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. 2001 Apr;48(4):536–541. doi: 10.1136/gut.48.4.536

Analysis of sporadic neuroendocrine tumours of the enteropancreatic system by comparative genomic hybridisation

H Tonnies 1, M Toliat 1, C Ramel 1, U Pape 1, H Neitzel 1, W Berger 1, B Wiedenmann 1
PMCID: PMC1728244  PMID: 11247899

Abstract

BACKGROUND—Chromosomal instability is observed in a wide spectrum of human cancer syndromes. However, to date, little is known of the characteristic genetic changes in sporadic neuroendocrine tumours of the gastroenteropancreatic system.
AIMS AND METHOD—We have studied copy number aberrations (CNAs) in 26 sporadic neuroendocrine tumours of the enteropancreatic system (12 foregut and 14 midgut tumours) by comparative genomic hybridisation (CGH), allowing simultaneous evaluation of the entire tumour genome.
RESULTS—Nearly all tumours (25/26; that is, 96%) showed chromosomal imbalances, including full chromosomal aneuploidies, losses and gains of chromosome arms, interstitial deletions, and amplifications. Whereas gains of chromosomes 4, 5, and 19 were found in both foregut and midgut tumours, gains of chromosomes 20q (58%), 19 (50%), as well as 17p (50%), and partial losses of chromosomes 1p (42%), 2q (42%), 3p, 4q, and 6q (25% each) were frequently observed only in foregut tumours. In contrast, midgut tumours displayed less CNAs. Gains were detected for chromosomes 17q and 19p (57%). Most frequent losses affected chromosomes 18 (43%) and 9p (21%).
CONCLUSIONS—The results of our CGH analyses revealed new distinct candidate regions in the human genome associated with sporadic neuroendocrine tumours. Some of the genetic alterations were shared by foregut and midgut tumours while others discriminated between the two groups. Thus our results allude to the involvement of identical as well as discriminative genetic loci in tumorigenesis and progression of neuroendocrine neoplasms of the foregut and midgut. Based on these findings potential new candidate genes will be discussed.


Keywords: gastroenteropancreatic tumours; comparative genomic hybridisation; foregut; midgut

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Figure 1  .

Figure 1  

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Copy number abnormalities in relation to chromosome arm affected for each tumour group investigated. Gains of chromosomal material are marked by a vertical bar above baseline (0 value) and losses below the baseline.

Figure 2  .

Figure 2  

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Summary of gains and losses of DNA sequence copy number detected in foregut tumours (A) and midgut tumours (B). Vertical lines on the left side (red) of each chromosome ideogram represent loss of genetic material in a given tumour at the marked chromosomal segment whereas vertical lines on the right side (green) correspond to gains of genetic material.

Figure 3  .

