韩序;楼文晖;
HAN Xu;LOU Wen-hui;Department of General Surgery, Zhongshan Hospital, Fudan University;

• 1:复旦大学附属中山医院普通外科

摘要(Abstract)：

大量研究发现,染色体重塑相关基因(ATRX/DAXX、ARID1A)、MEN-1基因、DNA损伤修复基因(MUTYH)和哺乳动物雷帕霉素靶蛋白信号通路相关基因的异常改变共同参与了无功能性胰腺神经内分泌肿瘤(pancreatic neuroendocrine neoplasia,pNEN)的发生发展。作为功能性pNEN的代表,胰岛素瘤常出现拷贝数异常,伴随转录因子YY1的热点突变。驱动基因突变、DNA损伤修复、DNA甲基化、组蛋白修饰、染色体重塑和端粒替代延长机制激活等表观遗传学的异常改变以及相关信号通路的异常激活协同引起pNEN增殖和侵袭。这些分子机制及基因分型具有十分重要的意义,可为临床个体化综合治疗和预后判断提供依据,使更多的pNEN患者从精准医学中获益。
Genomic sequencing studies have led to an increased understanding of the genotyping and molecular biology of pancreatic neuroendocrine neoplasias(pNENs). Recent studies reported that ATRX(α-thalassaemia/mental retardation syndrome X-linked)/DAXX(death-domain associated protein), ARID1 A(AT-rich interactive domain-containing protein 1 A, BAF250 A), MUTYH(mutY homolog), and MEN-1(multiple endocrine neoplasia type 1) genes are remarkably mutated in non-functional pNENs, as well as genes encoding core components of the mammalian target of rapamycin(mTOR) signaling pathway. As a representative of functional pNENs,insulinomas had CNV amplifications and copy neutral with YY1(Yin Yang 1) gene mutations. These mutated genes are involved in aberrations of chromatin remodeling, DNA damage repair, histone modification, and telomere maintenance, and thus might contribute to tumorigenesis and ultimately to the progression of pNENs characterized by divergent phenotypes. Differentiating genotypic subtypes of pNENs plays an important role in prognostication. Future therapies might be based on recent advances in molecular genotyping and mechanism.

关键词(KeyWords)： 神经内分泌肿瘤;胰腺;分子机制;基因突变;表观遗传学
neuroendocrine neoplasia;pancreas;molecular mechanism;genetics;epigenetics

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金(81702304、81773068)

作者(Authors): 韩序;楼文晖;
HAN Xu;LOU Wen-hui;Department of General Surgery, Zhongshan Hospital, Fudan University;

