nach oben

Reviews in Endocrine and Metabolic Disorders

Erschienen in:

31.07.2019

Clinical applications of (epi)genetics in gastroenteropancreatic neuroendocrine neoplasms: Moving towards liquid biopsies

verfasst von: Gitta Boons, Timon Vandamme, Marc Peeters, Guy Van Camp, Ken Op de Beeck

Erschienen in: Reviews in Endocrine and Metabolic Disorders | Ausgabe 3/2019

Einloggen, um Zugang zu erhalten

Abstract

High-throughput analysis, including next-generation sequencing and microarrays, have strongly improved our understanding of cancer biology. However, genomic data on rare cancer types, such as neuroendocrine neoplasms, has been lagging behind. Neuroendocrine neoplasms (NENs) develop from endocrine cells spread throughout the body and are highly heterogeneous in biological behavior. In this challenging disease, there is an urgent need for new therapies and new diagnostic, prognostic, follow-up and predictive biomarkers to aid patient management. The last decade, molecular data on neuroendocrine neoplasms of the gastrointestinal tract and pancreas, termed gastroenteropancreatic NENs (GEP-NENs), has strongly expanded. The aim of this review is to give an overview of the recent advances on (epi)genetic level and highlight their clinical applications to address the current needs in GEP-NENs. We illustrate how molecular alterations can be and are being used as therapeutic targets, how mutations in DAXX/ATRX and copy number variations could be used as prognostic biomarkers, how far we are in identifying predictive biomarkers and how genetics can contribute to GEP-NEN classification. Finally, we discuss recent studies on liquid biopsies in the field of GEP-NENs and illustrate how liquid biopsies can play a role in patient management. In conclusion, molecular studies have suggested multiple potential biomarkers, but further validation is ongoing.

Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y, et al. Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With Neuroendocrine Tumors in the United States. JAMA Oncol. 2017;3(10):1335–42. https://doi.org/10.1001/jamaoncol.2017.0589.CrossRefPubMedPubMedCentral

Pedraza-Arevalo S, Gahete MD, Alors-Perez E, Luque RM, Castano JP. Multilayered heterogeneity as an intrinsic hallmark of neuroendocrine tumors. Rev Endocr Metab Disord. 2018;19(2):179–92. https://doi.org/10.1007/s11154-018-9465-0.CrossRefPubMed

Fraenkel M, Kim M, Faggiano A, de Herder WW, Valk GD. Incidence of gastroenteropancreatic neuroendocrine tumours: a systematic review of the literature. Endocr Relat Cancer. 2014;21(3):R153–63. https://doi.org/10.1530/erc-13-0125.CrossRefPubMed

Zerbi A, Falconi M, Rindi G, Delle Fave G, Tomassetti P, Pasquali C, et al. Clinicopathological features of pancreatic endocrine tumors: a prospective multicenter study in Italy of 297 sporadic cases. AmJ Gastroenterol. 2010;105(6):1421–9. https://doi.org/10.1038/ajg.2009.747.CrossRef

Fottner C, Ferrata M, Weber MM. Hormone secreting gastro-entero-pancreatic neuroendocrine neoplasias (GEP-NEN): When to consider, how to diagnose? Rev Endocr Metab Disord. 2017;18(4):393–410. https://doi.org/10.1007/s11154-017-9438-8.CrossRefPubMed

Scarpa A, Mantovani W, Capelli P, Beghelli S, Boninsegna L, Bettini R, et al. Pancreatic endocrine tumors: improved TNM staging and histopathological grading permit a clinically efficient prognostic stratification of patients. Mod Pathol. 2010;23(6):824–33. https://doi.org/10.1038/modpathol.2010.58.CrossRefPubMed

Lloyd RVOR, Klöppel G, Rosai J. WHO classification of tumours of endocrine organs. 4th edition ed. Lyon, France: IARC Press; 2017.

Rindi G, Klimstra DS, Abedi-Ardekani B, Asa SL, Bosman FT, Brambilla E, et al. A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol. 2018;31(12):1770–86. https://doi.org/10.1038/s41379-018-0110-y.CrossRefPubMedPubMedCentral

Kulke MH, Shah MH, Benson AB 3rd, Bergsland E, Berlin JD, Blaszkowsky LS, et al. Neuroendocrine tumors, version 1.2015. Journal of the National Comprehensive Cancer Network : JNCCN. 2015;13(1):78–108.CrossRefPubMed

10.

Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, et al. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26(18):3063–72. https://doi.org/10.1200/JCO.2007.15.4377.CrossRef

11.

Koch CA, Petersenn S. Neuroendocrine neoplasms - think about it and choose the most appropriate diagnostic and therapeutic steps. Rev Endocr Metab Disord. 2018;19(2):107–9. https://doi.org/10.1007/s11154-018-9472-1.CrossRefPubMed

12.

O'Shea T, Druce M. When should genetic testing be performed in patients with neuroendocrine tumours? Rev Endocr Metab Disord. 2017;18(4):499–515. https://doi.org/10.1007/s11154-017-9430-3.CrossRefPubMedPubMedCentral

13.

Lemos MC, Thakker RV. Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. Hum Mutat. 2008;29(1):22–32. https://doi.org/10.1002/humu.20605.CrossRefPubMed

14.

Matkar S, Thiel A, Hua X. Menin: a scaffold protein that controls gene expression and cell signaling. Trends Biochem Sci. 2013;38(8):394–402. https://doi.org/10.1016/j.tibs.2013.05.005.CrossRefPubMedPubMedCentral

15.

Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM et al. von Hippel-Lindau disease. Lancet (London, England). 2003;361(9374):2059-67. https://doi.org/10.1016/s0140-6736(03)13643-4.CrossRef

16.

Pellegata NS, Quintanilla-Martinez L, Siggelkow H, Samson E, Bink K, Hofler H, et al. Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc Natl Acad Sci U S A. 2006;103(42):15558–63. https://doi.org/10.1073/pnas.0603877103.CrossRefPubMedPubMedCentral

17.

McClatchey AI. Neurofibromatosis. Annu Rev Pathol: Mech Dis. 2007;2(1):191–216. https://doi.org/10.1146/annurev.pathol.2.010506.091940.CrossRef

18.

Dworakowska D, Grossman AB. Are neuroendocrine tumours a feature of tuberous sclerosis? A systematic review. Endocr Relat Cancer. 2009;16(1):45–58. https://doi.org/10.1677/erc-08-0142.CrossRefPubMed

19.

Scarpa A, Chang DK, Nones K, Corbo V, Patch A-M, Bailey P, et al. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature. 2017;543(7643):65–71. https://doi.org/10.1038/nature21063.CrossRefPubMed

20.

Raj N, Shah R, Stadler Z, Mukherjee S, Chou J, Untch B, et al. Real-time genomic characterization of metastatic pancreatic neuroendocrine tumors has prognostic implications and identifies potential germline actionability. JCO Precis Oncol. 2018;2:1–18. https://doi.org/10.1200/po.17.00267.CrossRef

21.

Hemminki K, Li X. Incidence trends and risk factors of carcinoid tumors: a nationwide epidemiologic study from Sweden. Cancer. 2001;92(8):2204–10.CrossRefPubMed

22.

