Haixing Wang; Li Sun; Hua Bao; Ao Wang; Panpan Zhang; Xue Wu; Xiaoling Tong; Xiaonan Wang; Jie Luo; Lin Shen; Yang W. Shao; Ming Lu

doi:10.21147/j.issn.1000-9604.2019.06.08

Chin J Cancer Res> 2019, Vol. 31> Issue(6) : 918-929

Citation: Wang H, Sun L, Bao H, Wang A, Zhang P, Wu X, Tong X, Wang X, Luo J, Shen L, Shao YW, Lu M. Genomic dissection of gastrointestinal and lung neuroendocrine neoplasm. Chin J Cancer Res 2019;31(6):918-929. doi: 10.21147/j.issn.1000-9604.2019.06.08 shu

Genomic dissection of gastrointestinal and lung neuroendocrine neoplasm

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

*Those authors contributed equally to this work.
Correspondence to: Dr. Ming Lu. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital Institute, No. 52 Fucheng Road, Haidian District, Beijing 100142, China. Email: minglupku@163.com
Dr. Yang W. Shao. Translational Medicine Research Institute, Geneseeq Technology Inc., Suite 200, MaRS Center, South Tower, 101 College Street, Toronto, M5G 1L7, Canada. Email: yang.shao@geneseeq.com
Submitted: Jun 22, 2019
Accepted for publication: Nov 27, 2019

Figures(8) / Tables(7)

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 5q 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.
- Neuroendocrine carcinoma;
- whole-exome sequencing;
- chromosomal instability
[1]
Oronsky B, Ma PC, Morgensztern D, et al. Nothing but NET: A review of neuroendocrine tumors and carcinomas. Neoplasia 2017;19:991-1002. doi: 10.1016/j.neo.2017.09.002 [PubMed]

[2]
Anaizi A, Rizvi-Toner A, Valestin J, et al. Large cell neuroendocrine carcinoma of the lung presenting as pseudoachalasia: a case report. J Med Case Rep 2015;9:56. doi: 10.1186/s13256-015-0514-y [PubMed]

[3]
Klöppel G. Classification and pathology of gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer 2011;18 Suppl 1:S1-16. doi: 10.1530/ERC-11-0013 [PubMed]

[4]
Kulke MH, Shah MH, Benson AB 3rd, et al. Neuroendocrine tumors, version 1. 2015. J Natl Compr Canc Netw 2015;13:78-108. doi: 10.6004/jnccn.2015.0011 [PubMed]

[5]
Thomaz Araújo TM, Barra WF, Khayat AS, et al. Insights into gastric neuroendocrine tumors burden. Chi J Cancer Res 2017;29:137-43. doi: 10.21147/j.issn.1000-9604.2017.02.06

[6]
Strosberg JR, Fine RL, Choi J, et al. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer 2011;117:268-75. doi: 10.1002/cncr.25425 [PubMed]

[7]
Tang LH, Basturk O, Sue JJ, et al. A practical approach to the classification of WHO Grade 3 (G3) well-differentiated neuroendocrine tumor (WD-NET) and poorly differentiated neuroendocrine carcinoma (PD-NEC) of the pancreas. Am J Surg Pathol 2016;40:1192-202. doi: 10.1097/PAS.0000000000000662 [PubMed]

[8]
Nikou GC, Angelopoulos TP. Current concepts on gastric carcinoid tumors. Gastroenterol Res Pract 2012;2012:287825. doi: 10.1155/2012/287825 [PubMed]

[9]
Tang LH, Untch BR, Reidy DL, et al. Well-differentiated neuroendocrine tumors with a morphologically apparent high-grade component: A pathway distinct from poorly differentiated neuroendocrine carcinomas. Clin Cancer Res 2016;22:1011-7. doi: 10.1158/1078-0432.CCR-15-0548 [PubMed]

[10]
Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 2011;331:1199-203. doi: 10.1126/science.1200609 [PubMed]

