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Localization of sporadic neuroendocrine tumors by gene expression analysis of their metastases

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Abstract

A characteristic of human gastroenteropancreatic neuroendocrine tumors (GEP-NET) is a minute unobtrusive primary tumor which often cannot be detected by common physical examinations. It therefore remains unidentified until the tumor has spread and space-occupying metastases cause clinical symptoms leading to diagnosis. Cases in which the primary cannot be located are referred to as NET with CUP-syndrome (cancer of unknown primary syndrome). With the help of array-CGH (comparative genomic hybridization, Agilent 105K) and gene expression analysis (Agilent 44K), microdissected primaries and their metastases were compared to identify up- and down-regulated genes which can be used as a marker for tumor progression. In a next analysis step, a hierarchical clustering of 41.078 genes revealed three genes [C-type lectin domain family 13 member A (CD302), peptidylprolyl isomerase containing WD40 repeat (PPWD1) and abhydrolase domain containing 14B (ABHD14B)] which expression levels can categorize the metastases into three groups depending on the localization of their primary. Because cancer therapy is dependent on the localization of the primary, the gene expression level of these three genes are promising markers to unravel the CUP syndrome in NET.

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Abbreviations

ABHD14B :

Abhydrolase domain containing 14B

CD302 :

C-type lectin domain family 13 member A

CDH22 :

Cadherin 22

DACT2 :

Dapper, antagonist of beta-catenin, homolog 2

CGH:

Comparative genomic hybridization

CUP:

Cancer of unknown primary

GEP-NET:

Gastroenteropancreatic neuroendocrine tumor

GI-NET:

Gastrointestinal neuroendocrine tumor

IHC:

Immunohistochemistry

IL-8:

Interleukin 8

NET:

Neuroendocrine tumor

PDEC:

Poorly differentiated carcinoma

PNET:

Pancreatic neuroendocrine tumor

PPWD1 :

Peptidylprolyl isomerase containing WD40 repeat

RET :

Rearranged during transfection (proto-oncogene)

WDET:

Well differentiated neuroendocrine tumor

References

  1. Bornschein J, Kidd M, Malfertheiner P et al (2008) Gastrointestinal neuroendocrine tumors. Dtsch Med Wochenschr 133(28–29):1505–1510

    Article  PubMed  CAS  Google Scholar 

  2. Abbruzzese J, Abbruzzese M, Hess K et al (1994) Unknown primary carcinoma: natural history and prognostic factors in 657 consecutive patients. J Clin Oncol 12(6):1272–1280

    PubMed  CAS  Google Scholar 

  3. Duerr EM, Chung DC (2007) Molecular genetics of neuroendocrine tumors. Best Pract Res Clin Endocrinol Metab 21(1):1–14

    Article  PubMed  CAS  Google Scholar 

  4. Duerr E, Mizukami Y, Ng A et al (2008) Defining molecular classifications and targets in gastroenteropancreatic neuroendocrine tumors through DNA microarray analysis. Endocr Relat Cancer 15(1):243–256

    Article  PubMed  CAS  Google Scholar 

  5. Panzuto F, Nasoni S, Falconi M et al (2005) Prognostic factors and survival in endocrine tumor patients: comparison between gastrointestinal and pancreatic localization. Endocr Relat Cancer 12(4):1083–1092

    Article  PubMed  Google Scholar 

  6. Tomasetti P, Campana D, Piscitelli L et al (2005) Endocrine pancreatic tumors: factors correlated with survival. Ann Oncol 16(11):1806–1810

    Article  Google Scholar 

  7. Scholzen T, Gerdes J (2000) The Ki-67 protein: from the known and the unknown. J Cell Physiol 182(3):311–322

    Article  PubMed  CAS  Google Scholar 

  8. Rinke A, Müller H, Schade-Brittinger C et al (2009) 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 Clin Oncol 27(28):4656–4663

    Article  PubMed  CAS  Google Scholar 

  9. Berkovic MC, Jokic M, Marout J et al (2007) IL-6-174 C/G polymorphism in the gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Exp Mol Pathol 83(3):474–479

    Article  PubMed  CAS  Google Scholar 

  10. Capurso G, Lattimore S, Crnogorac-Jurcevic T et al (2006) Gene expression profiles of progressive pancreatic endocrine tumours and their liver metastases reveal potential novel markers and therapeutic targets. Endocr Relat Cancer 13(2):541–558

    Article  PubMed  CAS  Google Scholar 

  11. Hocker M, Wiedenmann B (1998) Molecular mechanisms of enteroendocrine differentiation. Ann N Y Acad Sci 859:160–174

    Article  PubMed  CAS  Google Scholar 

  12. Oberg K (2009) Genetics and molecular pathology of neuroendocrine gastrointestinal and pancreatic tumors (gastroenteropancreatic neuroendocrine tumors). Curr Opin Endocrinol Diabetes Obes 16(1):72–78

