. CONCLUSION: Although a high concordance of 96.1% was observed for DNA- and RNA-based NGS in detecting METex14 skipping, RNA-based sequencing appears the most accurate method, because some somatic variants not covering METex14 splices sites might also induce skipping. Without targeted treatment, patients with METex14 skipping had a shorter DFS. Because of the clinical significance of METex14 skipping and emerging effective treatment with MET TKI, the clinical screening for METex14 skipping should be encouraged, particularly in PSCpatients who have poor prognosis with no effective treatments.
Authors: Eleanor R Gray; Justyna M Mordaka; Efthimia R Christoforou; Kristine von Bargen; Nicola D Potts; Christina Xyrafaki; Ana-Luisa Silva; Magdalena Stolarek-Januszkiewicz; Katarzyna Anton; Paulina K Powalowska; Simonetta Andreazza; Alessandro Tomassini; Rebecca N Palmer; Aishling Cooke; Robert J Osborne; Barnaby W Balmforth Journal: BMC Med Genomics Date: 2022-10-12 Impact factor: 3.622