|
1
|
Li KY, Lowy AM, Fanta P. Quantification of PD-L1 expression and tumor mutational burden in biologically distinct advanced pancreatic cancers responding to pembrolizumab: case reports. Front Immunol 2024; 15:1452543. [PMID: 39687619 PMCID: PMC11646977 DOI: 10.3389/fimmu.2024.1452543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 11/14/2024] [Indexed: 12/18/2024] Open
Abstract
Background The advent of checkpoint therapy is one of the most important recent advancements in cancer therapy. Though checkpoint therapy is a mainstay in some cancers, it has been largely ineffective in treating cancers of the pancreas. Pancreatic ductal adenocarcinoma and pancreatic neuroendocrine tumors are seldom responsive to checkpoint inhibition. Case presentations Here we present two cases of advanced pancreatic cancers that either failed to respond or recurred following conventional treatments. Tissue from each tumor was sequenced and analyzed for PD-L1 expression. Each patient was started on checkpoint blockade after assessing for a predictive biomarker, either the combined positive score or the tumor mutational burden. In each case, checkpoint blockade led to durable radiographic responses. Conclusions We therefore propose that it is reasonable to assess combined positive score and tumor mutational burden in refractory or recurrent pancreatic cancers when initiation of ICB is being considered.
Collapse
Affiliation(s)
- Kevin Y. Li
- Department of Surgery, Division of Surgical Oncology, University of California, San
Diego, San Diego, CA, United States
- Moores Cancer Center, University of California, San Diego, San Diego, CA, United States
| | - Andrew M. Lowy
- Department of Surgery, Division of Surgical Oncology, University of California, San
Diego, San Diego, CA, United States
- Moores Cancer Center, University of California, San Diego, San Diego, CA, United States
| | - Paul Fanta
- Moores Cancer Center, University of California, San Diego, San Diego, CA, United States
- Division of Hematology Oncology, Department of Medicine, University of California, San Diego, San Diego, CA, United States
| |
Collapse
|
|
2
|
Choi JH, Paik WH. Risk Stratification of Pancreatic Neuroendocrine Neoplasms Based on Clinical, Pathological, and Molecular Characteristics. J Clin Med 2022; 11:7456. [PMID: 36556070 PMCID: PMC9786745 DOI: 10.3390/jcm11247456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 12/11/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Pancreatic neuroendocrine neoplasms consist of heterogeneous diseases. Depending on the novel features detected by various modern technologies, their classification and related prognosis predictions continue to change and develop. The role of traditional clinicopathological prognostic factors, including classification systems, is also being refined, and several attempts have been made to predict a more accurate prognosis through novel serum biomarkers, genetic factors, and epigenetic factors that have been identified through various state-of-the-art molecular techniques with multiomics sequencing. In this review article, the latest research results including the traditional approach to prognostic factors and recent advanced strategies for risk stratification of pancreatic neuroendocrine neoplasms based on clinical, pathological, and molecular characteristics are summarized. Predicting prognosis through multi-factorial assessments seems to be more efficacious, and prognostic factors through noninvasive methods are expected to develop further advances in liquid biopsy in the future.
Collapse
Affiliation(s)
| | - Woo Hyun Paik
- Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Republic of Korea
| |
Collapse
|
|
3
|
Lou X, Qin Y, Xu X, Yu X, Ji S. Spatiotemporal heterogeneity and clinical challenge of pancreatic neuroendocrine tumors. Biochim Biophys Acta Rev Cancer 2022; 1877:188782. [PMID: 36028148 DOI: 10.1016/j.bbcan.2022.188782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 08/11/2022] [Accepted: 08/19/2022] [Indexed: 11/18/2022]
Abstract
During the course of pancreatic neuroendocrine tumors (NETs), they generally become more heterogeneous with individual cells exhibiting distinct molecular fingerprints. This heterogeneity manifests itself through an unequal distribution of genetically-variant, tumor cell subpopulations within disease locations (i.e., spatial heterogeneity) or changes in the genomic landscape over time (i.e., temporal heterogeneity); these characteristics complicate clinical diagnosis and treatment. Effective, feasible tumor heterogeneity detection and eradication methods are essential to overcome the clinical challenges of pancreatic NETs. This review explores the molecular fingerprints of pancreatic NETs and the spectrum of tumoral heterogeneity. We then describe the challenges of assessing heterogeneity by liquid biopsies and imaging modalities and the therapeutic challenges for pancreatic NETs. In general, navigating these challenges, refining approaches for translational research, and ultimately improving patient care are available once we have a better understanding of intratumoral spatiotemporal heterogeneity.
Collapse
Affiliation(s)
- Xin Lou
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Yi Qin
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Xiaowu Xu
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - Xianjun Yu
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - Shunrong Ji
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| |
Collapse
|
|
4
|
Ban X, Mo S, Lu Z, Jia C, Shao H, Chang X, Mao X, Zhang Y, Pang J, Zhang Y, Yu S, Chen J. Expression and methylation status of MMR and MGMT in well-differentiated pancreatic neuroendocrine tumors and potential clinical applications. Endocrine 2022; 77:538-545. [PMID: 35708896 DOI: 10.1007/s12020-022-03102-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Accepted: 05/27/2022] [Indexed: 11/28/2022]
Abstract
PURPOSE Recent studies claim that immune checkpoint inhibitors are effective in defective mismatch repair (dMMR) cancers. This raises the question of whether similar therapies are effective in PanNETs (pancreatic neuroendocrine tumors); however, in general, assessment of MMR status in PanNETs has been inconsistent in previous studies. MGMT (O6-methylguanine-DNA methyltransferase) is potentially important for guiding temozolomide (TMZ) therapy in glioblastoma. The number of reports on MGMT expression and promoter methylation in PanNETs are limited. METHODS In this study we assessed the expression of MGMT and MMR proteins MSH2, MSH6, MLH1 and PMS2 in a series of PanNETs by IHC. The methylation status of MGMT and MMR genes in a subset of PanNETs was further assessed by MS-MLPA analysis. Survival curves were constructed using the Kaplan-Meier method, and differences were assessed using the log-rank test. Multivariate Cox proportional hazards regression models were used to determine the prognostic value of the variables. RESULTS According to evaluation criteria for mismatch repair defects, none of PanNETs shown nuclear staining loss for MSH2, MSH6, MLH1, and PMS2. MGMT low-intensity PanNETs were more commonly found in higher grade, higher Ki67 index and non-functional tumors (P < 0.05). In multivariate analysis, stage III-IV and low-intensity MGMT were shown to be independent risk factors for progression of PanNETs in the entire cohort, non-functioning subgroup and G2 subgroup (P < 0.05 for all). MGMT promoter methylation tended to be higher in the group with low expression of MGMT, However, methylation of MGMT did not statistically correlate with low expression of MGMT (P = 0.153). CONCLUSIONS In conclusion, our study suggests that decreased expression of MGMT but not MMR is associated with a higher risk of progression of pancreatic neuroendocrine tumors.
Collapse
Affiliation(s)
- Xinchao Ban
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Department of Pathology, Tianjin Medical University, Tianjin, China
- Department of Pathology, Tianjin Medical University General Hospital, Tianjin, China
| | - Shengwei Mo
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Zhaohui Lu
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Congwei Jia
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Huilin Shao
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiaoyan Chang
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xinxin Mao
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yue Zhang
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Junyi Pang
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yuhan Zhang
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Shuangni Yu
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
| | - Jie Chen
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
| |
Collapse
|
|
5
|
Crabtree JS. Epigenetic Regulation in Gastroenteropancreatic Neuroendocrine Tumors. Front Oncol 2022; 12:901435. [PMID: 35747820 PMCID: PMC9209739 DOI: 10.3389/fonc.2022.901435] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 05/09/2022] [Indexed: 12/11/2022] Open
Abstract
Gastroenteropancreatic neuroendocrine neoplasms are a rare, diverse group of neuroendocrine tumors that form in the pancreatic and gastrointestinal tract, and often present with side effects due to hormone hypersecretion. The pathogenesis of these tumors is known to be linked to several genetic disorders, but sporadic tumors occur due to dysregulation of additional genes that regulate proliferation and metastasis, but also the epigenome. Epigenetic regulation in these tumors includes DNA methylation, chromatin remodeling and regulation by noncoding RNAs. Several large studies demonstrate the identification of epigenetic signatures that may serve as biomarkers, and others identify innovative, epigenetics-based targets that utilize both pharmacological and theranostic approaches towards the development of new treatment approaches.
Collapse
|
|
6
|
Marini F, Giusti F, Brandi ML. Epigenetic-based targeted therapies for well-differentiated pancreatic neuroendocrine tumors: recent advances and future perspectives. Expert Rev Endocrinol Metab 2021; 16:295-307. [PMID: 34554891 DOI: 10.1080/17446651.2021.1982382] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 09/15/2021] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Well-differentiated pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of primary tumors of the endocrine pancreas. Dysregulation of chromatin remodeling, gene expression alteration, global DNA hypomethylation of non-coding regions, DNA hypermethylation and silencing of tumor suppressor gene promoters are frequent epigenetic changes in PanNETs. These changes exert a role in neoplastic transformation and progression. As epigenetic mechanisms, converse to genetic mutations, are potentially reversible, they are an interesting and promising therapeutic target for the treatment of PanNETs. AREAS COVERED We reviewed main epigenetic alterations associated with the development, biological and clinical features and progression of PanNETs, as well as emerging therapies targeting epigenetic changes, which may prove effective for the treatment of human PanNETs. EXPERT OPINION Constant advances in the PanNET medical approach, as reported in the clinical and therapeutic recommendations of ESMO, improved the overall survival of patients over the years. However, over 60% of the patients with metastatic disease still have poor prognosis. Epigenetic regulator drugs, currently approved to treat some human malignancies, that showed anti-tumoral activity also on PanNETs, in pre-clinical and clinical studies, could concur to ameliorate the prognosis and OS of advanced and metastatic PanNET, in combination with surgery and currently employed medical therapies.
