Top

Published in:

01-10-2011 | Research Paper

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

Authors: Nicole Posorski, Daniel Kaemmerer, Guenther Ernst, Patricia Grabowski, Dieter Hoersch, Merten Hommann, Ferdinand von Eggeling

Published in: Clinical & Experimental Metastasis | Issue 7/2011

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.

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

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):1272–1280PubMed

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

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):243–256PubMedCrossRef

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):1083–1092PubMedCrossRef

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

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

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):4656–4663PubMedCrossRef

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):474–479PubMedCrossRef

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):541–558PubMedCrossRef

11.

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

12.

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

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):451–458PubMedCrossRef

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):1903–1911PubMedCrossRef

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):109–114PubMedCrossRef

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):843–847PubMedCrossRef

17.

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

18.

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

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):e3767PubMedCrossRef

20.

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

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):1231–1238PubMedCrossRef

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):41–52PubMedCrossRef

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):4099–4104PubMedCrossRef

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):443–452PubMed

25.

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

26.

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

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):2094–2103PubMed

28.

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

29.

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

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):1787–1794PubMedCrossRef

31.

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

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):1803–1808PubMedCrossRef

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):812–815PubMedCrossRef

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):1079–1087PubMedCrossRef

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):2041–2046PubMedCrossRef

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):15149–15154PubMedCrossRef

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):7388–7393PubMed

38.

Yeang C, Ramaswamy S, Tamayo P et al (2001) Molecular classification of multiple tumor types. Bioinformatics 17(Suppl 1):S316–S322PubMedCrossRef

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):4435–4441PubMedCrossRef

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):5999–6005PubMed

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):822–827PubMedCrossRef

42.

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

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):4031–4040PubMedCrossRef

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):673–679PubMedCrossRef

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):320–329PubMedCrossRef

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):67–77PubMedCrossRef

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):2503–2508PubMedCrossRef

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):4442–4448PubMedCrossRef

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):1390–1397PubMedCrossRef

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):1425–1430PubMedCrossRef

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):465–473PubMed

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):3766–3772PubMedCrossRef

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):1561–1567PubMed

54.

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

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):591–603PubMedCrossRef

56.

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

57.

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

58.

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

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):6052–6063PubMed

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):34035–34041PubMedCrossRef

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):362–371PubMedCrossRef

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):2283–2295PubMedCrossRef

Title: Localization of sporadic neuroendocrine tumors by gene expression analysis of their metastases
Authors: Nicole Posorski
Daniel Kaemmerer
Guenther Ernst
Patricia Grabowski
Dieter Hoersch
Merten Hommann
Ferdinand von Eggeling
Publication date: 01-10-2011
Publisher: Springer Netherlands
Published in: Clinical & Experimental Metastasis / Issue 7/2011
Print ISSN: 0262-0898
Electronic ISSN: 1573-7276
DOI: https://doi.org/10.1007/s10585-011-9397-5

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 7/2011

The aldehyde dehydrogenase enzyme 7A1 is functionally involved in prostate cancer bone metastasis

Dairy milk fat augments paclitaxel therapy to suppress tumour metastasis in mice, and protects against the side-effects of chemotherapy

Inducible expression of TGFβ, Snail and Zeb1 recapitulates EMT in vitro and in vivo in a NSCLC model

Inhibition of T-cell responses by intratumoral hepatic stellate cells contribute to migration and invasion of hepatocellular carcinoma

The dual role of TLR3 in metastatic cell line

Tissue factor expression in ovarian cancer: implications for immunotherapy with hI-con1, a factor VII-IgGFc chimeric protein targeting tissue factor

Keynote webinar | Spotlight on antibody–drug conjugates in cancer