    Article  PubMed  Google Scholar 

  13. Barghorn A, Komminoth P, Bachmann D et al (2001) Deletion at 3p25.3-p23 is frequently encountered in endocrine pancreatic tumours and is associated with metastatic progression. J Pathol 194(4):451–458

    Article  PubMed  CAS  Google Scholar 

  14. Barghorn A, Speel EJ, Farspour B et al (2001) Putative tumor suppressor loci at 6q22 and 6q23–q24 are involved in the malignant progression of sporadic endocrine pancreatic tumors. Am J Pathol 158(6):1903–1911

    Article  PubMed  CAS  Google Scholar 

  15. Guo SS, Arora C, Shimoide AT et al (2002) Frequent deletion of chromosome 3 in malignant sporadic pancreatic endocrine tumors. Mol Cell Endocrinol 190(1–2):109–114

    Article  PubMed  CAS  Google Scholar 

  16. Guo SS, Wu AY, Sawicki MP (2002) Deletion of chromosome 1, but not mutation of MEN-1, predicts prognosis in sporadic pancreatic endocrine tumors. World J Surg 26(7):843–847

    Article  PubMed  Google Scholar 

  17. Wang EH, Ebrahimi SA, Wu AY et al (1998) Mutation of the MENIN gene in sporadic pancreatic endocrine tumors. Cancer Res 58(19):4417–4420

    PubMed  CAS  Google Scholar 

  18. Zikusoka MN, Kidd M, Eick G et al (2005) The molecular genetics of gastroenteropancreatic neuroendocrine tumors. Cancer 104(11):2292–2309

    Article  PubMed  CAS  Google Scholar 

  19. Melle C, Ernst G, Schimmel B et al (2008) Colon-derived liver metastasis, colorectal carcinoma, and hepatocellular carcinoma can be discriminated by the Ca(2+)-binding proteins S100A6 and S100A11. PLoS One 3(12):e3767

    Article  PubMed  Google Scholar 

  20. Modlin IM, Oberg K, Chung DC et al (2008) Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol 9(1):61–72

    Article  PubMed  CAS  Google Scholar 

  21. Giordano T, Shedden K, Schwartz D et al (2001) Organ-specific molecular classification of primary lung, colon, and ovarian adenocarcinomas using gene expression profiles. Am J Pathol 159(4):1231–1238

    Article  PubMed  CAS  Google Scholar 

  22. Alizadeh A, Ross D, Perou C et al (2001) Towards a novel classification of human malignancies based on gene expression patterns. J Pathol 195(1):41–52

    Article  PubMed  CAS  Google Scholar 

  23. Melle C, Ernst G, Schimmel B et al (2004) A technical triade for proteomic identification and characterization of cancer biomarkers. Cancer Res 64(12):4099–4104

    Article  PubMed  CAS  Google Scholar 

  24. Melle C, Ernst G, Schimmel B et al (2003) Biomarker discovery and identification in laser microdissected head and neck squamous cell carcinoma with ProteinChip technology, two-dimensional gel electrophoresis, tandem mass spectrometry, and immunohistochemistry. Mol Cell Proteomics 2(7):443–452

    PubMed  CAS  Google Scholar 

  25. Ramos-Vara J (2005) Technical aspects of immunohistochemistry. Vet Pathol 42(4):405–426

    Article  PubMed  CAS  Google Scholar 

  26. Bloom G, Yang I, Boulware D et al (2004) Multi-platform, multi-site, microarray-based human tumor classification. Am J Pathol 164(1):9–16

    Article  PubMed  CAS  Google Scholar 

  27. Abbruzzese J, Abbruzzese M, Lenzi R et al (1995) Analysis of a diagnostic strategy for patients with suspected tumors of unknown origin. J Clin Oncol 13(8):2094–2103

    PubMed  CAS  Google Scholar 

  28. Yuhas J, Pazmiño N (1974) Inhibition of subcutaneously growing line 1 carcinomas due to metastatic spread. Cancer Res 34(8):2005–2010

    PubMed  CAS  Google Scholar 

  29. Albertson D, Collins C, McCormick F et al (2003) Chromosome aberrations in solid tumors. Nat Genet 34(4):369–376

    Article  PubMed  CAS  Google Scholar 

  30. Speel E, Richter J, Moch H et al (1999) Genetic differences in endocrine pancreatic tumor subtypes detected by comparative genomic hybridization. Am J Pathol 155(6):1787–1794