Collapse
Affiliation(s)
- Francesca Marini
- Department of Experimental and Clinical Biomedical Sciences, University of refereFlorence, Florence, Italy
- F.I.R.M.O. Italian Foundation for the Research on Bone Diseases, Florence, Italy
| | - Francesca Giusti
- Department of Experimental and Clinical Biomedical Sciences, University of refereFlorence, Florence, Italy
| | - Maria Luisa Brandi
- F.I.R.M.O. Italian Foundation for the Research on Bone Diseases, Florence, Italy
| |
Collapse
|
|
7
|
Wu W, Liu Y, Zeng S, Han Y, Shen H. Intratumor heterogeneity: the hidden barrier to immunotherapy against MSI tumors from the perspective of IFN-γ signaling and tumor-infiltrating lymphocytes. J Hematol Oncol 2021; 14:160. [PMID: 34620200 PMCID: PMC8499512 DOI: 10.1186/s13045-021-01166-3] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Accepted: 09/07/2021] [Indexed: 12/15/2022] Open
Abstract
In this era of precision medicine, with the help of biomarkers, immunotherapy has significantly improved prognosis of many patients with malignant tumor. Deficient mismatch repair (dMMR)/microsatellite instability (MSI) status is used as a biomarker in clinical practice to predict favorable response to immunotherapy and prognosis. MSI is an important characteristic which facilitates mutation and improves the likelihood of a favorable response to immunotherapy. However, many patients with dMMR/MSI still respond poorly to immunotherapies, which partly results from intratumor heterogeneity propelled by dMMR/MSI. In this review, we discuss how dMMR/MSI facilitates mutations in tumor cells and generates intratumor heterogeneity, especially through type II interferon (IFN-γ) signaling and tumor-infiltrating lymphocytes (TILs). We discuss the mechanism of immunotherapy from the perspective of dMMR/MSI, molecular pathways and TILs, and we discuss how intratumor heterogeneity hinders the therapeutic effect of immunotherapy. Finally, we summarize present techniques and strategies to look at the tumor as a whole to design personalized regimes and achieve favorable prognosis.
Collapse
Affiliation(s)
- Wantao Wu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China, 410008
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China, 410008
| | - Yihan Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China, 410008
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China, 410008
| | - Shan Zeng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China, 410008.
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China, 410008.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China.
| | - Ying Han
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China, 410008.
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China, 410008.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China.
| | - Hong Shen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China, 410008.
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China, 410008.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China.
| |
Collapse
|
|
8
|
Das S, Al-Toubah T, Strosberg J. Chemotherapy in Neuroendocrine Tumors. Cancers (Basel) 2021; 13:4872. [PMID: 34638356 PMCID: PMC8507720 DOI: 10.3390/cancers13194872] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/23/2021] [Accepted: 09/24/2021] [Indexed: 12/16/2022] Open
Abstract
The role for cytotoxic chemotherapy in patients with well-differentiated neuroendocrine tumors (NETs) remains debated. Compared to patients with poorly differentiated neuroendocrine carcinomas (NECs) where chemotherapy is utilized ubiquitously, chemotherapy may play a more select role in patients with certain types of NETs (e.g., pancreatic tumors, higher grade tumors, and tumors possessing DNA damage repair defects). The primary types of chemotherapy that have been tested in patients with NETs include alkylating agent- and platinum agent-based combinations. Across regimens, chemotherapy appears to elicit greater antitumor activity in patients with pancreatic or grade 3 NETs. The role for chemotherapy in lower grade extra-pancreatic NETs remains undefined. Furthermore, while chemotherapy has demonstrated clinically meaningful benefit for patients in the systemic setting, its role in the adjuvant or neoadjuvant setting is as-of-yet undetermined. Finally, efforts to combine chemotherapy with targeted therapy and peptide receptor radionuclide therapy are ongoing, in hopes of improving the cytoreductive treatment options for patients with NETs.
Collapse
Affiliation(s)
- Satya Das
- Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN 37209, USA;
| | - Taymeyah Al-Toubah
- Moffitt Cancer Center, Department of Gastrointestinal Oncology, Tampa, FL 33612, USA;
| | - Jonathan Strosberg
- Moffitt Cancer Center, Department of Gastrointestinal Oncology, Tampa, FL 33612, USA;
| |
Collapse
|
|
9
|
Starr J, Puebla G, McMillan J, Lewis JT, Kasi PM. Microsatellite Instability-High, Malignant Insulinoma With Brain Metastasis. Cureus 2021; 13:e16969. [PMID: 34527457 PMCID: PMC8420138 DOI: 10.7759/cureus.16969] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/06/2021] [Indexed: 12/24/2022] Open
Abstract
Insulinomas are the most common type of functional pancreatic neuroendocrine tumor. Although insulinomas usually are noninvasive or benign, 10% are deemed invasive or malignant. The pathologic mechanisms that lead to the malignant phenotype are not well elucidated. In this case report, we present a patient with stage 4 malignant insulinoma with metastasis to the liver, bone, and brain. Genetic analysis of the tumor showed that the tumor was mismatch-repair deficient and had a high rate of microsatellite instability. There was loss of MLH1- and PMS2-encoded protein expression, and MLH1 and MEN1 variants were identified. Notably, the liver metastasis showed considerable tumor heterogeneity (well differentiated) compared with the brain metastasis (poorly differentiated).
Collapse
Affiliation(s)
- Jason Starr
- Hematology/Oncology, Mayo Clinic, Jacksonville, USA
| | - Guillermo Puebla
- Hematology/Oncology, University of Puerto Rico, Medical Sciences Campus, San Juan, PRI
| | | | - Jason T Lewis
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, USA
| | | |
Collapse
|
|
10
|
Sharma R, Lythgoe MP, Slaich B, Patel N. Exploring the Epigenome in Gastroenteropancreatic Neuroendocrine Neoplasias. Cancers (Basel) 2021; 13:4181. [PMID: 34439335 PMCID: PMC8394968 DOI: 10.3390/cancers13164181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 08/06/2021] [Accepted: 08/17/2021] [Indexed: 11/17/2022] Open
Abstract
Gastroenteropancreatic neuroendocrine neoplasias are a diverse group of neoplasms with different characteristics in terms of site, biological behaviour and metastatic potential. In comparison to other cancers, they are genetically quiet, harbouring relatively few somatic mutations. It is increasingly becoming evident that epigenetic changes are as relevant, if not more so, as somatic mutations in promoting oncogenesis. Despite significant tumour heterogeneity, it is obvious that DNA methylation, histone and chromatin modifications and microRNA expression profiles are distinctive for GEP-NEN subtypes and may correlate with clinical outcome. This review summarises existing knowledge on epigenetic changes, identifying potential contributions to pathogenesis and oncogenesis. In particular, we focus on epigenetic changes pertaining to well-differentiated neuroendocrine tumours, which make up the bulk of NENs. We also highlight both similarities and differences within the subtypes of GEP-NETs and how these relate and compare to other types of cancers. We relate epigenetic understanding to existing treatments and explore how this knowledge may be exploited in the development of novel treatment approaches, such as in theranostics and combining conventional treatment modalities. We consider potential barriers to epigenetic research in GEP-NENs and discuss strategies to optimise research and development of new therapies.
Collapse
Affiliation(s)
- Rohini Sharma
- Department of Surgery and Cancer, Imperial College London, London W12 ONN, UK;
| | - Mark P. Lythgoe
- Department of Surgery and Cancer, Imperial College London, London W12 ONN, UK;
| | - Bhavandeep Slaich
- Department of Medicine, University of Leicester, Leicester LE1 7RH, UK; (B.S.); (N.P.)
| | - Nishil Patel
- Department of Medicine, University of Leicester, Leicester LE1 7RH, UK; (B.S.); (N.P.)
| |
Collapse
|
|
11
|
Song YL, Xu J, Zhao DC, Zhang TP, Jin KZ, Zhu LM, Yu S, Chen YJ. Mutation and Expression of Gene YY1 in Pancreatic Neuroendocrine Tumors and Its Clinical Significance. Endocr Pract 2021; 27:874-880. [PMID: 33705973 DOI: 10.1016/j.eprac.2021.02.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 01/26/2021] [Accepted: 02/20/2021] [Indexed: 10/21/2022]
Abstract
OBJECTIVE The clinical significance of the YY1 gene mutation and expression in pancreatic neuroendocrine tumors (PNETs) remains unknown. Therefore, this study aimed to comprehensively analyze the somatic mutation of YY1 in the different subtypes of PNETs. METHODS A total of 143 PNETs were assessed by Sanger sequencing to identify the somatic mutation of YY1 gene in various subtypes of PNETs. YY1 protein expression was examined in 103 PNETs by immunohistochemical staining and western blot. Gene mutation and its protein expression were correlated with clinicopathologic features. RESULTS A recurrent mutation (chr14:100743807C>G) in the YY1 gene was identified in 15 of 83 insulinomas (18%) and in only 1 of 60 noninsulinoma PNETs (1.7%) (P = .0045). The YY1 mutation was not found in MEN1-associated insulinomas. The YY1 mutation in insulinomas was correlated with older age and lower serum glucose levels (age, 57 vs 42.5 years, P = .006; blood glucose, 25.2 vs 33.6 mg/dL, P = .008). YY1 protein expression was found in 100 of 103 PNETs, although expression was weaker in metastases than in localized tumors (P = .036). The stronger expression of YY1 protein was associated with favorable disease-free survival of patients with PNETs (log-rank, P = .011; n = 70). Multivariable statistical analysis showed that YY1 protein expression could be an independent predictor of prognosis. CONCLUSION The hotspot YY1 mutation mostly occurred in insulinomas and rarely in noninsulinoma PNETs. The stronger YY1 protein expression was correlated with the better prognosis of PNETs patients.