[11]
Vijayvergia N, Boland PM, Handorf E, et al. Molecular profiling of neuroendocrine malignancies to identify prognostic and therapeutic markers: a Fox Chase Cancer Center Pilot Study. Br J Cancer 2016;115:564-70. doi: 10.1038/bjc.2016.229 [PubMed]

[12]
Scarpa A, Chang DK, Nones K, et al. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature 2017;543:65-71. doi: 10.1038/nature21063 [PubMed]

[13]
Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011;364:514-23. doi: 10.1056/NEJMoa1009290 [PubMed]

[14]
Francis JM, Kiezun A, Ramos AH, et al. Somatic mutation of CDKN1B in small intestine neuroendocrine tumors. Nat Genet 2013;45:1483-6. doi: 10.1038/ng.2821 [PubMed]

[15]
Banck MS, Kanwar R, Kulkarni AA, et al. The genomic landscape of small intestine neuroendocrine tumors. J Clin Invest 2013;123:2502-8. doi: 10.1172/JCI67963 [PubMed]

[16]
Kidd M, Modlin I, Öberg K. Towards a new classification of gastroenteropancreatic neuroendocrine neoplasms. Nat Rev Clin Oncol 2016;13:691-705. doi: 10.1038/nrclinonc.2016.85 [PubMed]

[17]
Vélayoudom-Céphise FL, Duvillard P, Foucan L, et al. Are G3 ENETS neuroendocrine neoplasms heterogeneous? Endocr Relat Cancer 2013;20:649-57. doi: 10.1530/ERC-13-0027 [PubMed]

[18]
Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 2014;30:2114-220. doi: 10.1093/bioinformatics/btu170 [PubMed]

[19]
Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 2009;25:1754-60. doi: 10.1093/bioinformatics/btp324 [PubMed]

[20]
Peng HQ, Bailey D, Bronson D, et al. Loss of heterozygosity of tumor suppressor genes in testis cancer. Cancer Res 1995;55:2871-5. [PubMed]

[21]
Abdel Wahab AH, Abo-Zeid HI, El-Husseini MI, et al. Role of loss of heterozygosity on chromosomes 8 and 9 in the development and progression of cancer bladder. J Egypt Natl Canc Inst 2005;17:260-9. [PubMed]

[22]
Oesterreich S, Allredl DC, Mohsin SK, et al. High rates of loss of heterozygosity on chromosome 19p13 in human breast cancer. Br J Cancer 2001;84:493-8. doi: 10.1054/bjoc.2000.1606 [PubMed]

[23]
Shen R, Seshan VE. FACETS: allele-specific copy number and clonal heterogeneity analysis tool for high-throughput DNA sequencing. Nucleic Acids Res 2016;44:e131. doi: 10.1093/nar/gkw520 [PubMed]

[24]
Mermel CH, Schumacher SE, Hill B, et al. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol 2011;12:R41. doi: 10.1186/gb-2011-12-4-r41 [PubMed]

[25]
Cibulskis K, Lawrence MS, Carter SL, et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol 2013;31:213-9. doi: 10.1038/nbt.2514 [PubMed]

[26]
Fang H, Bergmann EA, Arora K, et al. Indel variant analysis of short-read sequencing data with Scalpel. Nat Protoc 2016;11:2529-48. doi: 10.1038/nprot.2016.150 [PubMed]

[27]
Lawrence MS, Stojanov P, Polak P, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 2013;499:214-8. doi: 10.1038/nature12213 [PubMed]

[28]
Corbo V, Dalai I, Scardoni M, et al. MEN1 in pancreatic endocrine tumors: analysis of gene and protein status in 169 sporadic neoplasms reveals alterations in the vast majority of cases. Endocr Relat Cancer 2010;17:771-83. doi: 10.1677/ERC-10-0028 [PubMed]

