Abstract
Background
Standard clinical and immunohistochemical methods cannot reliably determine whether a small intestinal carcinoid (SIC) is indolent or aggressive. We hypothesized that carcinoid malignancy could be defined by using quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) and immunohistochemical approaches that evaluate potential marker genes.
Methods
Candidate marker gene expression (nucleosome assembly protein 1–like 1 [NAP1L1], melanoma antigen D2 [MAGE-D2], and metastasis-associated protein 1 [MTA1]) identified by Affymetrix transcriptional profiling was examined by QRT-PCR in SIC, liver, and lymph node (LN) metastases, colorectal carcinomas, and healthy tissues. Immunohistochemical expression levels of MTA1 were analyzed quantitatively by a novel automated quantitative analysis in a tissue microarray of 102 gastrointestinal carcinoids and in a breast/prostate carcinoma array.
Results
Affymetrix transcriptional profiling identified three potentially useful malignancy-marker genes (out of 1709 significantly altered genes). By QRT-PCR, NAP1L1 was significantly (P < .03) overexpressed in SIC compared with colorectal carcinomas and healthy tissue. Increased levels (P < .05) were identified in both liver and LN metastases. Levels in colorectal carcinomas were the same as in healthy mucosa. MAGE-D2 and MTA1 were increased (P < .05) in primary tumors and metastases and overexpressed in carcinomas. Automated quantitative analysis demonstrated the highest levels of MTA1 immunostaining in malignant primary SICs and in metastases to the liver and LN. These were significantly increased (P < .02) compared with nonmetastatic primary tumors. MTA1 was overexpressed in breast and prostate carcinomas (P < .05).
Conclusions
SICs overexpress the neoplasia-related genes NAP1L1 (mitotic regulation), MAGE-D2 (adhesion), and MTA1 (estrogen antagonism). The ability to determine the malignant potential of these tumors and their propensity to metastasize provides a biological rationale for the management of carcinoids and may have prognostic utility.
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References
Modlin I, Lye K, Kidd M. A five-decade analysis of 13,715 carcinoid tumors. Cancer 2003;97:934–59
Gabos S, Berkel J, Robson D, et al. Small bowel cancer in Western Canada. Int J Epidemiol 1993;22:198–206
Burke AP, Thomas RM, Elsayed AM, et al. Carcinoids of the jejunum and ileum: an immunohistochemical and clinicopathologic study of 167 cases. Cancer 1997;79:1086–93
DiSario JA, Burt RW, Vargas H, et al. Small bowel cancer: epidemiological and clinical characteristics from a population-based registry. Am J Gastroenterol 1994;89:699–701
Schnirer II, Yao JC, Ajani JA. Carcinoid—a comprehensive review. Acta Oncol 2003;42:672–92
Godwin JD. Carcinoid tumors: an analysis of 2837 cases. Cancer 1975;36:560–9
Strodel WE, Talpos G, Eckhauser F, et al. Surgical therapy for small-bowel carcinoid tumors. Arch Surg 1983;118:391–7
Modlin IM, Lye K, Kidd M. A 50-year analysis of 562 gastric carcinoids: small tumor or larger problem? Am J Gastroenterol 2004;99:23–32
Okamoto Y, Fujii M, Tateiwa S, et al. Treatment of multiple rectal carcinoids by endoscopic mucosal resection using a device for esophageal variceal ligation. Endoscopy 2004;36:469–70
Johnson LA, Lavin P, Moertel CG, et al. Carcinoids: the association of histologic growth pattern and survival. Cancer 1983;51:882–9
Wallace S, Ajani JA, Charnsangavej C, et al. Carcinoid tumors: imaging procedures and interventional radiology. World J Surg 1996;20:147–56
Tomassetti P, Migliori M, Lalli S, et al. Epidemiology, clinical features and diagnosis of gastroenteropancreatic endocrine tumours. Ann Oncol 2001;12(Suppl 2):S95–9