Collapse
Affiliation(s)
- Yu-Li Song
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Da-Chun Zhao
- Departments of Pathology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Tai-Ping Zhang
- Department of Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Kai-Zhou Jin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Li-Ming Zhu
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Shuang Yu
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Yuan-Jia Chen
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
| |
Collapse
|
|
12
|
Xu G, Wang Y, Zhang H, She X, Yang J. Immunotherapy and potential predictive biomarkers in the treatment of neuroendocrine neoplasia. Future Oncol 2021; 17:1069-1081. [PMID: 33136448 DOI: 10.2217/fon-2020-0703] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Accepted: 08/28/2020] [Indexed: 12/14/2022] Open
Abstract
Neuroendocrine neoplasias (NENs) are a heterogeneous group of rare tumors scattered throughout the body. Surgery, locoregional or ablative therapies as well as maintenance treatments are applied in well-differentiated, low-grade NENs, whereas cytotoxic chemotherapy is usually applied in high-grade neuroendocrine carcinomas. However, treatment options for patients with advanced or metastatic NENs are limited. Immunotherapy has provided new treatment approaches for many cancer types, including neuroendocrine tumors, but predictive biomarkers of immune checkpoint inhibitors (ICIs) in the treatment of NENs have not been fully reported. By reviewing the literature and international congress abstracts, we summarize the current knowledge of ICIs, potential predicative biomarkers in the treatment of NENs, implications and efficacy of ICIs as well as biomarkers for NENs of gastroenteropancreatic system, lung NENs and Merkel cell carcinoma in clinical practice.
Collapse
Affiliation(s)
- Guanghui Xu
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases & Digestive Diseases of Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, PR China
| | - Yuhao Wang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases & Digestive Diseases of Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, PR China
| | - Hushan Zhang
- The Medical Department, 3D Medicines Inc., Shanghai, 201114, PR China
| | - Xueke She
- The Medical Department, 3D Medicines Inc., Shanghai, 201114, PR China
| | - Jianjun Yang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases & Digestive Diseases of Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, PR China
| |
Collapse
|
|
13
|
Arakelyan J, Zohrabyan D, Philip PA. Molecular profile of pancreatic neuroendocrine neoplasms (PanNENs): Opportunities for personalized therapies. Cancer 2020; 127:345-353. [PMID: 33270905 DOI: 10.1002/cncr.33354] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 11/08/2020] [Accepted: 11/10/2020] [Indexed: 02/06/2023]
Abstract
Pancreatic neuroendocrine neoplasms (panNENs) are the second most common epithelial tumors of the pancreas. Despite improvements in prognostic grading and staging systems, it remains a challenge to predict the clinical behavior of panNENs and the response to specific therapies given the high degree of heterogeneity of these tumors. Most panNENs are nonfunctional and present as advanced disease. However, systemic therapies provide modest benefits. Therefore, there is a need for predictive biomarkers to develop personalized treatment and to advance new drug development. The somatostatin receptors remain the only clinically established prognostic and predictive biomarkers in panNENs. Oncogenic drivers are at a very low frequency. Commonly mutated genes in panNENs include MEN1, chromatin remodeling genes (DAXX and ATRX), and mammalian target of rapamycin pathway genes. In contrast, poorly differentiated neuroendocrine carcinomas (panNECs), which carry a very poor prognosis, have distinctive mutations in certain genes (eg, RB1 and p53). Ongoing research to integrate epigenomics will provide tremendous opportunities to improve current understanding of the clinical heterogeneity of pancreatic neuroendocrine tumors and provide invaluable insight into the biology of these tumors, new drug development, and establishing personalized therapies.
Collapse
Affiliation(s)
- Jemma Arakelyan
- Department of Oncology, Yerevan State Medical University, Yerevan, Armenia.,Adult Solid Tumor Chemotherapy Clinic, Professor Yeolan Hematology Center, Yerevan, Armenia
| | - Davit Zohrabyan
- Department of Oncology, Yerevan State Medical University, Yerevan, Armenia.,Adult Solid Tumor Chemotherapy Clinic, Professor Yeolan Hematology Center, Yerevan, Armenia
| | - Philip A Philip
- Department of Oncology, Yerevan State Medical University, Yerevan, Armenia.,Department of Oncology, School of Medicine, Wayne State University, Detroit, Michigan.,Department of Pharmacology, School of Medicine, Wayne State University, Detroit, Michigan.,Barbara Ann Karmanos Cancer Center, Detroit, Michigan
| |
Collapse
|
|
14
|
Briest F, Koziolek EJ, Albrecht J, Schmidt F, Bernsen MR, Haeck J, Kühl AA, Sedding D, Hartung T, Exner S, Welzel M, Fischer C, Grötzinger C, Brenner W, Baum RP, Grabowski P. Does the proteasome inhibitor bortezomib sensitize to DNA-damaging therapy in gastroenteropancreatic neuroendocrine neoplasms? - A preclinical assessment in vitro and in vivo. Neoplasia 2020; 23:80-98. [PMID: 33246310 PMCID: PMC7701025 DOI: 10.1016/j.neo.2020.11.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 11/01/2020] [Accepted: 11/03/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Well-differentiated gastroenteropancreatic neuroendocrine neoplasms are rare tumors with a slow proliferation. They are virtually resistant to many DNA-damaging therapeutic approaches, such as chemo- and external beam therapy, which might be overcome by DNA damage inhibition induced by proteasome inhibitors such as bortezomib. METHODS AND RESULTS In this study, we assessed several combined treatment modalities in vitro and in vivo. By cell-based functional analyses, in a 3D in ovo and an orthotopic mouse model, we demonstrated sensitizing effects of bortezomib combined with cisplatin, radiation and peptide receptor radionuclide therapy (PRRT). By gene expression profiling and western blot, we explored the underlying mechanisms, which resulted in an impaired DNA damage repair. Therapy-induced DNA damage triggered extrinsic proapoptotic signaling as well as the induction of cell cycle arrest, leading to a decreased vital tumor volume and altered tissue composition shown by magnetic resonance imaging and F-18-FDG-PET in vivo, however with no significant additional benefit related to PRRT alone. CONCLUSIONS We demonstrated that bortezomib has short-term sensitizing effects when combined with DNA damaging therapy by interfering with DNA repair in vitro and in ovo. Nevertheless, due to high tumor heterogeneity after PRRT in long-term observations, we were not able to prove a therapeutic advantage of bortezomib-combined PRRT in an in vivo mouse model.
Collapse
Affiliation(s)
- Franziska Briest
- Department of Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany; Department of Biology, Chemistry, and Pharmacy, Institute of Chemistry and Biochemistry, Freie Universität (FU) Berlin, Berlin, Germany.