    Article  PubMed  CAS  Google Scholar 

  31. Zhao J, Moch H, Scheidweiler A et al (2001) Genomic imbalances in the progression of endocrine pancreatic tumors. Genes Chromosomes Cancer 32(4):364–372

    Article  PubMed  CAS  Google Scholar 

  32. Kytölä S, Höög A, Nord B et al (2001) Comparative genomic hybridization identifies loss of 18q22-qter as an early and specific event in tumorigenesis of midgut carcinoids. Am J Pathol 158(5):1803–1808

    Article  PubMed  Google Scholar 

  33. Löllgen RM, Hessman O, Szabo E et al (2001) Chromosome 18 deletions are common events in classical midgut carcinoid tumors. Int J Cancer 92(6):812–815

    Article  PubMed  Google Scholar 

  34. Wang GG, Yao JC, Worah S et al (2005) Comparison of genetic alterations in neuroendocrine tumors: frequent loss of chromosome 18 in ileal carcinoid tumors. Mod Pathol 18(8):1079–1087

    Article  PubMed  CAS  Google Scholar 

  35. Komminoth P, Roth J, Muletta-Feurer S et al (1996) RET proto-oncogene point mutations in sporadic neuroendocrine tumors. J Clin Endocrinol Metab 81(6):2041–2046

    Article  PubMed  CAS  Google Scholar 

  36. Ramaswamy S, Tamayo P, Rifkin R et al (2001) Multiclass cancer diagnosis using tumor gene expression signatures. Proc Natl Acad Sci U S A 98(26):15149–15154

    Article  PubMed  CAS  Google Scholar 

  37. Su A, Welsh J, Sapinoso L et al (2001) Molecular classification of human carcinomas by use of gene expression signatures. Cancer Res 61(20):7388–7393

    PubMed  CAS  Google Scholar 

  38. Yeang C, Ramaswamy S, Tamayo P et al (2001) Molecular classification of multiple tumor types. Bioinformatics 17(Suppl 1):S316–S322

    Article  PubMed  Google Scholar 

  39. Horlings H, van Laar R, Kerst J et al (2008) Gene expression profiling to identify the histogenetic origin of metastatic adenocarcinomas of unknown primary. J Clin Oncol 26(27):4435–4441

    Article  PubMed  CAS  Google Scholar 

  40. Dennis J, Vass J, Wit E et al (2002) Identification from public data of molecular markers of adenocarcinoma characteristic of the site of origin. Cancer Res 62(21):5999–6005

    PubMed  CAS  Google Scholar 

  41. Shedden K, Taylor J, Enkemann S et al (2008) Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study. Nat Med 14(8):822–827

    Article  PubMed  CAS  Google Scholar 

  42. Buckhaults P, Zhang Z, Chen Y et al (2003) Identifying tumor origin using a gene expression-based classification map. Cancer Res 63(14):4144–4149

    PubMed  CAS  Google Scholar 

  43. Tothill R, Kowalczyk A, Rischin D et al (2005) An expression-based site of origin diagnostic method designed for clinical application to cancer of unknown origin. Cancer Res 65(10):4031–4040

    Article  PubMed  CAS  Google Scholar 

  44. Khan J, Wei J, Ringnér M et al (2001) Classification and diagnostic prediction of cancers using gene expression profiling and artificial neural networks. Nat Med 7(6):673–679

    Article  PubMed  CAS  Google Scholar 

  45. Talantov D, Baden J, Jatkoe T et al (2006) A quantitative reverse transcriptase-polymerase chain reaction assay to identify metastatic carcinoma tissue of origin. J Mol Diagn 8(3):320–329

    Article  PubMed  CAS  Google Scholar 

  46. Dumur C, Lyons-Weiler M, Sciulli C et al (2008) Interlaboratory performance of a microarray-based gene expression test to determine tissue of origin in poorly differentiated and undifferentiated cancers. J Mol Diagn 10(1):67–77

    Article  PubMed  CAS  Google Scholar 

  47. Monzon F, Lyons-Weiler M, Buturovic L et al (2009) Multicenter validation of a 1,550-gene expression profile for identification of tumor tissue of origin. J Clin Oncol 27(15):2503–2508

    Article  PubMed  Google Scholar 

  48. Varadhachary G, Talantov D, Raber M et al (2008) Molecular profiling of carcinoma of unknown primary and correlation with clinical evaluation. J Clin Oncol 26(27):4442–4448

    Article  PubMed  CAS  Google Scholar 

  49. van Laar R, Ma X, de Jong D et al (2009) Implementation of a novel microarray-based diagnostic test for cancer of unknown primary. Int J Cancer 125(6):1390–1397

