Genomic characterization reveals distinct mutation landscapes and therapeutic implications in neuroendocrine carcinomas of the gastrointestinal tract

doi:10.1002/cac2.12372

HFCAS OpenIR

	Genomic characterization reveals distinct mutation landscapes and therapeutic implications in neuroendocrine carcinomas of the gastrointestinal tract
	Wu, Huanwen 1; Yu, Zicheng 2; Liu, Yueping 3; Guo, Lei 4; Teng, Lianghong 5; Guo, Lingchuan 6; Liang, Li 7; Wang, Jing 1; Gao, Jie 1; Li, Ruiyu 1; Yang, Ling 2; Nie, Xiu 8; Su, Dan 9; Liang, Zhiyong 1
	2022-10-20
发表期刊	CANCER COMMUNICATIONS
通讯作者	Liang, Zhiyong(liangzy@pumch.cn)
摘要	Background Neuroendocrine carcinomas of the gastrointestinal tract (GI-NECs) remain a disease of grim prognosis with limited therapeutic options. Their molecular characteristics are still undefined. This study aimed to explore the underlying genetic basis and heterogeneity of GI-NECs. Methods Comprehensive genomic analysis using whole-exome sequencing was performed on 143 formalin-fixed, paraffin-embedded samples of surgically resected GI-NEC with a thorough histological evaluation. Mutational signatures, somatic mutations, and copy number aberrations were analyzed and compared across anatomic locations and histological subtypes. Survival analysis was conducted to identify the independent factors. Results In total, 143 GI-NECs were examined: the stomach, 87 cases (60.8%); the esophagus, 29 cases (20.3%); the colorectum, 20 cases (14.0%); and the small intestine, 7 cases (4.9%). Eighty-three (58.0%) and 60 (42.0%) cases were subclassified into small cell and large cell subtypes, respectively. GI-NECs showed distinct genetic alterations from their lung counterparts and non-neuroendocrine carcinomas in the same locations. Obvious heterogeneity of mutational signatures, somatic mutations, and copy number variations was revealed across anatomic locations rather than histological subtypes. Except for tumor protein p53 (TP53) and retinoblastoma 1 (RB1), the most frequently mutated genes in the stomach, esophagus, colorectum, and small intestine were low-density lipoprotein receptor-related protein 1B (LRP1B), notch receptor 1 (NOTCH1), adenomatosis polyposis coli (APC), catenin beta 1 (CTNNB1), respectively. Mutations in the WNT-beta-catenin, NOTCH and erythroblastic leukemia viral oncogene B (ERBB) pathways were prevalently identified in gastric, esophageal, and colorectal NECs, respectively. Importantly, 104 (72.7%) GI-NECs harbored putative clinically relevant alterations, and non-gastric location and RB1 bi-allelic inactivation with copy number alterations were identified as two independent poor prognostic factors. Furthermore, we found that tumor cells in GI-NECs first gain clonal mutations in TP53, RB1, NOTCH1 and APC, followed by subsequent whole-genome doubling (WGD) and post-WGD clonal mutations in LRP1B, CUB and Sushi multiple domains 3 (CSMD3), FAT tumor suppressor homolog 4 (FAT4) and erb-b2 receptor tyrosine kinase 4 (ERBB4), and finally develop subclonal mutations. Conclusions GI-NECs harbor distinct genomic landscapes and demonstrate significant genetic heterogeneity across different anatomic locations. Moreover, potentially actionable alterations and prognostic factors were revealed for GI-NECs.
关键词	Neuroendocrine carcinomas Gastrointestinal tract Genomic characterization Heterogeneity Therapeutic implications
DOI	10.1002/cac2.12372
关键词[WOS]	SMALL-CELL
收录类别	SCI
语种	英语
资助项目	Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences[2021-I2M-1-002] ; National High Level Hospital Clinical Research Funding[2022-PUMCH-A-001] ; National Natural Science Foundation of China[82072747] ; National Natural Science Foundation of China[82072749]
项目资助者	Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences ; National High Level Hospital Clinical Research Funding ; National Natural Science Foundation of China
WOS研究方向	Oncology
WOS类目	Oncology
WOS记录号	WOS:000870350900001
出版者	WILEY
引用统计	被引频次：7[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://ir.hfcas.ac.cn:8080/handle/334002/129425
专题	中国科学院合肥物质科学研究院
通讯作者	Liang, Zhiyong
作者单位	1.Chinese Acad Med Sci & Peking Union Med Coll, Peking Union Med Coll Hosp, Mol Pathol Res Ctr, Dept Pathol,State Key Lab Complex Severe & Rare D, Beijing 100730, Peoples R China 2.Geneplus Beijing, Beijing 102200, Peoples R China 3.Hebei Med Univ, Dept Pathol, Hosp 4, Shijiazhuang 050011, Hebei, Peoples R China 4.Chinese Acad Med Sci & Peking Union Med Coll, Canc Hosp, Dept Pathol, Beijing 100021, Peoples R China 5.Capital Med Univ, Xuanwu Hosp, Dept Pathol, Beijing 100053, Peoples R China 6.Soochow Univ, Dept Pathol, Affiliated Hosp 1, Suzhou 215000, Jiangsu, Peoples R China 7.Southern Med Univ, Dept Pathol, Guangzhou 510515, Guangdong, Peoples R China 8.Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Pathol, Wuhan 430022, Hubei, Peoples R China 9.Chinese Acad Sci, Inst Basic Med & Canc IBMC, Zhejiang Canc Hosp, Dept Pathol,Canc Hosp,Univ Chinese Acad Sci, Hangzhou 310022, Zhejiang, Peoples R China
推荐引用方式 GB/T 7714	Wu, Huanwen,Yu, Zicheng,Liu, Yueping,et al. Genomic characterization reveals distinct mutation landscapes and therapeutic implications in neuroendocrine carcinomas of the gastrointestinal tract[J]. CANCER COMMUNICATIONS,2022.
APA	Wu, Huanwen.,Yu, Zicheng.,Liu, Yueping.,Guo, Lei.,Teng, Lianghong.,...&Liang, Zhiyong.(2022).Genomic characterization reveals distinct mutation landscapes and therapeutic implications in neuroendocrine carcinomas of the gastrointestinal tract.CANCER COMMUNICATIONS.
MLA	Wu, Huanwen,et al."Genomic characterization reveals distinct mutation landscapes and therapeutic implications in neuroendocrine carcinomas of the gastrointestinal tract".CANCER COMMUNICATIONS (2022).