Genomic dissection of gastrointestinal and lung neuroendocrine neoplasm  

作　　者：Haixing Wang Li Sun Hua Bao Ao Wang Panpan Zhang Xue Wu Xiaoling Tong Xiaonan Wang Jie Luo Lin Shen Yang WShao Ming Lu 

机构地区：[1]Department of Endoscopy Center,The First Affiliated Hospital of Xiamen University,Xiamen 361003,China [2]Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing),Department of Pathology,Peking University Cancer Hospital&Institute,Beijing 100142,China [3]Translational Medicine Research Institute,Geneseeq Technology Inc.,Toronto M5G 1L7,Canada [4]Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing),Department of Gastrointestinal Oncology,Peking University Cancer Hospital&Institute,Beijing 100142,China [5]Medical Department,Nanjing Geneseeq Technology Inc.,Nanjing 210032,China [6]Department of Pathology,China-Japan Friendship Hospital,Beijing 100029,China [7]School of Public Health,Nanjing Medical University,Nanjing 210029,China

出　　处：《Chinese Journal of Cancer Research》2019年第6期918-929,共12页中国癌症研究（英文版）

摘　　要：Objective:Neuroendocrine neoplasms(NENs)are relatively rare and heterogeneous malignancies with two major subtypes:low-grade neuroendocrine tumor(NET)and high-grade neuroendocrine carcinoma(NEC).Comprehensive molecular characterization of NENs is needed to refine our understanding of the biological underpinnings of different NEN subtypes and to predict disease progression more accurately.Methods:We performed whole-exome sequencing(WES)of NEN samples from 49 patients(25 NETs and 24 NECs)arising from the stomach,intestines or lung.Clinicopathologic features were assessed and associated with molecular events.Results:NENs generally harbor a low mutation burden,with TP53 being the top mutated gene found in 31%of patients.Consistent with other studies,p53 signaling pathway dysfunction is significantly enriched in NECs compared to NETs(P<0.01).Other than TP53,tissue type-specific mutation profiles of NENs were observed in our cohort compared to those reported in pancreatic NETs.Importantly,we observed significant genomic instability,with increased copy number alterations observed across the NEN genome,which was more profound in NECs and independently correlated with poor overall survival(OS)(P<0.001).NECs could be further stratified into two molecular subtypes based on OS(P<0.001)and the chromosomal instability score(CIS).Interestingly,we discovered that the gain of whole chromosome 5 occurred at the early stage of NEN development,followed by the loss of 5 q exclusively in NECs(P<0.001).Conclusions:These findings provide novel insights into the molecular characteristics of NENs and highlight the association of genomic stability with clinical outcomes.Objective: Neuroendocrine neoplasms(NENs) are relatively rare and heterogeneous malignancies with two major subtypes: low-grade neuroendocrine tumor(NET) and high-grade neuroendocrine carcinoma(NEC).Comprehensive molecular characterization of NENs is needed to refine our understanding of the biological underpinnings of different NEN subtypes and to predict disease progression more accurately.Methods: We performed whole-exome sequencing(WES) of NEN samples from 49 patients(25 NETs and 24 NECs) arising from the stomach, intestines or lung. Clinicopathologic features were assessed and associated with molecular events.Results: NENs generally harbor a low mutation burden, with TP53 being the top mutated gene found in 31% of patients. Consistent with other studies, p53 signaling pathway dysfunction is significantly enriched in NECs compared to NETs(P<0.01). Other than TP53, tissue type-specific mutation profiles of NENs were observed in our cohort compared to those reported in pancreatic NETs. Importantly, we observed significant genomic instability, with increased copy number alterations observed across the NEN genome, which was more profound in NECs and independently correlated with poor overall survival(OS)(P<0.001). NECs could be further stratified into two molecular subtypes based on OS(P<0.001) and the chromosomal instability score(CIS). Interestingly, we discovered that the gain of whole chromosome 5 occurred at the early stage of NEN development, followed by the loss of 5 q exclusively in NECs(P<0.001).Conclusions: These findings provide novel insights into the molecular characteristics of NENs and highlight the association of genomic stability with clinical outcomes.

关 键 词：Neuroendocrine carcinoma whole-exome sequencing chromosomal instability 

分 类 号：R730.2[医药卫生—肿瘤]