Sei Y, Zhao X, Forbes J, Szymczak S, Li Q, Trivedi A, et al. A hereditary form of small intestinal carcinoid associated with a germline mutation in inositol polyphosphate multikinase. Gastroenterology. 2015;149(1):67–78. https://doi.org/10.1053/j.gastro.2015.04.008.CrossRefPubMed

23.

Dumanski JP, Rasi C, Bjorklund P, Davies H, Ali AS, Gronberg M, et al. A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors. Endocr Relat Cancer. 2017;24(8):427–43. https://doi.org/10.1530/erc-17-0196.CrossRefPubMedPubMedCentral

24.

Calvete O, Reyes J, Zuniga S, Paumard-Hernandez B, Fernandez V, Bujanda L, et al. Exome sequencing identifies ATP4A gene as responsible of an atypical familial type I gastric neuroendocrine tumour. Hum Mol Genet. 2015;24(10):2914–22. https://doi.org/10.1093/hmg/ddv054.CrossRefPubMed

25.

Nagano Y, Kim DH, Zhang L, White JA, Yao JC, Hamilton SR, et al. Allelic alterations in pancreatic endocrine tumors identified by genome-wide single nucleotide polymorphism analysis. Endocr Relat Cancer. 2007;14(2):483–92. https://doi.org/10.1677/erc-06-0090.CrossRefPubMed

26.

Zhuang Z, Vortmeyer AO, Pack S, Huang S, Pham TA, Wang C, et al. Somatic mutations of the MEN1 tumor suppressor gene in sporadic gastrinomas and insulinomas. Cancer Res. 1997;57(21):4682–6.PubMed

27.

Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331(6021):1199–203. https://doi.org/10.1126/science.1200609.CrossRefPubMedPubMedCentral

28.

Missiaglia E, Dalai I, Barbi S, Beghelli S, Falconi M, della Peruta, M et al. Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway. J Clin Oncol 2010;28(2):245-255. https://doi.org/10.1200/JCO.2008.21.5988.CrossRefPubMed

29.

Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28(1):69–76. https://doi.org/10.1200/JCO.2009.24.2669.CrossRef

30.

Lawrence B, Blenkiron C, Parker K, Tsai P, Fitzgerald S, Shields P, et al. Recurrent loss of heterozygosity correlates with clinical outcome in pancreatic neuroendocrine cancer. NPJ Genom Med. 2018;3:18. https://doi.org/10.1038/s41525-018-0058-3.CrossRefPubMedPubMedCentral

31.

Cao Y, Gao Z, Li L, Jiang X, Shan A, Cai J, et al. Whole exome sequencing of insulinoma reveals recurrent T372R mutations in YY1. Nat Commun. 2013;4:2810. https://doi.org/10.1038/ncomms3810.CrossRefPubMed

32.

Irshad K, Jyotsna VP, Agarwal S, Chosdol K, Pal S, Deepak RK. T372R mutation status in Yin Yang 1 gene in insulinoma patients. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2017;49(6):452-6. https://doi.org/10.1055/s-0043-107244.CrossRefPubMed

33.

Parekh VI, Modali SD, Welch J, Simonds WF, Weinstein LS, Kebebew E, et al. Frequency and consequence of the recurrent YY1 p.T372R mutation in sporadic insulinomas. Endocr Relat Cancer. 2018;25(5):L31–l5. https://doi.org/10.1530/erc-17-0311.CrossRefPubMedPubMedCentral

34.

Cromer MK, Choi M, Nelson-Williams C, Fonseca AL, Kunstman JW, Korah RM, et al. Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas. Proc Natl Acad Sci U S A. 2015;112(13):4062–7. https://doi.org/10.1073/pnas.1503696112.CrossRefPubMedPubMedCentral

35.

Lichtenauer UD, Di Dalmazi G, Slater EP, Wieland T, Kuebart A, Schmittfull A, et al. Frequency and clinical correlates of somatic Ying Yang 1 mutations in sporadic insulinomas. J Clin Endocrinol Metab. 2015;100(5):E776–82. https://doi.org/10.1210/jc.2015-1100.CrossRefPubMed

36.

Wang H, Bender A, Wang P, Karakose E, Inabnet WB, Libutti SK, et al. Insights into beta cell regeneration for diabetes via integration of molecular landscapes in human insulinomas. Nature Commun. 2017. https://doi.org/10.1038/s41467-017-00992-9.

37.

Vandamme T, Beyens M, Boons G, Schepers A, Kamp K, Biermann K, et al. Hotspot DAXX, PTCH2 and CYFIP2 mutations in pancreatic neuroendocrine neoplasms. Endocr Relat Cancer. 2019;26(1):1–12. https://doi.org/10.1530/erc-18-0120.CrossRefPubMed

38.

Kytola S, Hoog A, Nord B, Cedermark B, Frisk T, Larsson C, et al. Comparative genomic hybridization identifies loss of 18q22-qter as an early and specific event in tumorigenesis of midgut carcinoids. Am J Pathol. 2001;158(5):1803–8. https://doi.org/10.1016/s0002-9440(10)64136-3.CrossRefPubMedPubMedCentral

39.

Lollgen RM, Hessman O, Szabo E, Westin G, Akerstrom G. Chromosome 18 deletions are common events in classical midgut carcinoid tumors. Int J Cancer. 2001;92(6):812–5. https://doi.org/10.1002/ijc.1276.CrossRefPubMed

40.

Tönnies H, Toliat MR, Ramel C, Pape UF, Neitzel H, Berger W, et al. Analysis of sporadic neuroendocrine tumours of the enteropancreatic system by comparative genomic hybridisation. Gut. 2001;48(4):536–41. https://doi.org/10.1136/gut.48.4.536.CrossRefPubMedPubMedCentral

41.

Cunningham JL, Diaz de Stahl T, Sjoblom T, Westin G, Dumanski JP, Janson ET. Common pathogenetic mechanism involving human chromosome 18 in familial and sporadic ileal carcinoid tumors. Genes, Chromosomes Cancer 2011;50(2):82-94. https://doi.org/10.1002/gcc.20834.CrossRef

42.

Banck MS, Kanwar R, Kulkarni AA, Boora GK, Metge F, Kipp BR, et al. The genomic landscape of small intestine neuroendocrine tumors. J Clin Invest. 2013;123(6):2502–8. https://doi.org/10.1172/JCI67963.CrossRefPubMedPubMedCentral

43.

Kulke MH, Freed E, Chiang DY, Philips J, Zahrieh D, Glickman JN, et al. High-resolution analysis of genetic alterations in small bowel carcinoid tumors reveals areas of recurrent amplification and loss. Genes Chromosomes Cancer. 2008;47(7):591–603. https://doi.org/10.1002/gcc.20561.CrossRefPubMed

44.

Kim DH, Nagano Y, Choi IS, White JA, Yao JC, Rashid A. Allelic alterations in well-differentiated neuroendocrine tumors (carcinoid tumors) identified by genome-wide single nucleotide polymorphism analysis and comparison with pancreatic endocrine tumors. Genes Chromosomes Cancer. 2008;47(1):84–92. https://doi.org/10.1002/gcc.20510.CrossRefPubMed

45.