[29]
Travis WD. Lung tumours with neuroendocrine differentiation. Eur J Cancer 2009;45 Suppl 1:251-66. doi: 10.1016/S0959-8049(09)70040-1 [PubMed]

[30]
Vollbrecht C, Werner R, Walter RF, et al. Mutational analysis of pulmonary tumours with neuroendocrine features using targeted massive parallel sequencing: a comparison of a neglected tumour group. Br J Cancer 2015;113:1704-11. doi: 10.1038/bjc.2015.397 [PubMed]

[31]
Liu NQ, De Marchi T, Timmermans AM, et al. Ferritin heavy chain in triple negative breast cancer: a favorable prognostic marker that relates to a cluster of differentiation 8 positive (CD8+) effector T-cell response. Mol Cell Proteomics 2014;13:1814-27. doi: 10.1074/mcp.M113.037176 [PubMed]

[32]
Yao J, Caballero OL, Yung WK, et al. Tumor subtype-specific cancer-testis antigens as potential biomarkers and immunotherapeutic targets for cancers. Cancer Immunol Res 2014;2:371-9. doi: 10.1158/2326-6066.CIR-13-0088 [PubMed]

[33]
Xu W, Liu LZ, Loizidou M, et al. The role of nitric oxide in cancer. Cell Res 2002;12:311-20. doi: 10.1038/sj.cr.7290133 [PubMed]

[34]
Klempner SJ, Gershenhorn B, Tran P, et al. BRAF^V600E mutations in high-grade colorectal neuroendocrine tumors may predict responsiveness to BRAF-MEK combination therapy. Cancer Discov 2016;6:594-600. doi: 10.1158/2159-8290.CD-15-1192 [PubMed]

[35]
Park C, Ha SY, Kim ST, et al. Identification of the BRAF V600E mutation in gastroenteropancreatic neuroendocrine tumors. Oncotarget 2016;7:4024-35. doi: 10.18632/oncotarget.6602 [PubMed]

[36]
Hashemi J, Fotouhi O, Sulaiman L, et al. Copy number alterations in small intestinal neuroendocrine tumors determined by array comparative genomic hybridization. BMC Cancer 2013;13:505. doi: 10.1186/1471-2407-13-505 [PubMed]

[37]
Zhao J, de Krijger RR, Meier D, et al. Genomic alterations in well-differentiated gastrointestinal and bronchial neuroendocrine tumors (carcinoids): marked differences indicating diversity in molecular pathogenesis. Am J Pathol 2000;157:1431-8. doi: 10.1016/S0002-9440(10)64780-3 [PubMed]

[38]
Capurso G, Festa S, Valente R, et al. Molecular pathology and genetics of pancreatic endocrine tumours. J Mol Endocrinol 2012;49:R37-50. doi: 10.1530/JME-12-0069 [PubMed]

[39]
Ayhan A, Kuhn E, Wu RC, et al. CCNE1 copy-number gain and overexpression identify ovarian clear cell carcinoma with a poor prognosis. Mod Pathol 2017;30:297-303. doi: 10.1038/modpathol.2016.160 [PubMed]

[40]
Nakayama K, Rahman MT, Rahman M, et al. CCNE1 amplification is associated with aggressive potential in endometrioid endometrial carcinomas. Int J Oncol 2016;48:506-16. doi: 10.3892/ijo.2015.3268 [PubMed]

[41]
Shao Y, Li X, Lu Y, et al. Aberrant LRP16 protein expression in primary neuroendocrine lung tumors. Int J Clin Exp Pathol 2015;8:6560-5. [PubMed]

[42]
Zikusoka MN, Kidd M, Eick G, et al. The molecular genetics of gastroenteropancreatic neuroendocrine tumors. Cancer 2005;104:2292-309. doi: 10.1002/cncr.21451 [PubMed]