| | - Eva J Koziolek
- German Cancer Consortium (DKTK), Germany; Department of Nuclear Medicine, Charité Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jakob Albrecht
- Department of Nuclear Medicine, Charité Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin Germany
| | - Fränze Schmidt
- German Cancer Consortium (DKTK), Germany; Department of Nuclear Medicine, Charité Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Institute for Biochemistry and Biotechnology, Martin-Luther-University (MLU) Halle-Wittenberg, Halle (Saale), Germany
| | | | - Joost Haeck
- Department of Radiology, Erasmus MC, Rotterdam, The Netherlands
| | - Anja A Kühl
- iPATH.Berlin, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin
| | - Dagmar Sedding
- Department of Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany; Institute of Biology, Humboldt-Universität (HU) Berlin, Berlin, Germany
| | - Teresa Hartung
- Department of Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Samantha Exner
- Department of Hepatology and Gastroenterology and Molecular Cancer Research Center, Tumor Targeting Laboratory, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Martina Welzel
- Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center (MDC) for Molecular Medicine, Berlin, Germany
| | - Christian Fischer
- Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center (MDC) for Molecular Medicine, Berlin, Germany
| | - Carsten Grötzinger
- German Cancer Consortium (DKTK), Germany; Department of Hepatology and Gastroenterology and Molecular Cancer Research Center, Tumor Targeting Laboratory, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Winfried Brenner
- German Cancer Consortium (DKTK), Germany; Department of Nuclear Medicine, Charité Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin Germany; Berlin Experimental Radionuclide Imaging Center (BERIC), Charité Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Richard P Baum
- Department of Nuclear Medicine, Zentralklinik Bad Berka GmbH, Bad Berka, Germany; CURANOSTICUM Wiesbaden-Frankfurt, DKD Helios Clinic, Wiesbaden, Germany
| | - Patricia Grabowski
- Department of Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany; Department of Gastroenterology and Endocrinology, Zentralklinik Bad Berka GmbH, Bad Berka, Germany; Department of Medical Immunology, Charité Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| |
Collapse
|
|
15
|
Fraune C, Simon R, Hube-Magg C, Makrypidi-Fraune G, Kluth M, Büscheck F, Amin T, Viol F, Fehrle W, Dum D, Höflmayer D, Burandt E, Clauditz TS, Perez D, Izbicki J, Wilczak W, Sauter G, Steurer S, Schrader J. Homogeneous MMR Deficiency Throughout the Entire Tumor Mass Occurs in a Subset of Colorectal Neuroendocrine Carcinomas. Endocr Pathol 2020; 31:182-189. [PMID: 32144630 PMCID: PMC7250944 DOI: 10.1007/s12022-020-09612-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Neuroendocrine neoplasms comprise a heterogeneous group of tumors, categorized into neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) depending on tumor differentiation. NECs and high-grade NETs (G3) confer a poor prognosis, demanding novel treatment strategies such as immune checkpoint inhibition in tumors with microsatellite instability (MSI). To study any possible intratumoral heterogeneity of MSI, a tissue microarray (TMA) containing 199 NETs and 40 NECs was constructed to screen for MSI using immunohistochemistry (IHC) for the mismatch repair (MMR) proteins MLH1, PMS2, MSH2, and MSH6. Four cases suspicious for MSI were identified. Validation of MSI by repeated IHC on large sections and polymerase chain reaction (PCR)-based analysis using the "Bethesda Panel" confirmed MSI in 3 cecal NECs. One pancreatic NET G3 with MSI-compatible TMA results was MMR intact on large section IHC and microsatellite stable (MSS). The remaining 235 tumors exhibited intact MMR. Protein loss of MLH1/PMS2 was found in two and MSH6 loss in one cancer with MSI. Large section IHC on all available tumor-containing tissue blocks in NECs with MSI did not identify aberrant tumor areas with intact MMR. Our data indicate that MSI is common in colorectal NECs (3 out of 10) but highly infrequent in neuroendocrine neoplasms from many other sites. The lack of intratumoral heterogeneity of MMR deficiency suggests early development of MSI during tumorigenesis in a subset of colorectal NECs and indicates that microsatellite status obtained from small biopsies may be representative for the entire cancer mass.
Collapse
Affiliation(s)
- Christoph Fraune
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
| | - Claudia Hube-Magg
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Georgia Makrypidi-Fraune
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Martina Kluth
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Franziska Büscheck
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Tania Amin
- I. Medical Department - Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Fabrice Viol
- I. Medical Department - Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Wilfrid Fehrle
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - David Dum
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Doris Höflmayer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Eike Burandt
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Till Sebastian Clauditz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Daniel Perez
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jakob Izbicki
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Waldemar Wilczak
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Stefan Steurer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Jörg Schrader
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- I. Medical Department - Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| |
Collapse
|
|
16
|
Wu HY, Li NS, Song YL, Bai CM, Wang Q, Zhao YP, Xiao Y, Yu S, Li M, Chen YJ. Plasma levels of acylated ghrelin in patients with insulinoma and expression of ghrelin and its receptor in insulinomas. Endocrine 2020; 68:448-457. [PMID: 32124259 PMCID: PMC7266859 DOI: 10.1007/s12020-020-02233-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 02/14/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Insulinoma is a subtype of pancreatic neuroendocrine tumors. Many patients with insulinoma are obese due to frequent food intake. Ghrelin is associated with obesity and blood levels of insulin. It is not clear if plasma levels of ghrelin in insulinoma patients correlate with hyperinsulinemia and obesity. Expression of ghrelin and its receptor has not been well demonstrated in insulinoma. OBJECTIVE To study if plasma levels of ghrelin is associated with obesity and hyperinsulinemia or hyperproinsulinemia in patients with insulinoma, and to detect the expression of ghrelin and its receptor in insulinoma. METHODS Plasma levels of acylated ghrelin, insulin, and proinsulin were measured in 37 patients with insulinoma and 25 controls by ELISA. Expression of ghrelin and its receptor GHS-R1A was examined in 20 insulinoma and paired pancreatic specimens by immunostaining. P ≤ 0.05 was considered significant. RESULTS The plasma levels of acylated ghrelin in patients with insulinoma were significantly lower than that in the controls (median 15 pg/ml vs. 19 pg/ml, respectively, P = 0.016). The reduced plasma levels of acylated ghrelin in patients were significantly correlated with obesity, hyperinsulinemia, and hyperproinsulinemia (P = 0.029 and P = 0.028, respectively). Expression of ghrelin and its receptor GHS-R1A was shown in the majority of insulinoma specimens. The expression of GHS-R1A was positively correlated with ghrelin expression in insulinoma (P = 0.014). CONCLUSIONS Plasma levels of acylated ghrelin decreased in patients with insulinoma, probably due to the hyperinsulinemia and obesity in the patients. Expression of both ghrelin and its receptor is common in insulinoma.
Collapse
Affiliation(s)
- Hai-Yan Wu
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China
| | - Nai-Shi Li
- Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China
| | - Yu-Li Song
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China
| | - Chun-Mei Bai
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China
| | - Qiang Wang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China
| | - Yu-Pei Zhao
- Department of Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China
| | - Yu Xiao
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China
| | - Shuang Yu
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China
| | - Ming Li
- Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China
| | - Yuan-Jia Chen
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China.
| |
Collapse
|
|
17
|
Chen YJ, Ojeaburu JV, Vortmeyer A, Yu S, Jensen RT. Alterations of chromosome 3p in 24 cases of gastrinomas and their correlations with clinicopathological and prognostic features. JOURNAL OF PANCREATOLOGY 2020; 3:42-49. [DOI: 10.1097/jp9.0000000000000034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Abstract
Purpose:
The pathogenesis of gastrinomas is largely unknown, and there is a lack of reliable genetic determinants that are useful to distinguish malignant and benign forms of this tumor or predict the prognosis of patients with this disease. Loss of heterozygosity (LOH) on chromosome 3p is reported to occur in pancreatic neuroendocrine tumors (PNETs) as well as in non-PNETs and its presence is reported to correlate with tumor prognosis in non-endocrine tumors. However, little data are available from prospective studies on gastrinomas.
Experimental design:
We assessed occurrence of 3p LOH in 24 gastrinomas and correlated its presence with tumor biological behavior and other clinicopathological features of gastrinomas.
Results:
Either 3p LOH or microsatellite instability involving 3p occurred in 11 of 24 tumors (46%). Seven (29%) gastrinomas had 3p LOH. Of the 7 gastrinomas with 3p LOH, 5 (71%) had 3p12 LOH with the marker D3S2406, which was the shortest region of highest overlap (SRO). Chromosome 3p LOH was not associated with aggressive biological behavior of gastrinomas or with poor prognosis of patients with gastrinoma. Similarly, 3p12 LOH (SRO) was not correlated with aggressive growth of tumors and/or liver metastases.
Conclusion:
Gastrinomas have a relative high frequency of 3p12 LOH suggesting this area may harbor putative tumor suppressor gene(s), which may play a role in the tumorigenesis, but not aggressiveness, of a subset of these tumors.
Collapse
Affiliation(s)
- Yuan-Jia Chen
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- Digestive Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases
| | - Jeremiah V. Ojeaburu
- Digestive Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases
| | - Alexander Vortmeyer
- Molecular Pathogenesis Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
| | - Shuang Yu
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Robert T. Jensen
- Digestive Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases
| |
Collapse
|
|
18
|
Gundara JS, Jamal K, Kurzawinski T. Dictating genomic destiny: Epigenetic regulation of pancreatic neuroendocrine tumours. Mol Cell Endocrinol 2018; 469:85-91. [PMID: 28385665 DOI: 10.1016/j.mce.2017.03.032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Revised: 03/30/2017] [Accepted: 03/30/2017] [Indexed: 12/21/2022]
Abstract
Pancreatic neuroendocrine tumours are a diverse group of neoplasms with an increasingly well-defined genomic basis. Despite this, much of what drives this disease is still unknown and epigenetic influences represent the next tier of gene, and hence disease modifiers that are of unquestionable importance. Moreover, they are of arguably more significance than the genes themselves given their malleable nature and potential to be exploited for not only diagnosis and prognosis, but also therapy. This review summarises what is known regarding the key epigenetic modifiers of disease through the domains of diagnosis, prognosis and treatment.
