Abstract
Carcinoid tumors are a heterogeneous group of neoplasms arising from the diffuse neuroendocrine system. Pulmonary as well as gastrointestinal carcinoids can be separated into those with low malignant and intermediate malignant potential. DNA losses of chromosome arm 11q are commonly seen in pulmonary neuroendocrine tumors. Conflicting results have been published comparing atypical with typical lung carcinoids with respect to imbalances of chromosome 11. In the present study, a DNA microarray with genomic clones mapped to chromosome 11 was created, and array comparative genomic hybridization (CGH) with DNA derived from formalin-fixed, paraffin-embedded tissue was performed. We investigated 4 typical and 12 atypical carcinoids of the lung and, for comparison, 9 gastrointestinal carcinoids and 6 endocrine pancreatic tumors. We have shown that formalin-fixed, paraffin-derived DNA can be successfully used for array CGH. Alterations of 11q were rarely detected not only in typical carcinoids of the lung but also in gastrointestinal carcinoids. Atypical lung carcinoids that comprised extensive DNA losses also presented retained fragments in between these deleted regions. The array CGH data were consistent with the data of a previously published classical CGH study and were additionally confirmed using fluorescence in situ hybridization in the present investigation.
Similar content being viewed by others
Explore related subjects
Discover the latest articles and news from researchers in related subjects, suggested using machine learning.References
Ausubel FM, Brent R, Kingston RE, Moore DD, Seidman JG, Smith JA, Struhl K (1998) Current protocols in molecular biology. John Wiley & Sons Inc., New York, pp 2.1.1–2.1.2
Bamias AT, Bai MC, Agnantis NJ, Michael MC, Alamanos YP, Stefanaki SV, Razi ED, Skarlos DV, Kappas AM, Pavlidis NA (2003) Prognostic significance of the deleted in colorectal cancer gene protein expression in high-risk resected gastric carcinoma. Cancer Invest 21:333–340
Chakrabarti R, Srivatsan ES, Wood TF, Eubanks PJ, Ebrahimi SA, Gatti RA, Passaro E Jr, Sawicki MP (1998) Deletion mapping of endocrine tumors localizes a second tumor suppressor gene on chromosome band 11q13. Genes Chromosomes Cancer 22:130–137
Daigo Y, Chin SF, Gorringe KL, Bobrow LG, Ponder BA, Pharoah PD, Caldas C (2001) Degenerate oligonucleotide primed-polymerase chain reaction-based array comparative genomic hybridization for extensive amplicon profiling of breast cancers: a new approach for the molecular analysis of paraffin-embedded cancer tissue. Am J Pathol 158:1623–1631
Debelenko LV, Brambilla E, Agarwal SK, Swalwell JI, Kester MB, Lubensky IA, Zhuang Z, Guru SC, Manickam P, Olufemi SE, Chandrasekharappa SC, Crabtree JS, Kim YS, Heppner C, Burns AL, Spiegel AM, Marx SJ, Liotta LA, Collins FS, Travis WD, Emmert-Buck MR (1997) Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung. Hum Mol Genet 6:2285–2290
Fearon ER, Pierceall WE (1995) The deleted in colorectal cancer (DCC) gene: a candidate tumour suppressor gene encoding a cell surface protein with similarity to neural cell adhesion molecules. Cancer Surv 24:3–17
Fiegler H, Carr P, Douglas EJ, Burford DC, Hunt S, Scott CE, Smith J, Vetrie D, Gorman P, Tomlinson IP, Carter NP (2003) DNA microarrays for comparative genomic hybridization based on DOP-PCR amplification of BAC and PAC clones. Genes Chromosomes Cancer 36:361–374
Fong KM, Kida Y, Zimmerman PV, Ikenaga M, Smith PJ (1995) Loss of heterozygosity frequently affects chromosome 17q in non-small cell lung cancer. Cancer Res 55:4268–4272
Guo SS, Wu X, Shimoide AT, Wong J, Moatamed F, Sawicki MP (2003) Frequent overexpression of cyclin D1 in sporadic pancreatic endocrine tumours. J Endocrinol 179:73–79