[43]
Rossi G, Bertero L, Marchiò C, et al. Molecular alterations of neuroendocrine tumours of the lung. Histopathology 2018;72:142-52. doi: 10.1111/his.13394 [PubMed]
1. [1]
  Qiyue Chen, Zhongliang Ning, Zhiyu Liu, Yanbing Zhou, Qingliang He, Yantao Tian, Hankun Hao, Wei Lin, Lixin Jiang, Gang Zhao, Ping Li, Chaohui Zheng, Changming Huang, on behalf of the Study Group for Gastric Neuroendocrine Tumors. Textbook Outcome as a measure of surgical quality assessment and prognosis in gastric neuroendocrine carcinoma: A large multicenter sample analysis. Chin J Cancer Res, 2021, 33(4): 433-446. doi: 10.21147/j.issn.1000-9604.2021.04.01
2. [2]
  Zheng Wang, Lin Zhang, Lei He, Di Cui, Chenglong Liu, Liangyu Yin, Min Zhang, Lei Jiang, Yuyan Gong, Wang Wu, Bi Liu, Xiaoyu Li, David S Cram, Dongge Liu. Low-depth whole genome sequencing reveals copy number variations associated with higher pathologic grading and more aggressive subtypes of lung non-mucinous adenocarcinoma. Chin J Cancer Res, 2020, 32(3): 334-346. doi: 10.21147/j.issn.1000-9604.2020.03.05
3. [3]
  Taíssa Maíra Thomaz Araújo, Williams Fernandes Barra, André Salim Khayat, Paulo Pimentel de Assumpção. Insights into gastric neuroendocrine tumors burden. Chin J Cancer Res, 2017, 29(2): 137-143. doi: 10.21147/j.issn.1000-9604.2017.02.06
4. [4]
  Jean-Charles Nault. Next generation sequencing, inter-tumor heterogeneity and prognosis of hepatitis B related hepatocellular carcinoma. Chin J Cancer Res, 2014, 26(6): 730-731. doi: 10.3978/j.issn.1000-9604.2014.12.11
5. [5]
  Qi Li, Connie S. Zhang, Yifen Zhang. Molecular aspects of prostate cancer with neuroendocrine differentiation. Chin J Cancer Res, 2016, 28(1): 122-129. doi: 10.3978/j.issn.1000-9604.2016.01.02
6. [6]
  Peng Liu, Xu Zhu, Jie Li, Ming Lu, Jiahua Leng, Ying Li, Jiangyuan Yu. Retrospective analysis of interventional treatment of hepatic metastasis from gastroenteropancreatic neuroendocrine tumors. Chin J Cancer Res, 2017, 29(6): 581-586. doi: 10.21147/j.issn.1000-9604.2017.06.13
7. [7]
  Wei Wang, Sharvesh Raj Seeruttun, Cheng Fang, Zhiwei Zhou. Comprehensive treatment of a functional pancreatic neuroendocrine tumor with multifocal liver metastases. Chin J Cancer Res, 2014, 26(4): 501-506. doi: 10.3978/j.issn.1000-9604.2014.08.16
8. [8]
  Yong Cui, Xiaoting Li, Shunyu Gao, Zhongwu Li, Yanling Li, Ming Lu, Yingshi Sun. Utility of CT in differentiating liver metastases of well-differentiated gastroenteropancreatic neuroendocrine neoplasms from poorly-differentiated neuroendocrine neoplasms. Chin J Cancer Res, 2018, 30(1): 31-39. doi: 10.21147/j.issn.1000-9604.2018.01.04
9. [9]
  Xuelong Jiao, Yujun Li, Hongyan Wang, Shanglong Liu, Dongfeng Zhang, Yanbing Zhou. Clinicopathological features and survival analysis of gastroenteropancreatic neuroendocrine neoplasms: a retrospective study in a single center of China. Chin J Cancer Res, 2015, 27(3): 258-266. doi: 10.3978/j.issn.1000-9604.2015.06.04
10. [10]