Collapse
Affiliation(s)
- Justin S Gundara
- Centre for Endocrine Surgery, University College London Hospital, London, United Kingdom.
| | - Karim Jamal
- Centre for Endocrine Surgery, University College London Hospital, London, United Kingdom
| | - Tom Kurzawinski
- Centre for Endocrine Surgery, University College London Hospital, London, United Kingdom
| |
Collapse
|
|
19
|
Weber MM, Fottner C. Immune Checkpoint Inhibitors in the Treatment of Patients with Neuroendocrine Neoplasia. Oncol Res Treat 2018; 41:306-312. [DOI: 10.1159/000488996] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 04/05/2018] [Indexed: 12/16/2022]
|
|
20
|
Uraki S, Ariyasu H, Doi A, Furuta H, Nishi M, Sugano K, Inoshita N, Nakao N, Yamada S, Akamizu T. Atypical pituitary adenoma with MEN1 somatic mutation associated with abnormalities of DNA mismatch repair genes; MLH1 germline mutation and MSH6 somatic mutation. Endocr J 2017; 64:895-906. [PMID: 28701629 DOI: 10.1507/endocrj.ej17-0036] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The mechanism of pituitary tumorigenesis remains largely unknown. Lynch syndrome is an autosomal, dominantly inherited syndrome caused by a defective mismatch repair (MMR) mechanism involved in the development of various tumors at an early age. In this case study, we showed the occurrence of pituitary tumors associated with Lynch syndrome for the first time and performed genetic and immunohistochemical analysis to evaluate the genetic aberrations that might be related to the tumorigenesis and proliferation. A 68-year-old female patient with Lynch syndrome due to mutL homolog 1 (MLH1) gene mutation suffered from hypersecretion of adrenocorticotrophic hormone (ACTH), hypercortisolism and a rapidly progressive pituitary tumor. We performed genetic analysis by whole genome sequencing with genomic DNA of the pituitary tumor and peripheral blood leukocytes, as well as immunohistochemical analysis of MMR proteins. Genetic analysis revealed that the tumor had homozygous gene mutation of MEN1 associated with pituitary tumorigenesis and mutS homolog 6 (MSH6) gene. Furthermore, immunohistochemical analysis showed that MLH1 and MSH6 immunoexpression were negative. We reveal for the first time that MMR abnormality could cause somatic mutation of MEN1 and pituitary tumor occurrence is associated with Lynch syndrome. We suggest that the identified gene mutations, especially those of MSH6 and MLH1 genes, may be involved in the pathogenesis and proliferation of pituitary tumor. The knowledge obtained from our case study is important to elucidate the pathogenesis and proliferation mechanisms of pituitary tumors.
Collapse
Affiliation(s)
- Shinsuke Uraki
- The 1st Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Hiroyuki Ariyasu
- The 1st Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Asako Doi
- The 1st Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Hiroto Furuta
- The 1st Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Masahiro Nishi
- The 1st Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Kokichi Sugano
- Oncogene Research Unit/Cancer Prevention Unit, Tochigi Cancer Center Research Institute, Tochigi, Japan
| | - Naoko Inoshita
- Department of Pathology, Toranomon Hospital, Tokyo 105-8470, Japan
| | - Naoyuki Nakao
- Department of Neurological Surgery, Wakayama Medical University, Wakayama, Japan
| | - Shozo Yamada
- Department of Hypothalamic and Pituitary Surgery, Toranomon Hospital, Tokyo 105-8470, Japan
| | - Takashi Akamizu
- The 1st Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| |
Collapse
|
|
21
|
Finnerty BM, Gray KD, Moore MD, Zarnegar R, Fahey III TJ. Epigenetics of gastroenteropancreatic neuroendocrine tumors: A clinicopathologic perspective. World J Gastrointest Oncol 2017; 9:341-353. [PMID: 28979716 PMCID: PMC5605334 DOI: 10.4251/wjgo.v9.i9.341] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2017] [Revised: 06/27/2017] [Accepted: 08/04/2017] [Indexed: 02/05/2023] Open
Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous group of rare tumors whose site-specific tumor incidence and clinical behavior vary widely. Genetic alterations associated with familial inherited syndromes have been well defined; however, the genetic profile of sporadic tumors is less clear as their tumorigenesis does not appear to be controlled by classic oncogenes such as P53, RB, or KRAS. Even within GEP-NETs, there are no common oncogenic drivers; for example, DAXX/ATRX mutations are strongly implicated in the tumorigenesis of pancreatic but not small bowel NETs. Accordingly, the dysregulation of epigenetic mechanisms has been hypothesized as a potential regulator of GEP-NET tumorigenesis and has become a major focus of recent studies. Despite the heterogeneity of tumor cohorts evaluated in these studies, it is obvious that there are methylation patterns, chromatin remodeling alterations, and microRNA and long non-coding RNA (lncRNA) differential expression profiles that are distinctive of GEP-NETs, some of which are correlated with significant differences in clinical outcomes. Several translational studies have provided convincing data identifying potential prognostic biomarkers, and some of these have demonstrated preliminary success as serum biomarkers that can be used clinically. Nevertheless, there are many opportunities to further define the mechanisms by which these epigenetic modifications influence tumorigenesis, and this will provide better insight into their prognostic and therapeutic utility. Furthermore, these findings form the foundation for future studies evaluating the clinical efficacy of epigenetic modifications as prognostic biomarkers, as well as potential therapeutic targets.
Collapse
Affiliation(s)
- Brendan M Finnerty
- Department of Surgery, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, United States
| | - Katherine D Gray
- Department of Surgery, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, United States
| | - Maureen D Moore
- Department of Surgery, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, United States
| | - Rasa Zarnegar
- Department of Surgery, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, United States
| | - Thomas J Fahey III
- Department of Surgery, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, United States
| |
Collapse
|
|
22
|
Song YL, Yu R, Qiao XW, Bai CM, Lu CM, Xiao Y, Zhong DR, Chen J, Zhao YP, Zhang TP, Song TT, Gao HL, Wan YH, Shen L, Chen J, Lv B, Hao JJ, Zhang Y, Tang L, Chen YJ. Prognostic relevance of UCH-L1 and α-internexin in pancreatic neuroendocrine tumors. Sci Rep 2017; 7:2205. [PMID: 28526880 PMCID: PMC5438410 DOI: 10.1038/s41598-017-02051-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Accepted: 04/05/2017] [Indexed: 02/05/2023] Open
Abstract
Prognostic biomarkers for the pancreatic neuroendocrine tumors are needed. Proteomic study on insulinoma has been rarely reported. We identified the differential expression of proteins between insulinoma and their paired tissues by proteomic analysis, and evaluated the prognostic significance of specific proteins in pancreatic neuroendocrine tumors including insulinoma. The differential expression of select proteins was validated in more than 300 tumors using immunohistochemical staining and western blot. Methylation of UCH-L1 promoter in tumors was examined by methylation specific PCR and validated by sequencing. The concurrent expression of UCH-L1 and α-internexin was correlated with the prognosis in 2 independent collectives of patients with tumors. Sixty-two and 219 proteins were significantly down-regulated and up-regulated in insulinomas, respectively. Demethylation of UCH-L1 promoter was associated with UCH-L1 expression in tumors (p = 0.002). The concurrent expression of UCH-L1 and α-internexin in pancreatic neuroendocrine tumors was significantly associated with better overall survival and disease-free survival in the combination of both cohorts (log rank p = 3.90 × 10−4 and p = 3.75 × 10−5, respectively) and in each of cohorts. The prognostic value of both proteins was also validated in patients with stage II and III tumors (p = 0.017 and p = 0.006, respectively). The proteins UCH-L1 and α-internexin could be independent prognostic biomarkers of pancreatic neuroendocrine tumors.
Collapse
Affiliation(s)
- Yu-Li Song
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Run Yu
- Division of Endocrinology, Cedars-Sinai Medical Center, and Division of Endocrinology, Diabetes & Metabolism, UCLA, Los Angeles, California, 90095, USA
| | - Xin-Wei Qiao
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Chun-Mei Bai
- Department of Oncology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Chong-Mei Lu
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Yu Xiao
- Department of Pathology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Ding-Rong Zhong
- Department of Pathology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Jie Chen
- Department of Pathology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Yu-Pei Zhao
- Department of Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Tai-Ping Zhang
- Department of Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Tian-Tian Song
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - He-Li Gao
- Department of Oncology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Ying-Hua Wan
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Lin Shen
- Department of Gastrointestinal Medical Oncology, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, 100142, China
| | - Jie Chen
- Department of Gastroenterology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China
| | - Bin Lv
- Department of Gastroenterology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310006, China
| | | | - Ye Zhang
- Department of Molecular and Biochemistry, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Laura Tang
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York City, 10065, USA
| | - Yuan-Jia Chen
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China.
| |
Collapse
|
|
23
|
Lee MS, O'Neil BH. Summary of emerging personalized medicine in neuroendocrine tumors: are we on track? J Gastrointest Oncol 2016; 7:804-818. [PMID: 27747094 DOI: 10.21037/jgo.2016.08.05] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Neuroendocrine tumors (NETs) comprise a heterogeneous group of malignancies, with differences in prognosis and effective therapies. Traditionally, NETs have been characterized by tumor grade, site of primary tumor, functional status, and presence of underlying familial syndrome. However, increased feasibility and utilization of next-generation sequencing and other methodologies have revealed new genomic and epigenetic aberrations. In the last decade, treatment options available for metastatic well-differentiated gastroenteropancreatic (GEP) NETs have expanded, with approval of antiangiogenic and mTOR-directed targeted therapies, and our armamentarium of active therapies is likely to further increase. Cytotoxic therapies also are an important option for pancreatic NETs, and MGMT promoter methylation and protein expression may be an important biomarker for efficacy of alkylating agents. Peptide receptor radioligand therapy is an emerging treatment that uses functional imaging to personalize dosimetry to the tumor and avoid nephrotoxicity. Nevertheless, there is a critical need for further biomarkers, particularly multianalyte biomarkers, to aid in prognostication and predict efficacy of therapies.