Francis JM, Kiezun A, Ramos AH, Serra S, Pedamallu CS, Qian ZR, et al. Somatic mutation of CDKN1B in small intestine neuroendocrine tumors. Nat Genet. 2013;45(12):1483–6. https://doi.org/10.1038/ng.2821.CrossRefPubMedPubMedCentral

46.

Walter D, Harter PN, Battke F, Winkelmann R, Schneider M, Holzer K, et al. Genetic heterogeneity of primary lesion and metastasis in small intestine neuroendocrine tumors. Sci Rep. 2018;8(1):3811. https://doi.org/10.1038/s41598-018-22115-0.CrossRefPubMedPubMedCentral

47.

Tang LH, Basturk O, Sue JJ, Klimstra DS. A practical approach to the classification of WHO grade 3 (G3) well differentiated neuroendocrine tumor (WD-NET) and poorly differentiated neuroendocrine carcinoma (PD-NEC) of the pancreas. Am J Surg Pathol. 2016;40(9):1192–202. https://doi.org/10.1097/PAS.0000000000000662.CrossRefPubMedPubMedCentral

48.

Makuuchi R, Terashima M, Kusuhara M, Nakajima T, Serizawa M, Hatakeyama K, et al. Comprehensive analysis of gene mutation and expression profiles in neuroendocrine carcinomas of the stomach. Biomed Res. 2017;38(1):19–27. https://doi.org/10.2220/biomedres.38.19.CrossRefPubMed

49.

Pizzi S, Azzoni C, Bassi D, Bottarelli L, Milione M, Bordi C. Genetic alterations in poorly differentiated endocrine carcinomas of the gastrointestinal tract. Cancer. 2003;98(6):1273–82. https://doi.org/10.1002/cncr.11621.CrossRefPubMed

50.

Furlan D, Cerutti R, Uccella S, La Rosa S, Rigoli E, Genasetti A, et al. Different molecular profiles characterize well-differentiated endocrine tumors and poorly differentiated endocrine carcinomas of the gastroenteropancreatic tract. Clin Cancer Res. 2004;10(3):947–57.CrossRefPubMed

51.

Nishikura K, Watanabe H, Iwafuchi M, Fujiwara T, Kojima K, Ajioka Y. Carcinogenesis of gastric endocrine cell carcinoma: analysis of histopathology and p53 gene alteration. Gastric Cancer. 2003;6(4):203–9. https://doi.org/10.1007/s10120-003-0249-0.CrossRefPubMed

52.

Sahnane N, Furlan D, Monti M, Romualdi C, Vanoli A, Vicari E, et al. Microsatellite unstable gastrointestinal neuroendocrine carcinomas: a new clinicopathologic entity. Endocri Relat Cancer. 2015;22(1):35–45. https://doi.org/10.1530/erc-14-0410.CrossRef

53.

Takizawa N, Ohishi Y, Hirahashi M, Takahashi S, Nakamura K, Tanaka M, et al. Molecular characteristics of colorectal neuroendocrine carcinoma; similarities with adenocarcinoma rather than neuroendocrine tumor. Hum Pathol. 2015;46(12):1890–900. https://doi.org/10.1016/j.humpath.2015.08.006.CrossRefPubMed

54.

Konukiewitz B, Jesinghaus M, Steiger K, Schlitter AM, Kasajima A, Sipos B, et al. Pancreatic neuroendocrine carcinomas reveal a closer relationship to ductal adenocarcinomas than to neuroendocrine tumors G3. Human Pathol. 2018;77:70–9. https://doi.org/10.1016/j.humpath.2018.03.018.CrossRef

55.

Yachida S, Vakiani E, White CM, Zhong Y, Saunders T, Morgan R, et al. Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors. Am J Surg Pathol. 2012;36(2):173–84. https://doi.org/10.1097/PAS.0b013e3182417d36.CrossRefPubMedPubMedCentral

56.

Sorbye H, Welin S, Langer SW, Vestermark LW, Holt N, Osterlund P, et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol. 2013;24(1):152–60. https://doi.org/10.1093/annonc/mds276.CrossRefPubMed

57.

Pea A, Yu J, Marchionni L, Noe M, Luchini C, Pulvirenti A, et al. Genetic analysis of small well-differentiated pancreatic neuroendocrine tumors identifies subgroups with differing risks of liver metastases. Ann Surg. 2018. https://doi.org/10.1097/sla.0000000000003022.

58.

Yao J, Garg A, Chen D, Capdevila J, Engstrom P, Pommier R, et al. Genomic profiling of NETs: a comprehensive analysis of the RADIANT trials. Endocr Relat Cancer. 2019;26(4):391–403. https://doi.org/10.1530/ERC-18-0332.CrossRefPubMed

59.

Andersson E, Sward C, Stenman G, Ahlman H, Nilsson O. High-resolution genomic profiling reveals gain of chromosome 14 as a predictor of poor outcome in ileal carcinoids. Endocr Relat Cancer. 2009;16(3):953–66. https://doi.org/10.1677/erc-09-0052.CrossRefPubMed

60.

Karpathakis A, Dibra H, Pipinikas C, Feber A, Morris T, Francis J, et al. Prognostic impact of novel molecular subtypes of small intestinal neuroendocrine tumor. Clin Cancer Res. 2016;22(1):250. https://doi.org/10.1158/1078-0432.CCR-15-0373.CrossRefPubMed

61.

Hechtman JF, Klimstra DS, Nanjangud G, Frosina D, Shia J, Jungbluth AA. Performance of DAXX Immunohistochemistry as a Screen for DAXX Mutations in Pancreatic Neuroendocrine Tumors. Pancreas. 2019. https://doi.org/10.1097/mpa.0000000000001256.CrossRefPubMedPubMedCentral

62.

Marinoni I, Kurrer AS, Vassella E, Dettmer M, Rudolph T, Banz V et al. Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors. Gastroenterology. 2014;146(2):453-60.e5. https://doi.org/10.1053/j.gastro.2013.10.020.CrossRef

63.

Lewis PW, Elsaesser SJ, Noh KM, Stadler SC, Allis CD. Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres. Proc Natl Acad Sci U S A. 2010;107(32):14075–80. https://doi.org/10.1073/pnas.1008850107.CrossRefPubMedPubMedCentral

64.

Heaphy CM, de Wilde RF, Jiao Y, Klein AP, Edil BH, Shi C, et al. Altered telomeres in tumors with ATRX and DAXX mutations. Science. 2011;333(6041):425. https://doi.org/10.1126/science.1207313.CrossRefPubMedPubMedCentral

65.

Kim JY, Brosnan-Cashman JA, An S, Kim SJ, Song KB, Kim MS, et al. Alternative lengthening of telomeres in primary pancreatic neuroendocrine tumors is associated with aggressive clinical behavior and poor survival. Clin Cancer Res. 2017;23(6):1598–606. https://doi.org/10.1158/1078-0432.Ccr-16-1147.CrossRefPubMed

66.

