Profiling Receptor Tyrosine Kinase Fusions in Chinese Breast Cancers

doi:10.3389/fonc.2021.741142

	Profiling Receptor Tyrosine Kinase Fusions in Chinese Breast Cancers
	Tao, Zhonghua 4,5; Liu, Jianxia 6; Li, Ting 4,5; Xu, Hong 7; Chen, Kai 7; Zhang, Jian 4,5; Zhou, Hao 6; Sun, Jie 6; Han, Jinming 1; Guo, Zhaoji 6
刊名	FRONTIERS IN ONCOLOGY
	2021-09-28
卷号	11
关键词	receptor tyrosine kinase gene fusion genomic rearrangments breast cancer next-generation sequencing
ISSN号	2234-943X
DOI	10.3389/fonc.2021.741142
通讯作者	Cao, Wen-Ming(caowm@zjcc.org.cn) ; Hu, Xichun(huxichun2017@163.com)
英文摘要	Background Receptor tyrosine kinases (RTKs) are a class of tyrosine kinases that regulate cell-to-cell communication and control a variety of complex biological functions. Dysregulation of RTK signaling partly due to chromosomal rearrangements leads to novel tyrosine kinase fusion oncoproteins that are possibly driver alterations to cancers. Targeting some RTK fusions with specific tyrosine kinases inhibitors (TKIs) is an effective therapeutic strategy across a spectrum of RTK fusion-related cancers. However, there is still a paucity of extensive RTK fusion investigations in breast cancer. This study aims to characterize RTK fusions in Chinese breast cancer patients. Methods An in-house DNA sequencing database of 1440 Chinese breast cancer patients with a capture-based panel (520 gene or 108 gene-panel) was thoroughly reviewed. A total of 2,229 samples including 1,045 tissues and 1,184 plasmas were analyzed. RTK fusion was defined as an in-frame fusion with the tyrosine kinase domain of the RTK completely retained. Concomitant mutations were also analyzed and tumor mutational burden (TMB) was calculated. Patients' clinical characteristics were retrieved from case records. Results A total of 30 RTK fusion events were identified from 27 breast cancer patients with a prevalence of 1.875%%. FGFR2 fusions were seen the most commonly (n=7), followed by RET (n=5), ROS1 (n=3), NTRK3 (n=3), BRAF (n=2), and NTRK1 (n=2). Other RTK fusions including ALK, EGFR, FGFR1, FGFR3, MET, and NTRK2 were identified in one patient each. A total of 27 unique resultant fusion proteins (22 with a novel partner) were discovered including 19 intrachromosomal rearrangements and 8 interchromosomal ones. Twenty-one fusions had the tyrosine kinase domain in-frame fused with a partner gene and six were juxtaposed with an intergenic space. Among the 27 fusions, FGFR2-WDR11 (E17: intergenic) (n=3) and ETV6-NTRK3 (E5:E15) (n=2) occurred recurrently. Of note, the normalized abundance of RTK fusion (fusion AF/max AF) correlated negatively with TMB (r=-0.48, P=0.017). Patients with TMB < 8 (Mutations/Mb) displayed a higher fusion abundance than those with TMB >= 8 (Mutations/Mb) (P=0.025). Moreover, CREBBP mutation only co-occurred with FGFR2 fusion (P=0.012), while NTRK3 fusion and TP53 mutation were mutually exclusive (P=0.019). Conclusion This is the first study comprehensively delineating the prevalence and spectrum of RTK fusions in Chinese breast cancers. Further study is ongoing to identify the enriched subpopulation who may benefit from RTK fusion inhibitors.
资助项目	National Science and Technology Major Project[2020ZX09201-013]
WOS关键词	GENE FUSIONS ; LANDSCAPE ; EFFICACY ; SMOKING ; DIVERSE ; GENOME ; TUMORS ; RET
WOS研究方向	Oncology
语种	英语
出版者	FRONTIERS MEDIA SA
WOS记录号	WOS:000706165800001
资助机构	National Science and Technology Major Project
内容类型	期刊论文
源URL	[http://ir.hfcas.ac.cn:8080/handle/334002/126480]
专题	中国科学院合肥物质科学研究院
通讯作者	Cao, Wen-Ming; Hu, Xichun
作者单位	1.Zhengzhou Univ, Affiliated Hosp 1, Dept Oncol, Zhengzhou, Peoples R China 2.Hebei Univ, Affiliated Hosp, Dept Med Oncol, Baoding, Peoples R China 3.Univ Chinese Acad Sci, Zhejiang Canc Hosp, Canc Hosp, Dept Breast Med Oncol, Hangzhou, Peoples R China 4.Fudan Univ, Shanghai Canc Ctr, Dept Med Oncol, Shanghai, Peoples R China 5.Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai, Peoples R China 6.Soochow Univ, Affiliated Hosp 1, Dept Gen Surg, Suzhou, Peoples R China 7.Soochow Univ, Affiliated Hosp 1, Dept Oncol, Suzhou, Peoples R China
推荐引用方式 GB/T 7714	Tao, Zhonghua,Liu, Jianxia,Li, Ting,et al. Profiling Receptor Tyrosine Kinase Fusions in Chinese Breast Cancers[J]. FRONTIERS IN ONCOLOGY,2021,11.
APA	Tao, Zhonghua.,Liu, Jianxia.,Li, Ting.,Xu, Hong.,Chen, Kai.,...&Hu, Xichun.(2021).Profiling Receptor Tyrosine Kinase Fusions in Chinese Breast Cancers.FRONTIERS IN ONCOLOGY,11.
MLA	Tao, Zhonghua,et al."Profiling Receptor Tyrosine Kinase Fusions in Chinese Breast Cancers".FRONTIERS IN ONCOLOGY 11(2021).