Collapse
Affiliation(s)
- Michael S Lee
- University of North Carolina at Chapel Hill, North Carolina, USA
| | | |
Collapse
|
|
24
|
Cives M, Simone V, Rizzo FM, Silvestris F. NETs: organ-related epigenetic derangements and potential clinical applications. Oncotarget 2016; 7:57414-57429. [PMID: 27418145 PMCID: PMC5302998 DOI: 10.18632/oncotarget.10598] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 06/30/2016] [Indexed: 12/15/2022] Open
Abstract
High-throughput next-generation sequencing methods have recently provided a detailed picture of the genetic landscape of neuroendocrine tumors (NETs), revealing recurrent mutations of chromatin-remodeling genes and little-to-no pathogenetic role for oncogenes commonly mutated in cancer. Concurrently, multiple epigenetic modifications have been described across the whole spectrum of NETs, and their putative function as tumorigenic drivers has been envisaged. As result, it is still unclear whether or not NETs are epigenetically-driven, rather than genetically-induced malignancies. Although the NET epigenome profiling has led to the identification of molecularly-distinct tumor subsets, validation studies in larger cohorts of patients are needed to translate the use of NET epitypes in clinical practice. In the precision medicine era, recognition of subpopulations of patients more likely to respond to therapeutic agents is critical, and future studies testing epigenetic biomarkers are therefore awaited. Restoration of the aberrant chromatin remodeling machinery is an attractive approach for future treatment of cancer and in several hematological malignancies a few epigenetic agents have been already approved. Although clinical outcomes of epigenetic therapies in NETs have been disappointing so far, further clinical trials are required to investigate the efficacy of these drugs. In this context, given the immune-stimulating effects of epidrugs, combination therapies with immune checkpoint inhibitors should be tested. In this review, we provide an overview of the epigenetic changes in both hereditary and sporadic NETs of the gastroenteropancreatic and bronchial tract, focusing on their diagnostic, prognostic and therapeutic implications.
Collapse
Affiliation(s)
- Mauro Cives
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari “Aldo Moro”, Bari, Italy
| | - Valeria Simone
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari “Aldo Moro”, Bari, Italy
| | - Francesca Maria Rizzo
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari “Aldo Moro”, Bari, Italy
| | - Franco Silvestris
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari “Aldo Moro”, Bari, Italy
| |
Collapse
|
|
25
|
Zhu LM, Tang L, Qiao XW, Wolin E, Nissen NN, Dhall D, Chen J, Shen L, Chi Y, Yuan YZ, Ben QW, Lv B, Zhou YR, Bai CM, Chen J, Song YL, Song TT, Lu CM, Yu R, Chen YJ. Differences and Similarities in the Clinicopathological Features of Pancreatic Neuroendocrine Tumors in China and the United States: A Multicenter Study. Medicine (Baltimore) 2016; 95:e2836. [PMID: 26886644 PMCID: PMC4998644 DOI: 10.1097/md.0000000000002836] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
The presentation, pathology, and prognosis of pancreatic neuroendocrine tumors (PNETs) in Asian patients have not been studied in large cohorts. We hypothesized that the clinicopathological features of PNETs of Chinese patients might be different from those of US patients. The objectives of this study were to address whether PNETs in Chinese patients exhibit unique clinicopathological features and natural history, and can be graded and staged using the WHO/ENETS criteria. This is a retrospective review of medical records of patients with PNETs in multiple academic medical centers in China (7) and the United States (2). Tumor grading and staging were based on WHO/ENETS criteria. The clinicopathological features of PNETs of Chinese and US patients were compared. Univariate and multivariate analyses were performed to find associations between survival and patient demographics, tumor grade and stage, and other clinicopathological characteristics. A total of 977 (527 Chinese and 450 US) patients with PNETs were studied. In general, Chinese patients were younger than US patients (median age 46 vs 56 years). In Chinese patients, insulinomas were the most common (52.2%), followed by nonfunctional tumors (39.7%), whereas the order was reversed in US patients. Tumor grade distribution was similar in the 2 countries (G1: 57.5% vs 55.0%; G2: 38.5% vs 41.3%; and G3: 4.0% vs 3.7%). However, age, primary tumor size, primary tumor location, grade, and stage of subtypes of PNETs were significantly different between the 2 countries. The Chinese nonfunctional tumors were significantly larger than US ones (median size 4 vs 3 cm) and more frequently located in the head/neck region (54.9% vs 34.8%). The Chinese and US insulinomas were similar in size (median 1.5 cm) but the Chinese insulinomas relatively more frequently located in the head/neck region (48.3% vs 26.1%). Higher grade, advanced stage, metastasis, and larger primary tumor size were significantly associated with unfavorable survival in both countries. Several clinicopathological differences are found between Chinese and US PNETs but the PNETs of both countries follow a similar natural history. The WHO tumor grading and ENETS staging criteria are applicable to both Chinese and US patients.
Collapse
Affiliation(s)
- Li-Ming Zhu
- From the Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing (L-MZ, X-WQ, Y-LS, T-TS, C-ML, Y-JC); Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY (LT); Markey Cancer Center, University of Kentucky, Lexington, KY (EW); Department of Surgery (NNN); Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA (DD); Department of Gastroenterology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou (JC); Department of Gastrointestinal Medical Oncology, Peking University School of Oncology, Beijing Cancer Hospital and Institute (LS); Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing (YC); Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University, Shanghai (Y-ZY, Q-WB); Department of Gastroenterology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou (BL); Department of Endocrinology, the Third Hospital of Hebei Medical University, Shijiazhuang (Y-RZ); Department of Oncology (C-MB); Department of Pathology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing (JC); and Division of Endocrinology and Carcinoid and Neuroendocrine Tumor Center, Cedars-Sinai Medical Center, University of California Los Angeles, Los Angeles, CA (RY)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
26
|
Liu IH, Ford JM, Kunz PL. DNA-repair defects in pancreatic neuroendocrine tumors and potential clinical applications. Cancer Treat Rev 2015; 44:1-9. [PMID: 26924193 DOI: 10.1016/j.ctrv.2015.11.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Revised: 11/18/2015] [Accepted: 11/19/2015] [Indexed: 01/09/2023]
Abstract
BACKGROUND The role of DNA repair in pathogenesis and response to treatment is not well understood in pancreatic neuroendocrine tumors (pNETs). However, the existing literature reveals important preliminary trends and targets in the genetic landscape of pNETs. Notably, pNETs have been shown to harbor defects in the direct reversal MGMT gene and the DNA mismatch repair genes, suggesting that these genes may be strong candidates for further prospective studies. METHODS PubMed searches were conducted for original studies assessing the DNA repair genes MGMT and MMR in pNETs, as well as for PTEN and MEN1, which are not directly DNA repair genes but are involved in DNA repair pathways. Searches were specific to pNETs, yielding five original studies on MGMT and four on MMR. Six original papers studied PTEN in pNETs. Five studied MEN1 in pNETs, and two others implicated MEN1 in DNA repair processes. RESULTS The five studies on MGMT in pNET tumor samples found MGMT loss of between 24% and 51% of tumor samples by IHC staining and between 0% and 40% by promoter hypermethylation, revealing discrepancies in methods assessing MGMT expression as well as potential weaknesses in the correlation between MGMT IHC expression and promoter hypermethylation rates. Four studies on MMR in pNET tumor samples indicated similar ambiguities, as promoter hypermethylation of the MLH1 MMR gene ranged from 0% to 31% of pNETs, while IHC staining revealed loss of MMR genes in between 0% and 36% of pNETs sampled. Studies also indicated that PTEN and MEN1 are commonly mutated or underexpressed genes in pNETs, although frequency of mutation or loss of expression was again variable among different studies. CONCLUSION Further studies are essential in determining a more thorough repertoire of DNA repair defects in pNETs and the clinical significance of these defects. This literature review synthesises the existing knowledge of relevant DNA repair pathways and studies of the specific genes that carry out these repair mechanisms in pNETs.
Collapse
Affiliation(s)
| | - James M Ford
- Stanford University School of Medicine, United States
| | - Pamela L Kunz
- Stanford University School of Medicine, 875 Blake Wilbur Drive, Stanford, CA 94305-5826, United States.
| |
Collapse
|
|
27
|
Mapelli P, Aboagye EO, Stebbing J, Sharma R. Epigenetic changes in gastroenteropancreatic neuroendocrine tumours. Oncogene 2015; 34:4439-47. [PMID: 25435371 DOI: 10.1038/onc.2014.379] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Revised: 09/25/2014] [Accepted: 10/10/2014] [Indexed: 02/07/2023]
Abstract
An understanding of epigenetic drivers of tumorigenesis has developed rapidly during the last years. The identification of these changes including DNA methylation and histone modifications in gastroenteropancreatic neuroendocrine tumours (GEP-NETs) is a step forward in trying to define underlying biologic processes in this heterogeneous disease. The reversible nature of these changes represents a potential therapeutic target. We present an overview of the current knowledge of epigenetic alterations related to GEP-NETs, focusing on the influence and impact these changes have on pathogenesis and prognosis. The potential role of demethylating agents in the management of this patient population is discussed.