Yuan F, Shi M, Ji J, Shi H, Zhou C, Yu Y, et al. KRAS and DAXX/ATRX gene mutations are correlated with the clinicopathological features, advanced diseases, and poor prognosis in chinese patients with pancreatic neuroendocrine tumors. Int J Biol Sci. 2014;10(9):957–65. https://doi.org/10.7150/ijbs.9773.CrossRefPubMedPubMedCentral

67.

Park JK, Paik WH, Lee K, Ryu JK, Lee SH, Kim YT. DAXX/ATRX and MEN1 genes are strong prognostic markers in pancreatic neuroendocrine tumors. Oncotarget. 2017;8(30):49796-806. https://doi.org/10.18632/oncotarget.17964.

68.

Chou A, Itchins M, de Reuver PR, Arena J, Clarkson A, Sheen A, et al. ATRX loss is an independent predictor of poor survival in pancreatic neuroendocrine tumors. Hum Pathol. 2018;82:249–57. https://doi.org/10.1016/j.humpath.2018.07.032.CrossRefPubMed

69.

Singhi AD, Liu TC, Roncaioli JL, Cao D, Zeh HJ, Zureikat AH, et al. Alternative lengthening of telomeres and loss of DAXX/ATRX expression predicts metastatic disease and poor survival in patients with pancreatic neuroendocrine tumors. Clin Cancer Res. 2017;23(2):600–9. https://doi.org/10.1158/1078-0432.Ccr-16-1113.CrossRefPubMed

70.

de Wilde RF, Heaphy CM, Maitra A, Meeker AK, Edil BH, Wolfgang CL, et al. Loss of ATRX or DAXX expression and concomitant acquisition of the alternative lengthening of telomeres phenotype are late events in a small subset of MEN-1 syndrome pancreatic neuroendocrine tumors. Mod Pathol. 2012;25(7):1033–9. https://doi.org/10.1038/modpathol.2012.53.CrossRefPubMedPubMedCentral

71.

Sato S, Tsuchikawa T, Nakamura T, Sato N, Tamoto E, Okamura K, et al. Impact of the tumor microenvironment in predicting postoperative hepatic recurrence of pancreatic neuroendocrine tumors. Oncol Rep. 2014;32(6):2753–9. https://doi.org/10.3892/or.2014.3530.CrossRefPubMed

72.

Pipinikas CP, Dibra H, Karpathakis A, Feber A, Novelli M, Oukrif D, et al. Epigenetic dysregulation and poorer prognosis in DAXX-deficient pancreatic neuroendocrine tumours. Endocr Relat Cancer. 2015;22(3):L13–L8. https://doi.org/10.1530/ERC-15-0108.CrossRefPubMedPubMedCentral

73.

Roy S, LaFramboise WA, Liu TC, Cao D, Luvison A, Miller C et al. Loss of chromatin-remodeling proteins and/or CDKN2A associates with metastasis of pancreatic neuroendocrine tumors and reduced patient survival times. Gastroenterology. 2018;154(8):2060-3.e8. https://doi.org/10.1053/j.gastro.2018.02.026.CrossRefPubMed

74.

Cives M, Ghayouri M, Morse B, Brelsford M, Black M, Rizzo A, et al. Analysis of potential response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors. Endocrine-related cancer. 2016;23(9):759–67. https://doi.org/10.1530/erc-16-0147.CrossRefPubMed

75.

Chen SF, Kasajima A, Yazdani S, Chan MS, Wang L, He YY, et al. Clinicopathologic significance of immunostaining of alpha-thalassemia/mental retardation syndrome X-linked protein and death domain-associated protein in neuroendocrine tumors. Hum Pathol. 2013;44(10):2199–203. https://doi.org/10.1016/j.humpath.2013.04.025.CrossRefPubMed

76.

Geis C, Fendrich V, Rexin P, Di Fazio P, Bartsch DK, Ocker M, et al. Ileal neuroendocrine tumors show elevated activation of mammalian target of rapamycin complex. J Surg Res. 2015;194(2):388–93. https://doi.org/10.1016/j.jss.2014.10.052.CrossRefPubMed

77.

Kim HS, Lee HS, Nam KH, Choi J, Kim WH. Telomere length abnormalities and telomerase RNA component expression in gastroenteropancreatic neuroendocrine tumors. Anticancer Res. 2015;35(6):3501–10.PubMed

78.

Thompson SL, Bakhoum SF, Compton DA. Mechanisms of chromosomal instability. Curr Biol. 2010;20(6):R285–95. https://doi.org/10.1016/j.cub.2010.01.034.CrossRefPubMedPubMedCentral

79.

Beyens M, Vandamme T, Peeters M, Camp GV. Beeck KOd. Resistance to targeted treatment of gastroenteropancreatic neuroendocrine tumors. 2019;26(3):R109. https://doi.org/10.1530/erc-18-0420.CrossRef

80.

Vandamme T, Beyens M, de Beeck KO, Dogan F, van Koetsveld PM, Pauwels P, et al. Long-term acquired everolimus resistance in pancreatic neuroendocrine tumours can be overcome with novel PI3K-AKT-mTOR inhibitors. Br J Cancer. 2016;114(6):650–8. https://doi.org/10.1038/bjc.2016.25.CrossRefPubMedPubMedCentral

81.

Vandamme T, Beyens M, Peeters M, Van Camp G, de Beeck KO. Next generation exome sequencing of pancreatic neuroendocrine tumor cell lines BON-1 and QGP-1 reveals different lineages. Cancer Genet. 2015;208(10):523. https://doi.org/10.1016/j.cancergen.2015.07.003.CrossRefPubMed

82.

Vandamme T, Peeters M, Dogan F, Pauwels P, Van Assche E, Beyens M, et al. Whole-exome characterization of pancreatic neuroendocrine tumor cell lines BON-1 and QGP-1. J Mol Endocrinol. 2015;54(2):137–47. https://doi.org/10.1530/JME-14-0304.CrossRefPubMed

83.

Serra S, Zheng L, Hassan M, Phan AT, Woodhouse LJ, Yao JC, et al. The FGFR4-G388R single-nucleotide polymorphism alters pancreatic neuroendocrine tumor progression and response to mTOR inhibition therapy. Cancer Res. 2012;72(22):5683–91. https://doi.org/10.1158/0008-5472.Can-12-2102.CrossRefPubMed

84.

Cros J, Moati E, Raffenne J, Hentic O, Svrcek M, de Mestier L, et al. Gly388Arg FGFR4 Polymorphism Is Not Predictive of Everolimus Efficacy in Well-Differentiated Digestive Neuroendocrine Tumors. Neuroendocrinology. 2016;103(5):495–9.CrossRefPubMed

85.

Meric-Bernstam F, Akcakanat A, Chen H, Do K-A, Sangai T, Adkins F, et al. PIK3CA/PTEN mutations and Akt activation as markers of sensitivity to allosteric mTOR inhibitors. Clin Cancer Res. 2012;18(6):1777–89. https://doi.org/10.1158/1078-0432.CCR-11-2123.CrossRefPubMedPubMedCentral

86.

Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet (London, England). 2016;387(10022):968-77. https://doi.org/10.1016/s0140-6736(15)00817-x.CrossRef

87.