Iizuka M, Sugiyama Y, Shiraishi M, Jones C, Sekiya T (1995) Allelic losses in human chromosome 11 in lung cancers. Genes Chromosomes Cancer 13:40–46
Johansson M, Heim S, Mandahl N, Hambraeus G, Johansson L, Mitelman F (1993) Cytogenetic analysis of six bronchial carcinoids. Cancer Genet Cytogenet 66:33–38
Klein CA, Schmidt-Kittler O, Schardt JA, Pantel K, Speicher MR, Riethmuller G (1999) Comparative genomic hybridization, loss of heterozygosity, and DNA sequence analysis of single cells. Proc Natl Acad Sci U S A 96:4494–4499
Kytola S, Hoog A, Nord B, Cedermark B, Frisk T, Larsson C, Kjellman M (2001) Comparative genomic hybridization identifies loss of 18q22-qter as an early and specific event in tumorigenesis of midgut carcinoids. Am J Pathol 158:1803–1808
Lantuejoul S, Moro D, Michalides RJ, Brambilla C, Brambilla E (1998) Neural cell adhesion molecules (NCAM) and NCAM-PSA expression in neuroendocrine lung tumors. Am J Surg Pathol 22:1267–1276
Lollgen RM, Hessman O, Szabo E, Westin G, Akerstrom G (2001) Chromosome 18 deletions are common events in classical midgut carcinoid tumors. Int J Cancer 92:812–815
Mertens F, Johansson B, Hoglund M, Mitelman F (1997) Chromosomal imbalance maps of malignant solid tumors: a cytogenetic survey of 3185 neoplasms. Cancer Res 57:2765–2780
O’Briant KC, Bepler G (1997) Delineation of the centromeric and telomeric chromosome segment 11p15.5 lung cancer suppressor regions LOH11A and LOH11B. Genes Chromosomes Cancer 18:111–114
Onuki N, Wistuba, II, Travis WD, Virmani AK, Yashima K, Brambilla E, Hasleton P, Gazdar AF (1999) Genetic changes in the spectrum of neuroendocrine lung tumors. Cancer 85:600–607
Paris PL, Albertson DG, Alers JC, Andaya A, Carroll P, Fridlyand J, Jain AN, Kamkar S, Kowbel D, Krijtenburg PJ, Pinkel D, Schroder FH, Vissers KJ, Watson VJ, Wildhagen MF, Collins C, Van Dekken H (2003) High-resolution analysis of paraffin-embedded and formalin-fixed prostate tumors using comparative genomic hybridization to genomic microarrays. Am J Pathol 162:763–770
Petersen I, Langreck H, Wolf G, Schwendel A, Psille R, Vogt P, Reichel MB, Ried T, Dietel M (1997) Small-cell lung cancer is characterized by a high incidence of deletions on chromosomes 3p, 4q, 5q, 10q, 13q and 17p. Br J Cancer 75:79–86
Petzmann S, Ullmann R, Klemen H, Renner H, Popper HH (2001) Loss of heterozygosity on chromosome arm 11q in lung carcinoids. Hum Pathol 32:333–338
Pinkel D, Segraves R, Sudar D, Clark S, Poole I, Kowbel D, Collins C, Kuo WL, Chen C, Zhai Y, Dairkee SH, Ljung BM, Gray JW, Albertson DG (1998) High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nat Genet 20:207–211
Rasio D, Negrini M, Manenti G, Dragani TA, Croce CM (1995) Loss of heterozygosity at chromosome 11q in lung adenocarcinoma: identification of three independent regions. Cancer Res 55:3988–3991
Roesler J, Srivatsan E, Moatamed F, Peters J, Livingston EH (1997) Tumor suppressor activity of neural cell adhesion molecule in colon carcinoma. Am J Surg 174:251–257
Shalon D, Smith SJ, Brown PO (1996) A DNA microarray system for analyzing complex DNA samples using two-color fluorescent probe hybridization. Genome Res 6:639–645
Snijders AM, Nowak N, Segraves R, Blackwood S, Brown N, Conroy J, Hamilton G, Hindle AK, Huey B, Kimura K, Law S, Myambo K, Palmer J, Ylstra B, Yue JP, Gray JW, Jain AN, Pinkel D, Albertson DG (2001) Assembly of microarrays for genome-wide measurement of DNA copy number. Nat Genet 29:263–264
Solinas-Toldo S, Lampel S, Stilgenbauer S, Nickolenko J, Benner A, Dohner H, Cremer T, Lichter P (1997) Matrix-based comparative genomic hybridization: biochips to screen for genomic imbalances. Genes Chromosomes Cancer 20:399–407
Speel EJ, Richter J, Moch H, Egenter C, Saremaslani P, Rutimann K, Zhao J, Barghorn A, Roth J, Heitz PU, Komminoth P (1999) Genetic differences in endocrine pancreatic tumor subtypes detected by comparative genomic hybridization. Am J Pathol 155:1787–1794