Figure 3  

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Average ratio profile of tumour 14 (midgut tumour, see table 1). Ratio profiles along the individual chromosomes are shown on the right side of each ideogram. Left (red), middle (grey), and right (green) vertical lanes represent the lower, middle, and upper threshold of the normal range (see text for details).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Agarwal S. K., Guru S. C., Heppner C., Erdos M. R., Collins R. M., Park S. Y., Saggar S., Chandrasekharappa S. C., Collins F. S., Spiegel A. M. Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription. Cell. 1999 Jan 8;96(1):143–152. doi: 10.1016/s0092-8674(00)80967-8. [DOI] [PubMed] [Google Scholar]
  2. Arlt M. F., Herzog T. J., Mutch D. G., Gersell D. J., Liu H., Goodfellow P. J. Frequent deletion of chromosome 1p sequences in an aggressive histologic subtype of endometrial cancer. Hum Mol Genet. 1996 Jul;5(7):1017–1021. doi: 10.1093/hmg/5.7.1017. [DOI] [PubMed] [Google Scholar]
  3. Bartsch D., Hahn S. A., Danichevski K. D., Ramaswamy A., Bastian D., Galehdari H., Barth P., Schmiegel W., Simon B., Rothmund M. Mutations of the DPC4/Smad4 gene in neuroendocrine pancreatic tumors. Oncogene. 1999 Apr 8;18(14):2367–2371. doi: 10.1038/sj.onc.1202585. [DOI] [PubMed] [Google Scholar]
  4. Capella C., Heitz P. U., Höfler H., Solcia E., Klöppel G. Revised classification of neuroendocrine tumours of the lung, pancreas and gut. Virchows Arch. 1995;425(6):547–560. doi: 10.1007/BF00199342. [DOI] [PubMed] [Google Scholar]
  5. Chakrabarti R., Srivatsan E. S., Wood T. F., Eubanks P. J., Ebrahimi S. A., Gatti R. A., Passaro E., Jr, Sawicki M. P. Deletion mapping of endocrine tumors localizes a second tumor suppressor gene on chromosome band 11q13. Genes Chromosomes Cancer. 1998 Jun;22(2):130–137. doi: 10.1002/(sici)1098-2264(199806)22:2<130::aid-gcc7>3.0.co;2-y. [DOI] [PubMed] [Google Scholar]
  6. Chandrasekharappa S. C., Guru S. C., Manickam P., Olufemi S. E., Collins F. S., Emmert-Buck M. R., Debelenko L. V., Zhuang Z., Lubensky I. A., Liotta L. A. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science. 1997 Apr 18;276(5311):404–407. doi: 10.1126/science.276.5311.404. [DOI] [PubMed] [Google Scholar]
  7. Clarke D. J., Giménez-Abián J. F., Tönnies H., Neitzel H., Sperling K., Downes C. S., Johnson R. T. Creation of monosomic derivatives of human cultured cell lines. Proc Natl Acad Sci U S A. 1998 Jan 6;95(1):167–171. doi: 10.1073/pnas.95.1.167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Debelenko L. V., Brambilla E., Agarwal S. K., Swalwell J. I., Kester M. B., Lubensky I. A., Zhuang Z., Guru S. C., Manickam P., Olufemi S. E. Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung. Hum Mol Genet. 1997 Dec;6(13):2285–2290. doi: 10.1093/hmg/6.13.2285. [DOI] [PubMed] [Google Scholar]
  9. Görtz B., Roth J., Krähenmann A., de Krijger R. R., Muletta-Feurer S., Rütimann K., Saremaslani P., Speel E. J., Heitz P. U., Komminoth P. Mutations and allelic deletions of the MEN1 gene are associated with a subset of sporadic endocrine pancreatic and neuroendocrine tumors and not restricted to foregut neoplasms. Am J Pathol. 1999 Feb;154(2):429–436. doi: 10.1016/S0002-9440(10)65289-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kallioniemi A., Kallioniemi O. P., Sudar D., Rutovitz D., Gray J. W., Waldman F., Pinkel D. Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science. 1992 Oct 30;258(5083):818–821. doi: 10.1126/science.1359641. [DOI] [PubMed] [Google Scholar]
  11. Kallioniemi O. P., Kallioniemi A., Piper J., Isola J., Waldman F. M., Gray J. W., Pinkel D. Optimizing comparative genomic hybridization for analysis of DNA sequence copy number changes in solid tumors. Genes Chromosomes Cancer. 1994 Aug;10(4):231–243. doi: 10.1002/gcc.2870100403. [DOI] [PubMed] [Google Scholar]
  12. Kohno T., Morishita K., Takano H., Shapiro D. N., Yokota J. Homozygous deletion at chromosome 2q33 in human small-cell lung carcinoma identified by arbitrarily primed PCR genomic fingerprinting. Oncogene. 1994 Jan;9(1):103–108. [PubMed] [Google Scholar]