Martins D, Spada F, Lambrescu I, Rubino M, Cella C, Gibelli B, et al. Predictive Markers of Response to Everolimus and Sunitinib in Neuroendocrine Tumors. Target Oncol. 2017;12(5):611–22. https://doi.org/10.1007/s11523-017-0506-5.CrossRefPubMed

88.

Hijioka S, Hosoda W, Matsuo K, Ueno M, Furukawa M, Yoshitomi H, et al. Rb Loss and KRAS Mutation Are Predictors of the Response to Platinum-Based Chemotherapy in Pancreatic Neuroendocrine Neoplasm with Grade 3: A Japanese Multicenter Pancreatic NEN-G3 Study. Clin Cancer Res. 2017;23(16):4625–32. https://doi.org/10.1158/1078-0432.Ccr-16-3135.CrossRefPubMed

89.

Shenker N, Flanagan JM. Intragenic DNA methylation: implications of this epigenetic mechanism for cancer research. Br J Cancer. 2012;106(2):248–53. https://doi.org/10.1038/bjc.2011.550.CrossRefPubMed

90.

Rahman MM, Qian ZR, Wang EL, Yoshimoto K, Nakasono M, Sultana R, et al. DNA methyltransferases 1, 3a, and 3b overexpression and clinical significance in gastroenteropancreatic neuroendocrine tumors. Hum Pathol. 2010;41(8):1069–78. https://doi.org/10.1016/j.humpath.2010.01.011.CrossRefPubMed

91.

House MG, Herman JG, Guo MZ, Hooker CM, Schulick RD, Lillemoe KD, et al. Aberrant hypermethylation of tumor suppressor genes in pancreatic endocrine neoplasms. Ann Surg. 2003;238(3):423–32. https://doi.org/10.1097/01.sla.0000086659.49569.9e.CrossRefPubMedPubMedCentral

92.

Arnold CN, Sosnowski A, Schmitt-Gräff A, Arnold R, Blum HE. Analysis of molecular pathways in sporadic neuroendocrine tumors of the gastro-entero-pancreatic system. Int J Cancer. 2007;120(10):2157-64. https://doi.org/10.1002/ijc.22569.CrossRefPubMed

93.

Fotouhi O, Adel Fahmideh M, Kjellman M, Sulaiman L, Höög A, Zedenius J, et al. Global hypomethylation and promoter methylation in small intestinal neuroendocrine tumors: an in vivo and in vitro study. Epigenetics. 2014;9(7):987–97. https://doi.org/10.4161/epi.28936.CrossRefPubMedPubMedCentral

94.

Choi IS, Estecio MR, Nagano Y, Kim DH, White JA, Yao JC, et al. Hypomethylation of LINE-1 and Alu in well-differentiated neuroendocrine tumors (pancreatic endocrine tumors and carcinoid tumors). Mod Pathol. 2007;20(7):802–10. https://doi.org/10.1038/modpathol.3800825.CrossRefPubMed

95.

Stricker I, Tzivras D, Nambiar S, Wulf J, Liffers ST, Vogt M, et al. Site- and grade-specific diversity of LINE1 methylation pattern in gastroenteropancreatic neuroendocrine tumours. Anticancer Res. 2012;32(9):3699–706.PubMed

96.

How-Kit A, Dejeux E, Dousset B, Renault V, Baudry M, Terris B, et al. DNA methylation profiles distinguish different subtypes of gastroenteropancreatic neuroendocrine tumors. Epigenomics. 2015;7(8):1245–58. https://doi.org/10.2217/epi.15.85.CrossRefPubMed

97.

Chan CS, Laddha SV, Lewis PW, Koletsky MS, Robzyk K, Da Silva E, et al. ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct alpha-cell signature subgroup. Nat Commun. 2018;9(1):4158. https://doi.org/10.1038/s41467-018-06498-2.CrossRefPubMedPubMedCentral

98.

Conemans EB, Lodewijk L, Moelans CB, Offerhaus GJA, Pieterman CRC, Morsink FH, et al. DNA methylation profiling in MEN1-related pancreatic neuroendocrine tumors reveals a potential epigenetic target for treatment. Eur J Endocrinol. 2018;179(3):153–60. https://doi.org/10.1530/eje-18-0195.CrossRefPubMed

99.

Tirosh A, Mukherjee S, Lack J, Gara SK, Wang S, Quezado MM, et al. Distinct genome-wide methylation patterns in sporadic and hereditary nonfunctioning pancreatic neuroendocrine tumors. Cancer. 2019. https://doi.org/10.1002/cncr.31930.CrossRefPubMed

100.

Verdugo AD, Crona J, Starker L, Stalberg P, Akerstrom G, Westin G, et al. Global DNA methylation patterns through an array-based approach in small intestinal neuroendocrine tumors. Endocr Relat Cancer. 2014;21(1):L5–7. https://doi.org/10.1530/erc-13-0481.CrossRefPubMed

101.

Karpathakis A, Dibra H, Pipinikas C, Feber A, Morris T, Francis J, et al. Progressive epigenetic dysregulation in neuroendocrine tumour liver metastases. Endocr Relat Cancer. 2017;24(2):L21–l5. https://doi.org/10.1530/erc-16-0419.CrossRefPubMed

102.

Barazeghi E, Prabhawa S, Norlén O, Hellman P, Stålberg P, Westin G. Decrease of 5-hydroxymethylcytosine and TET1 with nuclear exclusion of TET2 in small intestinal neuroendocrine tumors. BMC Cancer. 2018;18(1):764-. https://doi.org/10.1186/s12885-018-4579-z.

103.

Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435(7043):834–8. https://doi.org/10.1038/nature03702.CrossRefPubMed

104.

Yoshimoto T, Motoi N, Yamamoto N, Nagano H, Ushijima M, Matsuura M, et al. Pulmonary carcinoids and low-grade gastrointestinal neuroendocrine tumors show common MicroRNA expression profiles, different from adenocarcinomas and small cell carcinomas. Neuroendocrinology. 2018;106(1):47–57. https://doi.org/10.1159/000461582.CrossRefPubMed

105.

Malczewska A, Kidd M, Matar S, Kos-Kudla B, Modlin IM. A comprehensive assessment of the role of miRNAs as biomarkers in gastroenteropancreatic neuroendocrine tumors. Neuroendocrinology. 2018:73–90. https://doi.org/10.1159/000487326.CrossRefPubMed

106.

Roldo C, Missiaglia E, Hagan JP, Falconi M, Capelli P, Bersani S, et al. MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior. J Clin Oncol. 2006;24(29):4677–84. https://doi.org/10.1200/jco.2005.05.5194.CrossRefPubMed

107.

Thorns C, Schurmann C, Gebauer N, Wallaschofski H, Kumpers C, Bernard V, et al. Global microRNA profiling of pancreatic neuroendocrine neoplasias. Anticancer Res. 2014;34(5):2249–54.PubMed

108.

Lee YS, Kim H, Kim HW, Lee J-C, Paik K-H, Kang J et al. High expression of MicroRNA-196a indicates poor prognosis in resected pancreatic neuroendocrine tumor. Medicine. 2015;94(50):e2224-e. https://doi.org/10.1097/MD.0000000000002224.CrossRefPubMedPubMedCentral

109.