Modlin IM, Tang LH. Approaches to the diagnosis of gut neuroendocrine tumors: the last word (today). Gastroenterology 1997;112:583–90
Lauffer JM, Zhang T, Modlin IM. Review article: current status of gastrointestinal carcinoids. Aliment Pharmacol Ther 1999;13:271–87
Moertel CG, Dockerty MB, Judd ES. Carcinoid tumors of the vermiform appendix. Cancer 1968;21:270–8
Koura AN, Giacco GG, Curley SA, et al. Carcinoid tumors of the rectum: effect of size, histopathology, and surgical treatment on metastasis free survival. Cancer 1997;79:1294–8
Connor SJ, Hanna GB, Frizelle FA. Appendiceal tumors: retrospective clinicopathologic analysis of appendiceal tumors from 7,970 appendectomies. Dis Colon Rectum 1998;41:75–80
Canavese G, Azzoni C, Pizzi S, et al. p27: a potential main inhibitor of cell proliferation in digestive endocrine tumors but not a marker of benign behavior. Hum Pathol 2001;32:1094–101
Kloppel G, Perren A, Heitz PU. The gastroenteropancreatic neuroendocrine cell system and its tumors. Ann N Y Acad Sci 2004;1014:13–27
Al-Khafaji B, Noffsinger AE, Miller MA, et al. Immunohistologic analysis of gastrointestinal and pulmonary carcinoid tumors. Hum Pathol 1998;29:992–9
Moyana TN, Xiang J, Senthilselvan A, et al. The spectrum of neuroendocrine differentiation among gastrointestinal carcinoids: importance of histologic grading, MIB-1, p53, and bcl-2 immunoreactivity. Arch Pathol Lab Med 2000;124:570–6
Van Eeden S, Quaedvlieg PF, Taal BG, et al. Classification of low-grade neuroendocrine tumors of midgut and unknown origin. Hum Pathol 2002;33:1126–32
Notterman DA, Alon U, Sierk AJ, et al. Transcriptional gene expression profiles of colorectal adenoma, adenocarcinoma, and normal tissue examined by oligonucleotide arrays. Cancer Res 2001;61:3124–30
Bilchik AJ, Nora DT, Saha S, et al. The use of molecular profiling of early colorectal cancer to predict micrometastases. Arch Surg 2002;137:1377–83
Nagata T, Takahashi Y, Ishii Y, et al. Transcriptional profiling in hepatoblastomas using high-density oligonucleotide DNA array. Cancer Genet Cytogenet 2003;145:152–60
Li M, Lin YM, Hasegawa S, et al. Genes associated with liver metastasis of colon cancer, identified by genome-wide cDNA microarray. Int J Oncol 2004;24:305–12
Toh Y, Oki E, Oda S, et al. Overexpression of the MTA1 gene in gastrointestinal carcinomas: correlation with invasion and metastasis. Int J Cancer 1997;74:459–63
Moon WS, Chang K, Tarnawski AS. Overexpression of metastatic tumor antigen 1 in hepatocellular carcinoma: relationship to vascular invasion and estrogen receptor-alpha. Hum Pathol 2004;35:424–9
Toh Y, Ohga T, Endo K, et al. Expression of the metastasis-associated MTA1 protein and its relationship to deacetylation of the histone H4 in esophageal squamous cell carcinomas. Int J Cancer 2004;110:362–7
Toh Y, Pencil SD, Nicolson GL. Analysis of the complete sequence of the novel metastasis-associated candidate gene, mta1, differentially expressed in mammary adenocarcinoma and breast cancer cell lines. Gene 1995;159:97–104
Toh Y, Pencil SD, Nicolson GL. A novel candidate metastasis-associated gene, mta1, differentially expressed in highly metastatic mammary adenocarcinoma cell lines. cDNA cloning, expression, and protein analyses. J Biol Chem 1994;269:22958–63
Hofer MD, Kuefer R, Varambally S, et al. The role of metastasis-associated protein 1 in prostate cancer progression. Cancer Res 2004;64:825–9
Kidd M, Eick G, Shapiro MD, et al. Microsatellite instability and gene mutations in TGF?RII are absent in small bowel carcinoid tumors. Cancer 2005;103:229–36
Li C, Wong WH. Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. Proc Natl Acad Sci U S A 2001;98:31–6
Li C, Wong WH. Model-based analysis of oligonucleotide arrays: model validation, design issues and standard error application. Genome Biol 2001;2:0032.1–0032.11.