  Xiaofang Wang, Yangqiu Li. Extensive exploration of T cell heterogeneity in cancers by single cell sequencing. Chin J Cancer Res, 2019, 31(2): 410-418. doi: 10.21147/j.issn.1000-9604.2019.02.15
11. [11]
  Zhou Su, Lin Zhou, Jianxin Xue, You Lu. Integration of stereotactic radiosurgery or whole brain radiation therapy with immunotherapy for treatment of brain metastases. Chin J Cancer Res, 2020, 32(4): 448-466. doi: 10.21147/j.issn.1000-9604.2020.04.03
12. [12]
  Ted C. Ling, Joseph I. Kang, David A. Bush, Jerry D. Slater, Gary Y. Yang. Proton therapy for hepatocellular carcinoma. Chin J Cancer Res, 2012, 24(4): 361-367. doi: 10.3978/j.issn.1000-9604.2012.10.09
13. [13]
  Nan Wang, Kun Li, Wenfa Huang, Weiyao Kong, Xiaoran Liu, Weijie Shi, Feng Xie, Hanfang Jiang, Guohong Song, Lijun Di, Quanren Wang, Jianjun Yu, Huiping Li. Efficacy of platinum in advanced triple-negative breast cancer with germline BRCA mutation determined by next generation sequencing. Chin J Cancer Res, 2020, 32(2): 149-162. doi: 10.21147/j.issn.1000-9604.2020.02.03
14. [14]
  Xuanhao Xu, Zemin Zhang. Prudent application of single-cell RNA sequencing in understanding cellular features and functional phenotypes in cancer studies. Chin J Cancer Res, 2021, 33(6): 719-723. doi: 10.21147/j.issn.1000-9604.2021.06.08
15. [15]
  Francesca De Felice, Daniela Musio, Anna Lisa Magnante, Nadia Bulzonetti, Irene De Francesco, Vincenzo Tombolini. Solitary rib metastasis of nasopharyngeal carcinoma. Chin J Cancer Res, 2014, 26(2): 219-221. doi: 10.3978/j.issn.1000-9604.2014.03.02
16. [16]
  Lei Fu, Ying Zhu, Wang Jing, Dong Guo, Li Kong, Jinming Yu. Incorporation of circulating tumor cells and whole-body metabolic tumor volume of ¹⁸F-FDG PET/CT improves prediction of outcome in IIIB stage small-cell lung cancer. Chin J Cancer Res, 2018, 30(6): 596-604. doi: 10.21147/j.issn.1000-9604.2018.06.04
17. [17]
  Quan Wang, Zhu Wang, Zhen Zhang, Wei Zhang, Mengmeng Zhang, Zhanlong Shen, Yingjiang Ye, Kewei Jiang, Shan Wang. Landscape of cell heterogeneity and evolutionary trajectory in ulcerative colitis-associated colon cancer revealed by single-cell RNA sequencing. Chin J Cancer Res, 2021, 33(2): 271-288. doi: 10.21147/j.issn.1000-9604.2021.02.13
18. [18]
  Wei Dai, Kyu-sung Chung. Carcinoma of Colon: a rare cause of fever of unknown origin. Chin J Cancer Res, 2012, 24(2): 157-160. doi: 10.1007/s11670-012-0157-0
19. [19]
  Hong Ni, Mao Yang, Zhi Guo, Ti Zhang. Sorafenib Combined with Cryoablation to Treat Unresectable Hepatocellular Carcinoma. Chin J Cancer Res, 2011, 23(3): 188-193. doi: 10.1007/s11670-011-0188-y
20. [20]
  Giuseppe Maria Ettorre, Giovanni Battista Levi Sandri. Laparoscopic approach for hepatocellular carcinoma: where is the limit?. Chin J Cancer Res, 2014, 26(3): 222-223. doi: 10.3978/j.issn.1000-9604.2014.06.12
cjcr-31-6-luming.pdf

PDF

Get Citation

Metrics

Abstract Views(637)
HTML views(1387)
PDF Downloads(52)
Cited by(0)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142