Sadanandam A, Wullschleger S, Lyssiotis CA, Grötzinger C, Barbi S, Bersani S, et al. A cross-species analysis in pancreatic neuroendocrine tumors reveals molecular subtypes with distinctive clinical, metastatic, developmental, and metabolic characteristics. Cancer Discov. 2015;5(12):1296–313. https://doi.org/10.1158/2159-8290.CD-15-0068.CrossRefPubMedPubMedCentral

110.

Ruebel K, Leontovich AA, Stilling GA, Zhang S, Righi A, Jin L, et al. MicroRNA expression in ileal carcinoid tumors: downregulation of microRNA-133a with tumor progression. Mod Pathol. 2010;23(3):367–75. https://doi.org/10.1038/modpathol.2009.161.CrossRefPubMed

111.

Li SC, Essaghir A, Martijn C, Lloyd RV, Demoulin JB, Oberg K, et al. Global microRNA profiling of well-differentiated small intestinal neuroendocrine tumors. Mod Pathol. 2013;26(5):685–96. https://doi.org/10.1038/modpathol.2012.216.CrossRefPubMedPubMedCentral

112.

Mandal R, Hardin H, Baus R, Rehrauer W, Lloyd RV. Analysis of miR-96 and miR-133a Expression in Gastrointestinal Neuroendocrine Neoplasms. Endocr Pathol. 2017;28(4):345–50. https://doi.org/10.1007/s12022-017-9504-5.CrossRefPubMed

113.

Miller HC, Frampton AE, Malczewska A, Ottaviani S, Stronach EA, Flora R, et al. MicroRNAs associated with small bowel neuroendocrine tumours and their metastases. Endocr Relat Cancer. 2016;23(9):711–26. https://doi.org/10.1530/erc-16-0044.CrossRefPubMed

114.

Døssing KBV, Binderup T, Kaczkowski B, Jacobsen A, Rossing M, Winther O, et al. Down-regulation of miR-129-5p and the let-7 family in neuroendocrine tumors and metastases leads to up-regulation of their targets Egr1, G3bp1, Hmga2 and Bach1. Genes. 2014;6(1):1–21. https://doi.org/10.3390/genes6010001.CrossRefPubMedPubMedCentral

115.

Heverhagen AE, Legrand N, Wagner V, Fendrich V, Bartsch DK, Slater EP. Overexpression of MicroRNA miR-7-5p is a potential biomarker in neuroendocrine neoplasms of the small intestine. Neuroendocrinology. 2018;106(4):312–7. https://doi.org/10.1159/000480121.CrossRefPubMed

116.

Hamfjord J, Stangeland AM, Hughes T, Skrede ML, Tveit KM, Ikdahl T, et al. Differential expression of miRNAs in colorectal cancer: comparison of paired tumor tissue and adjacent normal mucosa using high-throughput sequencing. Plos One. 2012;7(4):e34150. https://doi.org/10.1371/journal.pone.0034150.CrossRefPubMedPubMedCentral

117.

Wang M, Xia X, Chu W, Xia L, Meng T, Liu L, et al. Roles of miR-186 and PTTG1 in colorectal neuroendocrine tumors. Int J Clin Exp Med. 2015;8(12):22149–57.PubMedPubMedCentral

118.

Mitsuhashi K, Yamamoto I, Kurihara H, Kanno S, Ito M, Igarashi H et al. Analysis of the molecular features of rectal carcinoid tumors to identify new biomarkers that predict biological malignancy. Oncotarget. 2015;6(26):22114-25. https://doi.org/10.18632/oncotarget.4294.

119.

Arnold CN, Nagasaka T, Goel A, Scharf I, Grabowski P, Sosnowski A, et al. Molecular characteristics and predictors of survival in patients with malignant neuroendocrine tumors. Int J Cancer. 2008;123(7):1556–64. https://doi.org/10.1002/ijc.23690.CrossRefPubMedPubMedCentral

120.

Cros J, Hentic O, Rebours V, Zappa M, Gille N, Theou-Anton N, et al. MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors. Endocr Relat Cancer. 2016;23(8):625–33. https://doi.org/10.1530/erc-16-0117.CrossRefPubMed

121.

Walter T, van Brakel B, Vercherat C, Hervieu V, Forestier J, Chayvialle JA, et al. O6-Methylguanine-DNA methyltransferase status in neuroendocrine tumours: prognostic relevance and association with response to alkylating agents. Br J Cancer. 2015;112(3):523–31. https://doi.org/10.1038/bjc.2014.660.CrossRefPubMedPubMedCentral

122.

Dussol AS, Joly MO, Vercherat C, Forestier J, Hervieu V, Scoazec JY, et al. Gemcitabine and oxaliplatin or alkylating agents for neuroendocrine tumors: Comparison of efficacy and search for predictive factors guiding treatment choice. Cancer. 2015;121(19):3428–34. https://doi.org/10.1002/cncr.29517.CrossRefPubMed

123.

Campana D, Walter T, Pusceddu S, Gelsomino F, Graillot E, Prinzi N, et al. Correlation between MGMT promoter methylation and response to temozolomide-based therapy in neuroendocrine neoplasms: an observational retrospective multicenter study. Endocrine. 2018;60(3):490–8. https://doi.org/10.1007/s12020-017-1474-3.CrossRefPubMed

124.

Lemelin A, Barritault M, Hervieu V, Payen L, Peron J, Couvelard A, et al. O6-methylguanine-DNA methyltransferase (MGMT) status in neuroendocrine tumors: a randomized phase II study (MGMT-NET). Dig Liver Dis. 2019. https://doi.org/10.1016/j.dld.2019.02.001.CrossRefPubMed

125.

Stefanoli M, La Rosa S, Sahnane N, Romualdi C, Pastorino R, Marando A, et al. Prognostic relevance of aberrant DNA methylation in g1 and g2 pancreatic neuroendocrine tumors. Neuroendocrinology. 2014;100(1):26–34. https://doi.org/10.1159/000365449.CrossRefPubMed

126.

Ashworth T. A case of cancer in which cells similar to those in the tumours were seen in the blood after death. Med J Aust. 1869;14:146–7.

127.

Allard WJ, Matera J, Miller MC, Repollet M, Connelly MC, Rao C, et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res. 2004;10(20):6897–904. https://doi.org/10.1158/1078-0432.Ccr-04-0378.CrossRefPubMed

128.

Khan MS, Tsigani T, Rashid M, Rabouhans JS, Yu D, Luong TV, et al. Circulating tumor cells and EpCAM expression in neuroendocrine tumors. Clin Cancer Res. 2011;17(2):337–45. https://doi.org/10.1158/1078-0432.Ccr-10-1776.CrossRefPubMed

129.

Khan MS, Kirkwood A, Tsigani T, Garcia-Hernandez J, Hartley JA, Caplin ME, et al. Circulating tumor cells as prognostic markers in neuroendocrine tumors. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(3):365–72. https://doi.org/10.1200/jco.2012.44.2905.CrossRef

130.