Collapse
Affiliation(s)
- P Mapelli
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK
| | - E O Aboagye
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK
| | - J Stebbing
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK
| | - R Sharma
- Department of Experimental Medicine, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK
| |
Collapse
|
|
28
|
Qiao XW, Qiu L, Chen YJ, Meng CT, Sun Z, Bai CM, Zhao DC, Zhang TP, Zhao YP, Song YL, Wang YH, Chen J, Lu CM. Chromogranin A is a reliable serum diagnostic biomarker for pancreatic neuroendocrine tumors but not for insulinomas. BMC Endocr Disord 2014; 14:64. [PMID: 25099181 PMCID: PMC4130880 DOI: 10.1186/1472-6823-14-64] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Accepted: 07/30/2014] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Pancreatic neuroendocrine tumors (PNETs) are a group of rare tumors. Chromogranin A (CgA) was considered as the most practical and useful serum tumor marker in PNET patients. But peripheral blood levels of CgA are not routinely tested in Chinese patients with PNETs. This study was to assess the diagnostic value of CgA in Chinese patients with PNETs especially in patients with insulinomas. METHODS Eighty-nine patients with PNETs including 57 insulinomas and 32 non-insulinoma PNETs as well as 86 healthy participants were enrolled in this study between September 2003 and June 2013. Serum levels of CgA were measured by ELISA method. Expression of CgA protein was detected in 26 PNET tissues including 14 insulinomas by immunohistochemical staining. RESULTS Serum levels of CgA in 89 PNET patients were significantly higher than that in healthy controls (P = 7.2 × 10-9). Serum levels of CgA in 57 patients with insulinomas (median 64.8 ng/ml, range 25-164) were slightly higher than the levels in healthy controls (median 53.4 ng/ml, range 39-94) but much lower than the levels in 32 patients with non-insulinoma PNETs (median 193 ng/ml, range 27-9021), P = 0.001. The serum CgA levels were reduced in 16 of 17 patients with insulinomas after tumor resection. ROC curve showed that CgA values at 60 ng/ml distinguished patients with insulinomas from healthy controls but its sensitivity and specificity were 66.7% and 73.3%, respectively. In contrast, CgA values at 74 ng/ml distinguished patients with non-insulinoma PNETs from healthy controls, and the sensitivity and specificity were 65.6% and 91.9%, respectively. Except for two insulinomas with negative staining of CgA, 12 insulinoma tissues showed positive staining of CgA. CONCLUSION CgA is a reliable serum diagnostic biomarker for PNETs but not for insulinomas.
Collapse
Affiliation(s)
- Xin-Wei Qiao
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, People’s Republic of China
| | - Ling Qiu
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, People’s Republic of China
| | - Yuan-Jia Chen
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, People’s Republic of China
- Key Laboratory of Endocrinology (Ministry of Health), Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, People’s Republic of China
| | - Chang-Ting Meng
- Department of Oncology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, People’s Republic of China
| | - Zhao Sun
- Department of Oncology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, People’s Republic of China
| | - Chun-Mei Bai
- Department of Oncology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, People’s Republic of China
| | - Da-Chun Zhao
- Department of Pathology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, People’s Republic of China
| | - Tai-Ping Zhang
- Department of Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, People’s Republic of China
| | - Yu-Pei Zhao
- Key Laboratory of Endocrinology (Ministry of Health), Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, People’s Republic of China
- Department of Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, People’s Republic of China
| | - Yu-Li Song
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, People’s Republic of China
| | - Yu-Hong Wang
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, People’s Republic of China
| | - Jie Chen
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, People’s Republic of China
| | - Chong-Mei Lu
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, People’s Republic of China
| |
Collapse
|
|
29
|
The analysis of microsatellite instability in extracolonic gastrointestinal malignancy. Pathology 2014; 45:540-52. [PMID: 24018804 DOI: 10.1097/pat.0b013e3283653307] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Microsatellite instability (MSI) is a genetic feature of sporadic and familial cancers of multiple sites and is related to defective mismatch repair (MMR) protein function. Lynch syndrome (LS) is a familial form of MMR deficiency that may present with a spectrum of MSI positive cancers including gastrointestinal (GI) malignancies. The incidence of high level MSI (MSI-H) in colorectal carcinoma is well defined in both familial and sporadic cases and these tumours portend a better overall prognosis in colorectal carcinoma (CRC). There are certain morphological features that suggest MSI-H CRC and international guidelines have been established for the evaluation of MSI in CRC. The prevalence and morphological features of extracolonic GI MSI-H tumours are less well documented. Furthermore, it is unclear whether the guidelines for the assessment of MSI in CRC are appropriate for application to extracolonic GI malignancies. This review aims to summarise the recent literature on MSI in extracolonic LS-related GI tract malignancies with special attention to the assessment of the MMR system by evaluation of specific microsatellite markers and/or immunohistochemical evaluation of MMR protein expression. The reported prevalence of sporadic and LS-related MSI-H tumours along with their associated unique morphological patterns and related prognostic or therapeutic implications will be discussed.
Collapse
|
|
30
|
Meeker A, Heaphy C. Gastroenteropancreatic endocrine tumors. Mol Cell Endocrinol 2014; 386:101-20. [PMID: 23906538 DOI: 10.1016/j.mce.2013.07.015] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Revised: 07/19/2013] [Accepted: 07/22/2013] [Indexed: 02/06/2023]
Abstract
Gastroenteropancreatic endocrine tumors (GEP-NETs) are relatively uncommon; comprising approximately 0.5% of all human cancers. Although they often exhibit relatively indolent clinical courses, GEP-NETs have the potential for lethal progression. Due to their scarcity and various technical challenges, GEP-NETs have been understudied. As a consequence, we have few diagnostic, prognostic and predictive biomarkers for these tumors. Early detection and surgical removal is currently the only reliable curative treatment for GEP-NET patients; many of whom, unfortunately, present with advanced disease. Here, we review the genetics and epigenetics of GEP-NETs. The last few years have witnessed unprecedented technological advances in these fields, and their application to GEP-NETS has already led to important new information on the molecular abnormalities underlying them. As outlined here, we expect that "omics" studies will provide us with new diagnostic and prognostic biomarkers, inform the development of improved pre-clinical models, and identify novel therapeutic targets for GEP-NET patients.
Collapse
Affiliation(s)
- Alan Meeker
- The Johns Hopkins University School of Medicine, Department of Pathology, Bond Street Research Annex Bldg., Room B300, 411 North Caroline Street, Baltimore, MD 21231, United States.
| | - Christopher Heaphy
- The Johns Hopkins University School of Medicine, Department of Pathology, Bond Street Research Annex Bldg., Room B300, 411 North Caroline Street, Baltimore, MD 21231, United States
| |
Collapse
|
|
31
|
Walenkamp A, Crespo G, Fierro Maya F, Fossmark R, Igaz P, Rinke A, Tamagno G, Vitale G, Öberg K, Meyer T. Hallmarks of gastrointestinal neuroendocrine tumours: implications for treatment. Endocr Relat Cancer 2014; 21:R445-60. [PMID: 25296914 DOI: 10.1530/erc-14-0106] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
In the past few years, there have been advances in the treatment of neuroendocrine tumours (NETs) and improvements in our understanding of NET biology. However, the benefits to patients have been relatively modest and much remains yet to be done. The 'Hallmarks of Cancer', as defined by Hanahan and Weinberg, provide a conceptual framework for understanding the aberrations that underlie tumourigenesis and to help identify potential targets for therapy. In this study, our objective is to review the major molecular characteristics of NETs, based on the recently modified 'Hallmarks of Cancer', and highlight areas that require further research.
Collapse
Affiliation(s)
- Annemiek Walenkamp
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK
| | - Guillermo Crespo
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK
| | - Felipe Fierro Maya
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK
| | - Reidar Fossmark
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK
| | - Peter Igaz
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK
| | - Anja Rinke
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK
| | - Gianluca Tamagno
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK
| | - Giovanni Vitale
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Au
| | - Kjell Öberg
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK
| | - Tim Meyer
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK
| |
Collapse
|
|
32
|
Abstract
The field of epigenetics has evolved rapidly over recent years providing insight into the tumorigenesis of many solid and haematological malignancies. Determination of epigenetic modifications in neuroendocrine tumour (NET) development is imperative if we are to improve our understanding of the biology of this heterogenous group of tumours. Epigenetic marks such as DNA methylation at RASSF1A are frequent findings in NETs of all origins and may be associated with worse prognosis. MicroRNA signatures and histone modifications have been identified which can differentiate subtypes of NET and distinguish NET from adenocarcinoma in cases of diagnostic uncertainty. Historically, candidate gene-driven approaches have yielded limited insight into the epigenetics of NET. Recent progress has been facilitated by development of high-throughput tools including second-generation sequencing and arrays for analysis of the 'epigenome' of tumour and normal tissue, permitting unbiased approaches such as exome sequencing that identified mutations of chromatin-remodelling genes ATRX/DAXX in 44% of pancreatic NETs. Epigenetic changes are reversible and therefore represent an attractive therapeutic target; to date, clinical outcomes of epigenetic therapies in solid tumours have been disappointing; however, in vitro studies on NETs are promising and further clinical trials are required to determine utility of this class of novel agents. In this review, we perform a comprehensive evaluation of epigenetic changes found in NETs to date, including rare NETs such as phaeochromocytoma and adrenocortical tumours. We suggest priorities for future research and discuss potential clinical applications and novel therapies.
Collapse
Affiliation(s)
- A Karpathakis
- University College London Cancer Institute, 72 Huntley Street, London WC1E 6BT, UK
| | | | | |
Collapse
|
|
33
|
Ro C, Chai W, Yu VE, Yu R. Pancreatic neuroendocrine tumors: biology, diagnosis,and treatment. CHINESE JOURNAL OF CANCER 2012; 32:312-24. [PMID: 23237225 PMCID: PMC3845620 DOI: 10.5732/cjc.012.10295] [Citation(s) in RCA: 118] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Pancreatic neuroendocrine tumors (PNETs), a group of endocrine tumors arising in the pancreas, are among the most common neuroendocrine tumors. The genetic causes of familial and sporadic PNETs are somewhat understood, but their molecular pathogenesis remains unknown. Most PNETs are indolent but have malignant potential. The biological behavior of an individual PNET is unpredictable; higher tumor grade, lymph node and liver metastasis, and larger tumor size generally indicate a less favorable prognosis. Endocrine testing, imaging, and histological evidence are necessary to accurately diagnose PNETs. A 4-pronged aggressive treatment approach consisting of surgery, locoregional therapy, systemic therapy, and complication control has become popular in academic centers around the world. The optimal application of the multiple systemic therapeutic modalities is under development; efficacy, safety, availability, and cost should be considered when treating a specific patient. The clinical presentation, diagnosis, and treatment of specific types of PNETs and familial PNET syndromes, including the novel Mahvash disease, are summarized.