参考文献(References)：

• [1] Yao JC,Hassan M,Phan A,et al.One hundred years after “carcinoid”:epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States[J].J Clin Oncol,2008,26:3063- 3072.
• [2] Halfdanarson TR,Rabe KG,Rubin J,et al.Pancreatic neuroendocrine tumors (PNETs):incidence,prognosis and recent trend toward improved survival[J].Ann Oncol,2008,19:1727- 1733.
• [3] Garcia-Carbonero R,Capdevila J,Crespo-Herrero G,et al.Incidence,patterns of care and prognostic factors for outcome of gastroenteropancreatic neuroendocrine tumors (GEP-NETs):results from the National Cancer Registry of Spain(RGETNE)[J].Ann Oncol,2010,21:1794- 1803.
• [4] Yachida S,Vakiani E,White CM,et al.Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancrea-tic neuroendocrine tumors[J].Am J Surg Pathol,2012,36:173- 184.
• [5] Scarpa A,Chang DK,Nones K,et al.Whole-genome landscape of pancreatic neuroendocrine tumours[J].Nature,2017,543:65- 71.
• [6] Jiao Y,Shi C,Edil BH,et al.DAXX/ATRX,MEN1,and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors[J].Science,2011,331:1199- 1203.
• [7] Hong X,Qiao S,Li F,et al.Whole-genome sequencing reveals distinct genetic bases for insulinomas and non-functional pancreatic neuroendocrine tumours:leading to a new classification system[J].Gut,2020,69:877- 887.
• [8] Chan CS,Laddha SV,Lewis PW,et al.ATRX,DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct alpha-cell signature subgroup[J].Nat Commun,2018,9:4158.
• [9] Xiao Y,Yang Y,Wang Y,et al.Five Novel Genes Related to the Pathogenesis and Progression of Pancreatic Neuroendocrine Tumors by Bioinformatics Analysis With RT-qPCR Verification[J].Front Neurosci,2019,13:937.
• [10] Goldberg AD,Banaszynski LA,Noh KM,et al.Distinct factors control histone variant H3.3 localization at specific genomic regions[J].Cell,2010,140:678- 691.
• [11] Elsasser SJ,Allis CD,Lewis PW.Cancer.New epigenetic drivers of cancers[J].Science,2011,331:1145- 1146.
• [12] Marinoni I,Kurrer AS,Vassella E,et al.Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors[J].Gastroenterology,2014,146:453- 460.e5.
• [13] Singhi AD,Liu TC,Roncaioli JL,et al.Alternative Lengthening of Telomeres and Loss of DAXX/ATRX Expression Predicts Metastatic Disease and Poor Survival in Patients with Pancreatic Neuroendocrine Tumors[J].Clin Cancer Res,2017,23:600- 609.
• [14] Kim JY,Brosnan-Cashman JA,An S,et al.Alternative Lengthening of Telomeres in Primary Pancreatic Neuroendocrine Tumors Is Associated with Aggressive Clinical Behavior and Poor Survival[J].Clin Cancer Res,2017,23:1598- 1606.
• [15] Roy S,LaFramboise WA,Liu TC,et al.Loss of Chromatin-Remodeling Proteins and/or CDKN2A Associates With Metastasis of Pancreatic Neuroendocrine Tumors and Reduced Patient Survival Times[J].Gastroenterology,2018,154:2060- 2063.e8.
• [16] Pea A,Yu J,Marchionni L,et al.Genetic Analysis of Small Well-differentiated Pancreatic Neuroendocrine Tumors Identifies Subgroups With Differing Risks of Liver Metastases[J].Ann Surg,2020,271:566- 573.
• [17] Zang ZJ,Cutcutache I,Poon SL,et al.Exome sequencing of gastric adenocarci-noma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes[J].Nat Genet,2012,44:570- 574.
• [18] Wang SC,Nassour I,Xiao S,et al.SWI/SNF component ARID1A restrains pancreatic neoplasia formation[J].Gut,2019,68:1259- 1270.
• [19] Zhang L,Jia CW,Lu ZH,et al.ARID1A expression of SWI/SNF remodeling complex in pancreatic neuroendocrine tumor[J].Zhonghua Bing Li Xue Za Zhi,2016,45:571- 574.
• [20] Han X,Chen W,Chen P,et al.Aberration of ARID1A Is Associated With the Tumorigenesis and Prognosis of Sporadic Nonfunctional Pancreatic Neuroendocrine Tumors[J].Pancreas,2020,49:514- 523.
• [21] Thakker RV,Newey PJ,Walls GV,et al.Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1)[J].J Clin Endocrinol Metab,2012,97:2990- 3011.
• [22] Parsons DW,Li M,Zhang X,et al.The genetic landscape of the childhood cancer medulloblastoma[J].Science,2011,331:43.
• [23] 吴婷,黄小花.MENl胰岛素瘤中细胞周期蛋白cyclin B2高表达的作用[J].生理学报,2011,63:555- 564.
• [24] Gurung B,Feng Z,Iwamoto DV,et al.Menin epigenetically represses Hedgehog signaling in MEN1 tumor syndrome[J].Cancer Res,2013,73:2650- 2658.
• [25] Sparmann A,van Lohuizen M.Polycomb silencers control cell fate,development and cancer[J].Nat Rev Cancer,2006,6:846- 856.
• [26] Thiel AT,Blessington P,Zou T,et al.MLL-AF9-induced leukemogenesis requires coexpression of the wild-type Mll allele[J].Cancer Cell,2010,17:148- 159.
• [27] Feng Z,Wang L,Sun Y,et al.Menin and Daxx Interact to Suppress Neuroendocrine Tumors through Epigenetic Control of the Membrane Metallo-Endopeptidase[J].Cancer research,2017,77:401- 411.
• [28] Vandamme T,Beyens M,Boons G,et al.Hotspot DAXX,PTCH2 and CYFIP2 mutations in pancreatic neuroendocrine neoplasms[J].Endocr Relat Cancer,2019,26:1- 12.
• [29] Dumanski JP,Rasi C,Bjorklund P,et al.A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors[J].Endocr Relat Cancer,2017,24:427- 443.
• [30] Meric-Bernstam F,Gonzalez-Angulo AM.Targeting the mTOR signaling network for cancer therapy[J].J Clin Oncol,2009,27:2278- 2287.
• [31] Das S,Dixon JE,Cho W.Membrane-binding and activation mechanism of PTEN[J].Proc Natl Acad Sci U S A,2003,100:7491- 7496.
• [32] Han X,Ji Y,Zhao J,et al.Expression of PTEN and mTOR in pancreatic neuroendocrine tumors[J].Tumour Biol,2013,34:2871- 2879.
• [33] Pavel ME,Hainsworth JD,Baudin E,et al.Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome(RADIANT- 2):a randomised,placebo-control-led,phase 3 study[J].Lancet,2011,378:2005- 2012.
• [34] Yao JC,Shah MH,Ito T,et al.Everolimus for advanced pancreatic neuroendocrine tumors[J].N Engl J Med,2011,364:514- 523.
• [35] Susini C,Buscail L.Rationale for the use of somatostatin analogs as antitumor agents[J].Ann Oncol,2006,17:1733- 1742.
• [36] Rinke A,Muller HH,Schade-Brittinger C,et al.Placebo-controlled,double-blind,prospective,randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors:a report from the PROMID Study Group[J].J Clin Oncol,2009,27:4656- 4663.
• [37] Caplin ME,Pavel M,Cwikla JB,et al.Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours:the CLARINET open-label extension study[J].Endocr Relat Cancer,2016,23:191- 199.
• [38] Cao Y,Gao Z,Li L,et al.Whole exome sequencing of insulinoma reveals recurrent T372R mutations in YY1[J].Nat Commun,2013,4:2810.