Khan MS, Kirkwood AA, Tsigani T, Lowe H, Goldstein R, Hartley JA, et al. Early changes in circulating tumor cells are associated with response and survival following treatment of metastatic neuroendocrine neoplasms. Clin Cancer Res. 2016;22(1):79–85. https://doi.org/10.1158/1078-0432.Ccr-15-1008.CrossRefPubMed

131.

Grande E, Capdevila J, Castellano D, Teule A, Duran I, Fuster J, et al. Pazopanib in pretreated advanced neuroendocrine tumors: a phase II, open-label trial of the Spanish Task Force Group for Neuroendocrine Tumors (GETNE). Ann Oncol. 2015;26(9):1987–93. https://doi.org/10.1093/annonc/mdv252.CrossRefPubMed

132.

Childs A, Vesely C, Ensell L, Lowe H, Luong TV, Caplin ME, et al. Expression of somatostatin receptors 2 and 5 in circulating tumour cells from patients with neuroendocrine tumours. Br J Cancer. 2016;115(12):1540–7. https://doi.org/10.1038/bjc.2016.377.CrossRefPubMedPubMedCentral

133.

Cives M, Quaresmini D, Rizzo FM, Felici C, D'Oronzo S, Simone V et al. Osteotropism of neuroendocrine tumors: role of the CXCL12/ CXCR4 pathway in promoting EMT in vitro. Oncotarget. 2017;8(14):22534-49. https://doi.org/10.18632/oncotarget.15122.

134.

Rizzo FM, Vesely C, Childs A, Marafioti T, Khan MS, Mandair D, et al. Circulating tumour cells and their association with bone metastases in patients with neuroendocrine tumours. Br J Cancer. 2019. https://doi.org/10.1038/s41416-018-0367-4.CrossRefPubMedPubMedCentral

135.

Zhu Z, Qiu S, Shao K, Hou Y. Progress and challenges of sequencing and analyzing circulating tumor cells. Cell Biol Toxicol. 2018;34(5):405–15. https://doi.org/10.1007/s10565-017-9418-5.CrossRefPubMed

136.

Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 2011;11(6):426–37. https://doi.org/10.1038/nrc3066.CrossRefPubMed

137.

Tan EM, Schur PH, Carr RI, Kunkel HG. Deoxybonucleic acid (DNA) and antibodies to DNA in the serum of patients with systemic lupus erythematosus. J Clin Invest. 1966;45(11):1732–40. https://doi.org/10.1172/JCI105479.CrossRefPubMedPubMedCentral

138.

Leon SA, Shapiro B, Sklaroff DM, Yaros MJ. Free DNA in the serum of cancer patients and the effect of therapy. Cancer Res. 1977;37(3):646–50.PubMed

139.

Wan JCM, Massie C, Garcia-Corbacho J, Mouliere F, Brenton JD, Caldas C, et al. Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat Rev Cancer. 2017;17(4):223–38. https://doi.org/10.1038/nrc.2017.7.CrossRefPubMed

140.

Zhao B, Wang L, Qiu H, Zhang M, Sun L, Peng P et al. Mechanisms of resistance to anti-EGFR therapy in colorectal cancer. Oncotarget. 2016;8(3):3980-4000. https://doi.org/10.18632/oncotarget.14012.

141.

Boons G, Vandamme T, Peeters M, Beyens M, Driessen A, Janssens K, et al. Cell-free DNA from metastatic pancreatic neuroendocrine tumor patients contains tumor-specific mutations and copy number variations. Front Oncol. 2018;8:467. https://doi.org/10.3389/fonc.2018.00467.CrossRefPubMedPubMedCentral

142.

Botezatu I, Serdyuk O, Potapova G, Shelepov V, Alechina R, Molyaka Y, et al. Genetic analysis of DNA excreted in urine: a new approach for detecting specific genomic DNA sequences from cells dying in an organism. Clin Chem. 2000;46(8 Pt 1):1078–84.PubMed

143.

Klempner SJ, Gershenhorn B, Tran P, Lee TK, Erlander MG, Gowen K, et al. BRAFV600E mutations in high-grade colorectal neuroendocrine tumors may predict responsiveness to BRAF-MEK combination therapy. Cancer Discov. 2016;6(6):594–600. https://doi.org/10.1158/2159-8290.CD-15-1192.CrossRefPubMedPubMedCentral

144.

Manier S, Park J, Capelletti M, Bustoros M, Freeman SS, Ha G, et al. Whole-exome sequencing of cell-free DNA and circulating tumor cells in multiple myeloma. Nat Commun. 2018;9(1):1691. https://doi.org/10.1038/s41467-018-04001-5.CrossRefPubMedPubMedCentral

145.

Riviere P, Fanta PT, Ikeda S, Baumgartner J, Heestand GM, Kurzrock R. The Mutational Landscape of Gastrointestinal Malignancies as Reflected by Circulating Tumor DNA. Mol Cancer Ther. 2018;17(1):297–305. https://doi.org/10.1158/1535-7163.MCT-17-0360.CrossRefPubMed

146.

Schrock AB, Pavlick D, Klempner SJ, Chung JH, Forcier B, Welsh A, et al. Hybrid capture-based genomic profiling of circulating tumor DNA from patients with advanced cancers of the gastrointestinal tract or anus. Clin Cancer Res. 2018;24(8):1881–90. https://doi.org/10.1158/1078-0432.Ccr-17-3103.CrossRefPubMedPubMedCentral

147.

Garrigou S, Perkins G, Garlan F, Normand C, Didelot A, Le Corre D, et al. A study of hypermethylated circulating tumor DNA as a universal colorectal cancer biomarker. Clin Chem. 2016;62(8):1129–39. https://doi.org/10.1373/clinchem.2015.253609.CrossRefPubMed

148.

Warton K, Mahon KL, Samimi G. Methylated circulating tumor DNA in blood: power in cancer prognosis and response. Endocr Relat Cancer. 2016;23(3):R157–R71. https://doi.org/10.1530/ERC-15-0369.CrossRefPubMedPubMedCentral

149.

Warton K, Samimi G. Methylation of cell-free circulating DNA in the diagnosis of cancer. Front Mol Biosci. 2015;2:13. https://doi.org/10.3389/fmolb.2015.00013.CrossRefPubMedPubMedCentral

150.

Modlin IM, Gustafsson BI, Drozdov I, Nadler B, Pfragner R, Kidd M. Principal component analysis, hierarchical clustering, and decision tree assessment of plasma mrna and hormone levels as an early detection strategy for small intestinal neuroendocrine (carcinoid) tumors. Ann Surg Oncol. 2008;16(2):487. https://doi.org/10.1245/s10434-008-0251-1.CrossRefPubMed

151.

Li S-C, Khan M, Caplin M, Meyer T, Öberg K, Giandomenico V. Somatostatin analogs treated small intestinal neuroendocrine tumor patients circulating MicroRNAs. Plos One. 2015;10(5):e0125553. https://doi.org/10.1371/journal.pone.0125553.CrossRefPubMedPubMedCentral

152.

Bowden M, Zhou CW, Zhang S, Brais L, Rossi A, Naudin L et al. Profiling of metastatic small intestine neuroendocrine tumors reveals characteristic miRNAs detectable in plasma. Oncotarget. 2017;8(33):54331-44. https://doi.org/10.18632/oncotarget.16908.