Collapse
Affiliation(s)
- Cynthia Ro
- Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
| | | | | | | |
Collapse
|
|
34
|
Karamurzin Y, Zeng Z, Stadler ZK, Zhang L, Ouansafi I, Al-Ahmadie HA, Sempoux C, Saltz LB, Soslow RA, O'Reilly EM, Paty PB, Coit DG, Shia J, Klimstra DS. Unusual DNA mismatch repair-deficient tumors in Lynch syndrome: a report of new cases and review of the literature. Hum Pathol 2012; 43:1677-87. [PMID: 22516243 DOI: 10.1016/j.humpath.2011.12.012] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2011] [Revised: 12/09/2011] [Accepted: 12/14/2011] [Indexed: 12/24/2022]
Abstract
Immunohistochemical detection of DNA mismatch repair proteins and polymerase chain reaction detection of microsatellite instability have enhanced the recognition of mismatch repair-deficient neoplasms in patients with Lynch syndrome and, consequently, led to the identification of tumors that have not been included in the currently known Lynch syndrome tumor spectrum. Here, we report 4 such unusual tumors. Three of the 4, a peritoneal mesothelioma, a pancreatic acinar cell carcinoma, and a pancreatic well-differentiated neuroendocrine tumor, represented tumor types that, to the best of our knowledge, have not been previously reported in Lynch syndrome. The fourth tumor was an adrenocortical carcinoma, which has rarely been reported previously in Lynch syndrome. Three of our 4 patients carried a pathogenic germ-line mutation in a mismatch repair gene. The unusual tumor in each of the 3 patients showed loss of the mismatch repair protein corresponding to the mutation. The fourth patient did not have mutation information but had a history of colonic and endometrial carcinomas; both lacked MSH2 and MSH6 proteins. Interestingly, none of the 4 unusual tumors revealed microsatellite instability on polymerase chain reaction testing, whereas an appendiceal carcinoma from 1 of the study patients who was tested simultaneously did. The recognition of such tumors expands the repertoire of usable test samples for the workup of high-risk families. As yet, however, there are no data to support the inclusion of these tumors into general screening guidelines for detecting Lynch syndrome, nor are there data to warrant surveillance for these tumors in patients with Lynch syndrome.
Collapse
Affiliation(s)
- Yevgeniy Karamurzin
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Arnason T, Sapp HL, Rayson D, Barnes PJ, Drewniak M, Nassar BA, Huang WY. Loss of Expression of DNA Mismatch Repair Proteins Is Rare in Pancreatic and Small Intestinal Neuroendocrine Tumors. Arch Pathol Lab Med 2011; 135:1539-44. [DOI: 10.5858/arpa.2010-0560-oa] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Context.—Two recent studies have identified a high rate of microsatellite instability (MSI) in pancreatic neuroendocrine tumors (pNETs). Microsatellite instability is rare in small intestinal neuroendocrine tumors (NETs). It is unclear why there is discordance in the frequency of MSI in the 2 studies of pNETs and why this mechanism is comparatively rare in small intestinal tumors. Loss of expression of DNA mismatch repair (MMR) proteins, which is known to correlate strongly with MSI, is not well studied in pancreatic or small intestinal NETs.
Objective.—To determine if there is loss of expression of MMR protein expression in pancreatic or small intestinal NETs.
Design.—Sixty-nine patients (31 male, 38 female; mean age, 59.2 years) were identified who had a resection for a primary pancreatic (n = 35) or primary small intestinal (n = 34) NET during an 18-year period. Immunohistochemical stains for MLH1, MSH2, MSH6, and PMS2 were applied to archived tissue from all cases. All pNETs with adequate tissue (n = 32) were also assessed by MSI analysis.
Results.—There was preserved expression of MLH1, MSH2, MSH6, and PMS2 in all 35 pNETs. Of 32 pNETs tested by polymerase chain reaction, 28 were microsatellite stable and DNA did not amplify in 4. In 34 small intestinal NETs, 2 cases had indeterminate MLH1 and 1 case had indeterminate PMS2 expression. The remainder had intact MMR protein expression.
Conclusion.—Defects in DNA MMR proteins are rare in pancreatic and small intestinal NETs, raising doubt that MSI plays a significant role in the pathogenesis of these tumors.
Collapse
|
|
36
|
Methylation of the 3p22 region encompassing MLH1 is representative of the CpG island methylator phenotype in colorectal cancer. Mod Pathol 2011; 24:396-411. [PMID: 21102416 DOI: 10.1038/modpathol.2010.212] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Epigenetic silencing of cancer-related genes by promoter methylation is a frequent event in sporadic colorectal cancer. The CpG island methylator phenotype (CIMP+), in which discrete genes throughout the genome are simultaneously methylated, and long-range epigenetic silencing, whereby multiple genes within contiguous chromosomal regions are methylated, have been described in subsets of colorectal cancer. We previously reported the concurrent methylation of the mismatch repair gene MLH1 with a cluster of flanking genes in chromosome region 3p22 in sporadic colorectal carcinoma exhibiting microsatellite instability and the BRAF V600E mutation. Herein, we aimed to determine whether methylation of MLH1 and neighbouring 3p22 genes, singly or concomitantly, correlate with the germline c.-93G>A SNP within the MLH1 promoter, CIMP+ and other clinicopathological and molecular features of the tumours. By studying a cohort of 946 sporadic colorectal cancer cases, we show a strong association between concordant methylation of ≥ 3 of five 3p22 genes with CIMP+ and the BRAF V600E mutation (P<0.001). These associations were independent of microsatellite instability, as concomitant methylation of 3p22 genes other than MLH1 was found in microsatellite stable cancers. These findings show that long-range epigenetic silencing across 3p22 occurs in the context of CIMP+ and the BRAF V600E mutation, and only gives rise to microsatellite instability when this process encompasses MLH1. Furthermore, the strong relationship between long-range epigenetic silencing of 3p22 and CIMP+ provides further evidence that these two purportedly distinct epigenetic phenotypes represent a single entity with a common aetiology. Low-level methylation of MLH1 and flanking 3p22 genes, as well as the BRAF V600E mutation, were detected in the apparently normal colonic mucosa of a small number of cases whose tumours showed a similar molecular profile, suggesting that these concurring genetic and epigenetic events can occur as a field defect in neoplastic development.
Collapse
|
|
37
|
Abstract
Insulinomas are rare causes of hypoglycemia. After having ruled out non insulinomatous causes of hypoglycemia in a patient in whom Whipple's triad is documented, hyperinsulinism must be demonstrated biochemically, either during a spontaneous hypoglycemic episode or, more often, during a supervised fast which may be prolonged up to 72 h. A mixed-meal test may also help to diagnose the very rare cases of postprandial hypoglycemia related to non insulinoma pancreatogenic hypoglycemic syndrome (NIPHS) or to some rare insulinomas. Only when diagnosis of hypoglycemic hyperinsulinism is made, the tumor localization process may be initiated. This may be difficult due to the small size of insulinomas (generally < 1 cm). Multimodal approach is necessary. The association of endoscopic ultrasound and CT-scan or MRI seems optimal. Octreoscan will be also performed. First results with a very new technique, the GLP-1 receptor imaging, are promising for localizing very small tumors. This localization aims to allow a sparing surgery; enucleation of benign tumors, if possible, allows a pancreatic tissue preservation in patients with quite normal survival.
Collapse
Affiliation(s)
- L Cazabat
- Hôpitaux de Paris, Service d'Endocrinologie et des Maladies de la Reproduction, Hôpital de Bicêtre et Faculté de Médicine Paris-Sud, Université Paris Sud 11, 78, rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France.
| | | |
Collapse
|
|
38
|
Deng D, Liu Z, Du Y. Epigenetic alterations as cancer diagnostic, prognostic, and predictive biomarkers. ADVANCES IN GENETICS 2010; 71:125-76. [PMID: 20933128 DOI: 10.1016/b978-0-12-380864-6.00005-5] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Alterations of DNA methylation and transcription of microRNAs (miRNAs) are very stable phenomena in tissues and body fluids and suitable for sensitive detection. These advantages enable us to translate some important discoveries on epigenetic oncology into biomarkers for control of cancer. A few promising epigenetic biomarkers are emerging. Clinical trials using methylated CpG islands of p16, Septin9, and MGMT as biomarkers are carried out for predication of cancer development, diagnosis, and chemosensitivity. Circulating miRNAs are promising biomarkers, too. Breakthroughs in the past decade imply that epigenetic biomarkers may be useful in reducing the burden of cancer.
Collapse
Affiliation(s)
- Dajun Deng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry ofEducation), Peking University School of Oncology, Beijing Cancer Hospitaland Institute, Fu-Cheng-Lu, Haidian District, Beijing, 100142, PR China
| | | | | |
Collapse
|