Camp R, Dolled-Filhart M, King B, et al. Quantitative analysis of breast cancer tissue microarrays shows that both high and normal levels of Her2 expression are associated with poor outcome. Cancer Res 2003;63:1445–8
Camp R, Chung G, Rimm D. Automated subcellular localization and quantification of protein expression in tissue microarrays. Nat Med 2002;8:1323–8
Ohkuni K, Shirahige K, Kikuchi A. Genome-wide expression analysis of NAP1 in Saccharomyces cerevisiae. Biochem Biophys Res Commun 2003;306:5–9
Mortensen EM, McDonald H, Yates J III, et al. Cell cycle-dependent assembly of a Gin4-septin complex. Mol Biol Cell 2002;13:2091–105
Simon HU, Mills GB, Kozlowski M, et al. Molecular characterization of hNRP, a cDNA encoding a human nucleosome-assembly-protein-I-related gene product involved in the induction of cell proliferation. Biochem J 1994;297(Pt 2):389–97
Nagata T, Takahashi Y, Ishii Y, et al. Profiling of genes differentially expressed between fetal liver and postnatal liver using high-density oligonucleotide DNA array. Int J Mol Med 2003;11:713-21
Line A, Slucka Z, Stengrevics A, et al. Characterisation of tumour-associated antigens in colon cancer. Cancer Immunol Immunother 2002;51:574–82
Lucas S, Brasseur F, Boon T. A new MAGE gene with ubiquitous expression does not code for known MAGE antigens recognized by T cells. Cancer Res 1999;59:4100–3
Chomez P, De Backer O, Bertrand M, De Plaen E, Boon T, Lucas S. An overview of the MAGE gene family with the identification of all human members of the family. Cancer Res 2001;61:5544–51
Li M, Lin YM, Hasegawa S, et al. Genes associated with liver metastasis of colon cancer, identified by genome-wide cDNA microarray. Int J Oncol 2004;24:305–12
Langnaese K, Kloos DU, Wehnert M, et al. Expression pattern and further characterization of human MAGED2 and identification of rodent orthologues. Cytogenet Cell Genet 2001;94:233–40
Toh Y, Oki E, Oda S, et al. Overexpression of the MTA1 gene in gastrointestinal carcinomas: correlation with invasion and metastasis. Int J Cancer 1997;74:459–63
Xue Y, Wong J, Moreno GT, et al. NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities. Mol Cell 1998;2:851–61
Mazumdar A, Wang RA, Mishra SK, et al. Transcriptional repression of oestrogen receptor by metastasis-associated protein 1 corepressor. Nat Cell Biol 2001;3:30–7
Jensen EV, Cheng G, Palmieri C, et al. Estrogen receptors and proliferation markers in primary and recurrent breast cancer. Proc Natl Acad Sci U S A 2001;98:15197–202.
Paterno GD, Li Y, Luchman HA, et al. cDNA cloning of a novel, developmentally regulated immediate early gene activated by fibroblast growth factor and encoding a nuclear protein. J Biol Chem 1997;272:25591–5
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Supported by National Institutes of Health grant R01-CA-097050 (I.M.M.) and the Bruggeman Medical Foundation.
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Kidd, M., Modlin, I.M., Mane, S.M. et al. The Role of Genetic Markers— NAP1L1, MAGE-D2, and MTA1—in Defining Small-Intestinal Carcinoid Neoplasia. Ann Surg Oncol 13, 253–262 (2006). https://doi.org/10.1245/ASO.2006.12.011
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DOI: https://doi.org/10.1245/ASO.2006.12.011