  13. Kohno T., Otsuka T., Takano H., Yamamoto T., Hamaguchi M., Terada M., Yokota J. Identification of a novel phospholipase C family gene at chromosome 2q33 that is homozygously deleted in human small cell lung carcinoma. Hum Mol Genet. 1995 Apr;4(4):667–674. doi: 10.1093/hmg/4.4.667. [DOI] [PubMed] [Google Scholar]
  14. Larramendy M. L., El-Rifai W., Knuutila S. Comparison of fluorescein isothiocyanate- and Texas red-conjugated nucleotides for direct labeling in comparative genomic hybridization. Cytometry. 1998 Mar 1;31(3):174–179. [PubMed] [Google Scholar]
  15. Lemmens I., Van de Ven W. J., Kas K., Zhang C. X., Giraud S., Wautot V., Buisson N., De Witte K., Salandre J., Lenoir G. Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1. Hum Mol Genet. 1997 Jul;6(7):1177–1183. doi: 10.1093/hmg/6.7.1177. [DOI] [PubMed] [Google Scholar]
  16. Modlin I. M., Sandor A. An analysis of 8305 cases of carcinoid tumors. Cancer. 1997 Feb 15;79(4):813–829. doi: 10.1002/(sici)1097-0142(19970215)79:4<813::aid-cncr19>3.0.co;2-2. [DOI] [PubMed] [Google Scholar]
  17. Muscarella P., Melvin W. S., Fisher W. E., Foor J., Ellison E. C., Herman J. G., Schirmer W. J., Hitchcock C. L., DeYoung B. R., Weghorst C. M. Genetic alterations in gastrinomas and nonfunctioning pancreatic neuroendocrine tumors: an analysis of p16/MTS1 tumor suppressor gene inactivation. Cancer Res. 1998 Jan 15;58(2):237–240. [PubMed] [Google Scholar]
  18. Richter J., Jiang F., Görög J. P., Sartorius G., Egenter C., Gasser T. C., Moch H., Mihatsch M. J., Sauter G. Marked genetic differences between stage pTa and stage pT1 papillary bladder cancer detected by comparative genomic hybridization. Cancer Res. 1997 Jul 15;57(14):2860–2864. [PubMed] [Google Scholar]
  19. Rindi G., Capella C., Solcia E. Cell biology, clinicopathological profile, and classification of gastro-enteropancreatic endocrine tumors. J Mol Med (Berl) 1998 May;76(6):413–420. doi: 10.1007/s001090050233. [DOI] [PubMed] [Google Scholar]
  20. Speel E. J., Richter J., Moch H., Egenter C., Saremaslani P., Rütimann K., Zhao J., Barghorn A., Roth J., Heitz P. U. Genetic differences in endocrine pancreatic tumor subtypes detected by comparative genomic hybridization. Am J Pathol. 1999 Dec;155(6):1787–1794. doi: 10.1016/S0002-9440(10)65495-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Terris B., Meddeb M., Marchio A., Danglot G., Fléjou J. F., Belghiti J., Ruszniewski P., Bernheim A. Comparative genomic hybridization analysis of sporadic neuroendocrine tumors of the digestive system. Genes Chromosomes Cancer. 1998 May;22(1):50–56. doi: 10.1002/(sici)1098-2264(199805)22:1<50::aid-gcc7>3.0.co;2-6. [DOI] [PubMed] [Google Scholar]
  22. Toliat M. R., Berger W., Ropers H. H., Neuhaus P., Wiedenmann B. Mutations in the MEN I gene in sporadic neuroendocrine tumours of gastroenteropancreatic system. Lancet. 1997 Oct 25;350(9086):1223–1223. doi: 10.1016/S0140-6736(05)63453-8. [DOI] [PubMed] [Google Scholar]
  23. WILLIAMS E. D., SANDLER M. The classification of carcinoid tum ours. Lancet. 1963 Feb 2;1(7275):238–239. doi: 10.1016/s0140-6736(63)90951-6. [DOI] [PubMed] [Google Scholar]
  24. Wiedenmann B., John M., Ahnert-Hilger G., Riecken E. O. Molecular and cell biological aspects of neuroendocrine tumors of the gastroenteropancreatic system. J Mol Med (Berl) 1998 Aug;76(9):637–647. doi: 10.1007/s001090050261. [DOI] [PubMed] [Google Scholar]
  25. Xu X., Weaver Z., Linke S. P., Li C., Gotay J., Wang X. W., Harris C. C., Ried T., Deng C. X. Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. Mol Cell. 1999 Mar;3(3):389–395. doi: 10.1016/s1097-2765(00)80466-9. [DOI] [PubMed] [Google Scholar]
  26. Zhou H., Kuang J., Zhong L., Kuo W. L., Gray J. W., Sahin A., Brinkley B. R., Sen S. Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet. 1998 Oct;20(2):189–193. doi: 10.1038/2496. [DOI] [PubMed] [Google Scholar]
  27. du Manoir S., Schröck E., Bentz M., Speicher M. R., Joos S., Ried T., Lichter P., Cremer T. Quantitative analysis of comparative genomic hybridization. Cytometry. 1995 Jan 1;19(1):27–41. doi: 10.1002/cyto.990190105. [DOI] [PubMed] [Google Scholar]

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