Stumpf E, Aalto Y, Hoog A, Kjellman M, Otonkoski T, Knuutila S, Andersson LC (2000) Chromosomal alterations in human pancreatic endocrine tumors. Genes Chromosomes Cancer 29:83–87
Terris B, Meddeb M, Marchio A, Danglot G, Flejou JF, Belghiti J, Ruszniewski P, Bernheim A (1998) Comparative genomic hybridization analysis of sporadic neuroendocrine tumors of the digestive system. Genes Chromosomes Cancer 22:50–56
Travis WD, Gal AA, Colby TV, Klimstra DS, Falk R, Koss MN (1998) Reproducibility of neuroendocrine lung tumor classification. Hum Pathol 29:272–279
Ullmann R, Schwendel A, Klemen H, Wolf G, Petersen I, Popper HH (1998) Unbalanced chromosomal aberrations in neuroendocrine lung tumors as detected by comparative genomic hybridization. Hum Pathol 29:1145–1149
Ullmann R, Petzmann S, Klemen H, Fraire AE, Hasleton P, Popper HH (2002) The position of pulmonary carcinoids within the spectrum of neuroendocrine tumors of the lung and other tissues. Genes Chromosomes Cancer 34:78–85
Veltman JA, Schoenmakers EF, Eussen BH, Janssen I, Merkx G, van Cleef B, van Ravenswaaij CM, Brunner HG, Smeets D, van Kessel AG (2002) High-throughput analysis of subtelomeric chromosome rearrangements by use of array-based comparative genomic hybridization. Am J Hum Genet 70:1269–1276
Walch AK, Zitzelsberger HF, Aubele MM, Mattis AE, Bauchinger M, Candidus S, Prauer HW, Werner M, Hofler H (1998) Typical and atypical carcinoid tumors of the lung are characterized by 11q deletions as detected by comparative genomic hybridization. Am J Pathol 153:1089–1098
Wang SS, Virmani A, Gazdar AF, Minna JD, Evans GA (1999) Refined mapping of two regions of loss of heterozygosity on chromosome band 11q23 in lung cancer. Genes Chromosomes Cancer 25:154–159
Wessendorf S, Fritz B, Wrobel G, Nessling M, Lampel S, Goettel D, Kuepper M, Joos S, Hopman T, Kokocinski F, Dohner H, Bentz M, Schwaenen C, Lichter P (2002) Automated screening for genomic imbalances using matrix-based comparative genomic hybridization. Lab Invest 82:47–60
Whang-Peng J, Knutsen T, Gazdar A, Steinberg SM, Oie H, Linnoila I, Mulshine J, Nau M, Minna JD (1991) Nonrandom structural and numerical chromosome changes in non-small-cell lung cancer. Genes Chromosomes Cancer 3:168–188
World Health Organization (1999) World Health Organization: histological typing of lung and pleural tumors, 3rd edn. Springer, Berlin Heidelberg New York
World Health Organization (2000) World Health Organization: histological typing of endocrine tumors, 2nd edn. Springer, Berlin Heidelberg New York
Zhao J, de Krijger RR, Meier D, Speel EJ, Saremaslani P, Muletta-Feurer S, Matter C, Roth J, Heitz PU, Komminoth P (2000) Genomic alterations in well-differentiated gastrointestinal and bronchial neuroendocrine tumors (carcinoids): marked differences indicating diversity in molecular pathogenesis. Am J Pathol 157:1431–1438
Acknowledgments
We thank Dr. Mariano Rocchi, Resources for Molecular Cytogenetics, for providing us with BAC/PAC clones of chromosome 11. We would like to thank the Mapping Core and Map Finishing groups of the Wellcome Trust Sanger Institute for initial clone supply and verification. We thank Margit Gogg-Kammerer for her technical assistance. This work was supported by the Austrian National Bank Jubilee Fund, Project 8454 and the Austrian Research Fund, Project P14759.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Petzmann, S., Ullmann, R., Halbwedl, I. et al. Analysis of chromosome-11 aberrations in pulmonary and gastrointestinal carcinoids: an array comparative genomic hybridization-based study. Virchows Arch 445, 151–159 (2004). https://doi.org/10.1007/s00428-004-1052-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00428-004-1052-y