153.

Modlin IM, Drozdov I, Kidd M. The identification of gut neuroendocrine tumor disease by multiple synchronous transcript analysis in blood. PLoS One. 2013;8(5):e63364. https://doi.org/10.1371/journal.pone.0063364.CrossRefPubMedPubMedCentral

154.

Modlin IM, Drozdov I, Alaimo D, Callahan S, Teixiera N, Bodei L, et al. A multianalyte PCR blood test outperforms single analyte ELISAs (chromogranin A, pancreastatin, neurokinin A) for neuroendocrine tumor detection. Endocrine-related cancer. 2014;21(4):615–28. https://doi.org/10.1530/erc-14-0190.CrossRefPubMed

155.

Modlin IM, Drozdov I, Kidd M. Gut neuroendocrine tumor blood qPCR fingerprint assay: characteristics and reproducibility. Clin Chem Lab Med. 2014;52(3):419–29. https://doi.org/10.1515/cclm-2013-0496.CrossRefPubMed

156.

Modlin IM, Kidd M, Bodei L, Drozdov I, Aslanian H. The clinical utility of a novel blood-based multi-transcriptome assay for the diagnosis of neuroendocrine tumors of the gastrointestinal tract. Am J Gastroenterol. 2015;110(8):1223–32. https://doi.org/10.1038/ajg.2015.160.CrossRefPubMed

157.

Bodei L, Kidd M, Modlin IM, Prasad V, Severi S, Ambrosini V, et al. Gene transcript analysis blood values correlate with (6)(8)Ga-DOTA-somatostatin analog (SSA) PET/CT imaging in neuroendocrine tumors and can define disease status. Eur J Nucl Med Mol Imaging. 2015;42(9):1341–52. https://doi.org/10.1007/s00259-015-3075-9.CrossRefPubMed

158.

Kidd M, Drozdov I, Modlin I. Blood and tissue neuroendocrine tumor gene cluster analysis correlate, define hallmarks and predict disease status. Endocr Relat Cancer. 2015;22(4):561–75. https://doi.org/10.1530/erc-15-0092.CrossRefPubMed

159.

Pavel M, Jann H, Prasad V, Drozdov I, Modlin IM, Kidd M. NET Blood Transcript analysis defines the crossing of the clinical rubicon: when stable disease becomes progressive. Neuroendocrinology. 2017;104(2):170–82. https://doi.org/10.1159/000446025.CrossRefPubMed

160.

Modlin IM, Frilling A, Salem RR, Alaimo D, Drymousis P, Wasan HS, et al. Blood measurement of neuroendocrine gene transcripts defines the effectiveness of operative resection and ablation strategies. Surgery. 2016;159(1):336–47. https://doi.org/10.1016/j.surg.2015.06.056.CrossRefPubMed

161.

Cwikla JB, Bodei L, Kolasinska-Cwikla A, Sankowski A, Modlin IM, Kidd M. Circulating transcript analysis (NETest) in GEP-NETs treated with somatostatin analogs defines therapy. J Clin Endocrinol Metab. 2015;100(11):E1437–45. https://doi.org/10.1210/jc.2015-2792.CrossRefPubMed

162.

Bodei L, Kidd M, Modlin IM, Severi S, Drozdov I, Nicolini S, et al. Measurement of circulating transcripts and gene cluster analysis predicts and defines therapeutic efficacy of peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors. Eur J Nucl Med Mol Imaging. 2016;43(5):839–51. https://doi.org/10.1007/s00259-015-3250-z.CrossRefPubMed

163.

van Treijen MJC, Korse CM, van Leeuwaarde RS, Saveur LJ, Vriens MR, Verbeek WHM, et al. Blood transcript profiling for the detection of neuroendocrine tumors: results of a large independent validation study. Front Endocrinol. 2018;9:740. https://doi.org/10.3389/fendo.2018.00740.CrossRef

164.

Mafficini A, Scarpa A. Genetics and epigenetics of gastroenteropancreatic neuroendocrine neoplasms. Endocr Rev. 2019. https://doi.org/10.1210/er.2018-00160.CrossRefPubMedPubMedCentral

165.

Kim ST, Lee SJ, Park SH, Park JO, Lim HY, Kang WK, et al. Genomic profiling of metastatic gastroenteropancreatic neuroendocrine tumor (GEP-NET) patients in the personalized-medicine era. J Cancer. 2016;7(9):1044–8. https://doi.org/10.7150/jca.14815.CrossRefPubMedPubMedCentral

166.

Horak P, Klink B, Heining C, Gröschel S, Hutter B, Fröhlich M, et al. Precision oncology based on omics data: The NCT Heidelberg experience. Int J Cancer. 2017;141(5):877–86. https://doi.org/10.1002/ijc.30828.CrossRefPubMed

167.

Apostolidis L, Kreutzfeldt S, Oles M, Gieldon L, Heining C, Horak P et al. Abstract Book of the 43rd ESMO Congress (ESMO 2018) 19–23 October 2018, Munich, Germany: Prospective genome and transcriptome sequencing in advanced-stage neuroendocrine neoplasms. Ann Oncol. 2018;29(suppl_8):viii467-viii78. https://doi.org/10.1093/annonc/mdy293.003.

Titel: Clinical applications of (epi)genetics in gastroenteropancreatic neuroendocrine neoplasms: Moving towards liquid biopsies
verfasst von: Gitta Boons
Timon Vandamme
Marc Peeters
Guy Van Camp
Ken Op de Beeck
Publikationsdatum: 31.07.2019
Verlag: Springer US
Erschienen in: Reviews in Endocrine and Metabolic Disorders / Ausgabe 3/2019
Print ISSN: 1389-9155
Elektronische ISSN: 1573-2606
DOI: https://doi.org/10.1007/s11154-019-09508-w

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

19.04.2024 | Vorhofflimmern | Nachrichten

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Clinical applications of (epi)genetics in gastroenteropancreatic neuroendocrine neoplasms: Moving towards liquid biopsies

Abstract

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Parodontalbehandlung verbessert Prognose bei Katheterablation

Antihypertensiva schützen auch alte Menschen noch vor Demenz

Stereotaktische Radiatio schlägt konventionelle Bestrahlung

Denken Sie bei starker Blutung auch an die Hemmkörper-Hämophilie

Update Innere Medizin

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 3/2019

Vitamin D in physiological and pathological aging: Lesson from centenarians

Genetics, adaptation to environmental changes and archaic admixture in the pathogenesis of diabetes mellitus in Indigenous Australians

Calcium citrate: from biochemistry and physiology to clinical applications

Risk of vertebral fractures in hypoparathyroidism

Current perspectives on the impact of clinical disease and biochemical control on comorbidities and quality of life in acromegaly

Neuroendocrinological mechanisms underlying impulsive and compulsive behaviors in obesity: a narrative review of fMRI studies

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Parodontalbehandlung verbessert Prognose bei Katheterablation

Antihypertensiva schützen auch alte Menschen noch vor Demenz

Stereotaktische Radiatio schlägt konventionelle Bestrahlung

Denken Sie bei starker Blutung auch an die Hemmkörper-Hämophilie

Update Innere Medizin