    Article  PubMed  Google Scholar 

  50. Bridgewater J, van Laar R, Floore A et al (2008) Gene expression profiling may improve diagnosis in patients with carcinoma of unknown primary. Br J Cancer 98(8):1425–1430

    Article  PubMed  CAS  Google Scholar 

  51. Ma X, Patel R, Wang X et al (2006) Molecular classification of human cancers using a 92-gene real-time quantitative polymerase chain reaction assay. Arch Pathol Lab Med 130(4):465–473

    PubMed  CAS  Google Scholar 

  52. Dennis J, Hvidsten T, Wit E et al (2005) Markers of adenocarcinoma characteristic of the site of origin: development of a diagnostic algorithm. Clin Cancer Res 11(10):3766–3772

    Article  PubMed  CAS  Google Scholar 

  53. Park S, Kim B, Kim J et al (2007) Panels of immunohistochemical markers help determine primary sites of metastatic adenocarcinoma. Arch Pathol Lab Med 131(10):1561–1567

    PubMed  CAS  Google Scholar 

  54. Lubensky I, Zhuang Z (2007) Molecular genetic events in gastrointestinal and pancreatic neuroendocrine tumors. Endocr Pathol 18(3):156–162

    Article  PubMed  CAS  Google Scholar 

  55. Kulke MH, Freed E, Chiang DY et al (2008) High-resolution analysis of genetic alterations in small bowel carcinoid tumors reveals areas of recurrent amplification and loss. Genes Chromosomes Cancer 47(7):591–603

    Article  PubMed  CAS  Google Scholar 

  56. Moll R (2009) The initial CUP situation and CUP syndrome: pathological diagnostics. Pathologe 30(Suppl 2):161–167

    Article  PubMed  Google Scholar 

  57. von Eggeling F, Ernst G (2007) Microdissected tissue: an underestimated source for biomarker discovery? Biomark Med 1(2):217–219

    Article  Google Scholar 

  58. von Eggeling F, Melle C, Ernst G (2007) Microdissecting the proteome. Proteomics 7(16):2729–2737

    Article  Google Scholar 

  59. Kato M, Khan S, d’Aniello E et al (2007) The novel endocytic and phagocytic C-type lectin receptor DCL-1/CD302 on macrophages is colocalized with F-actin, suggesting a role in cell adhesion and migration. J Immunol 179(9):6052–6063

    PubMed  CAS  Google Scholar 

  60. Kato M, Khan S, Gonzalez N et al (2003) Hodgkin’s lymphoma cell lines express a fusion protein encoded by intergenically spliced mRNA for the multilectin receptor DEC-205 (CD205) and a novel C-type lectin receptor DCL-1. J Biol Chem 278(36):34035–34041

    Article  PubMed  CAS  Google Scholar 

  61. Butler M, Morel A, Jordan W et al (2007) Altered expression and endocytic function of CD205 in human dendritic cells, and detection of a CD205-DCL-1 fusion protein upon dendritic cell maturation. Immunology 120(3):362–371

    Article  PubMed  CAS  Google Scholar 

  62. Davis T, Walker J, Ouyang H et al (2008) The crystal structure of human WD40 repeat-containing peptidylprolyl isomerase (PPWD1). FEBS J 275(9):2283–2295

    Article  PubMed  CAS  Google Scholar 

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Disclosure

I have no relevant financial interests related to this manuscript. I certify that all my affiliations with or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript have been disclosed.

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Authors and Affiliations

  1. Core Unit Chip Application, Institute of Human Genetics, UKJ, University Hospital Jena, 07740, Jena, Germany

    Nicole Posorski, Guenther Ernst & Ferdinand von Eggeling

  2. Department of General and Visceral Surgery, Zentralklinik Bad Berka, Bad Berka, Germany

    Daniel Kaemmerer & Merten Hommann

  3. Department of Internal Medicine, Gastroenterology and Oncology, Zentralklinik Bad Berka, Bad Berka, Germany

    Patricia Grabowski & Dieter Hoersch

  4. Department of Internal Medicine, Gastroenterology, Infectious Diseases and Rheumatology, Charité-Campus Benjamin Franklin, Berlin, Germany

    Patricia Grabowski

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  1. Nicole Posorski
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Correspondence to Ferdinand von Eggeling.

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Nicole Posorski, Daniel Kaemmerer are the authors contributed equally.

Merten Hommann, Ferdinand von Eggeling are the authors contributed equally.

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Posorski, N., Kaemmerer, D., Ernst, G. et al. Localization of sporadic neuroendocrine tumors by gene expression analysis of their metastases. Clin Exp Metastasis 28, 637–647 (2011). https://doi.org/10.1007/s10585-011-9397-5

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  • DOI: https://doi.org/10.1007/s10585-011-9397-5

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