Objectives: This study investigates the clinical significance of the gene encoding AP-2ε (TFAP2E) in colorectal cancer (CRC) patients undergoing curative resection. Methods: A single-institution cohort of 248 patients who underwent curative resection of stage I/II/III CRCs between March and December 2004 was enrolled, and 193 patients whose tumors were available for the determination of the TFAP2E methylation status were included in the analysis. Results: TFAP2E hypermethylation was detected in 112 patients (58%) and was significantly associated with distally located CRCs, low pathologic T stage (T1/T2), and stage I tumors. After a median follow-up of 86.3 months, the patients with TFAP2E hypermethylation tended to show better relapse-free survival (RFS) and overall survival (OS) than the patients with TFAP2E hypomethylation (5-year RFS rate: 90 vs. 80%, p = 0.063; 6-year OS rate: 88 vs. 80%, p = 0.083). Multivariate analysis showed that the pathologic nodal stage and TFAP2E methylation status were independent prognostic factors for RFS and OS, and they remained significant factors in the subgroup analysis that included 154 patients with stage II/III CRCs who had received adjuvant chemotherapy. Conclusions: TFAP2E hypermethylation is associated with good clinical outcomes and may be considered as an independent prognostic factor in patients with curatively resected CRCs. © 2014 S. Karger AG, Basel

1.
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893-2917.
2.
Ferrari P, Jenab M, Norat T, Moskal A, Slimani N, Olsen A, Tjonneland A, Overvad K, Jensen MK, Boutron-Ruault MC, Clavel-Chapelon F, Morois S, Rohrmann S, Linseisen J, Boeing H, Bergmann M, Kontopoulou D, Trichopoulou A, Kassapa C, Masala G, Krogh V, Vineis P, Panico S, Tumino R, van Gils CH, Peeters P, Bueno-de-Mesquita HB, Ocke MC, Skeie G, Lund E, Agudo A, Ardanaz E, Lopez DC, Sanchez MJ, Quiros JR, Amiano P, Berglund G, Manjer J, Palmqvist R, Van Guelpen B, Allen N, Key T, Bingham S, Mazuir M, Boffetta P, Kaaks R, Riboli E: Lifetime and baseline alcohol intake and risk of colon and rectal cancers in the European prospective investigation into cancer and nutrition (EPIC). Int J Cancer 2007;121:2065-2072.
3.
Goel A, Boland CR: Recent insights into the pathogenesis of colorectal cancer. Curr Opin Gastroenterol 2010;26:47-52.
4.
Theodoratou E, Montazeri Z, Hawken S, Allum GC, Gong J, Tait V, Kirac I, Tazari M, Farrington SM, Demarsh A, Zgaga L, Landry D, Benson HE, Read SH, Rudan I, Tenesa A, Dunlop MG, Campbell H, Little J: Systematic meta-analyses and field synopsis of genetic association studies in colorectal cancer. J Natl Cancer Inst 2012;104:1433-1457.
5.
Baehner FL, Lee M, Demeure MJ, Bussey KJ, Kiefer JA, Barrett MT: Genomic signatures of cancer: basis for individualized risk assessment, selective staging and therapy. J Surg Oncol 2011;103:563-573.
6.
Williams T, Tjian R: Characterization of a dimerization motif in AP-2 and its function in heterologous DNA-binding proteins. Science 1991;251:1067-1071.
7.
Eckert D, Buhl S, Weber S, Jäger R, Schorle H: The AP-2 family of transcription factors. Genome Biol 2005;6:246.
8.
Pellikainen JM, Kosma VM: Activator protein-2 in carcinogenesis with a special reference to breast cancer - a mini review. Int J Cancer 2007;120:2061-2067.
9.
Anttila MA, Kellokoski JK, Moisio KI, Mitchell PJ, Saarikoski S, Syrjanen K, Kosma VM: Expression of transcription factor AP-2alpha predicts survival in epithelial ovarian cancer. Br J Cancer 2000;82:1974-1983.
10.
Heimberger AB, McGary EC, Suki D, Ruiz M, Wang H, Fuller GN, Bar-Eli M: Loss of the AP-2alpha transcription factor is associated with the grade of human gliomas. Clin Cancer Res 2005;11:267-272.
11.
Karjalainen JM, Kellokoski JK, Eskelinen MJ, Alhava EM, Kosma VM: Downregulation of transcription factor AP-2 predicts poor survival in stage I cutaneous malignant melanoma. J Clin Oncol 1998;16:3584-3591.
12.
Hoei-Hansen CE, Nielsen JE, Almstrup K, Sonne SB, Graem N, Skakkebaek NE, Leffers H, Rajpert-De Meyts E: Transcription factor AP-2gamma is a developmentally regulated marker of testicular carcinoma in situ and germ cell tumors. Clin Cancer Res 2004;10:8521-8530.
13.
Pauls K, Jager R, Weber S, Wardelmann E, Koch A, Buttner R, Schorle H: Transcription factor AP-2gamma, a novel marker of gonocytes and seminomatous germ cell tumors. Int J Cancer 2005;115:470-477.
14.
Kulak MV, Cyr AR, Woodfield GW, Bogachek M, Spanheimer PM, Li T, Price DH, Domann FE, Weigel RJ: Transcriptional regulation of the GPX1 gene by TFAP2C and aberrant CPG methylation in human breast cancer. Oncogene 2013;32:4043-4051.
15.
Pellikainen J, Naukkarinen A, Ropponen K, Rummukainen J, Kataja V, Kellokoski J, Eskelinen M, Kosma VM: Expression of HER2 and its association with AP-2 in breast cancer. Eur J Cancer 2004;40:1485-1495.
16.
Woodfield GW, Horan AD, Chen Y, Weigel RJ: TFAP2C controls hormone response in breast cancer cells through multiple pathways of estrogen signaling. Cancer Res 2007;67:8439-8443.
17.
Ropponen KM, Kellokoski JK, Lipponen PK, Pietilainen T, Eskelinen MJ, Alhava EM, Kosma VM: p22/WAF1 expression in human colorectal carcinoma: association with p53, transcription factor AP-2 and prognosis. Br J Cancer 1999;81:133-140.
18.
Ropponen KM, Kellokoski JK, Pirinen RT, Moisio KI, Eskelinen MJ, Alhava EM, Kosma VM: Expression of transcription factor AP-2 in colorectal adenomas and adenocarcinomas; comparison of immunohistochemistry and in situ hybridisation. J Clin Pathol 2001;54:533-538.
19.
Dracopoli NC, Bruns GA, Brodeur GM, Landes GM, Matise TC, Seldin MF, Vance JM, Weith A: Report and abstracts of the First International Workshop on Human Chromosome 1 Mapping 1994. Bethesda, Maryland, March 25-27, 1994. Cytogenet Cell Genet 1994;67:144-165.
20.
Di Vinci A, Infusini E, Peveri C, Risio M, Rossini FP, Giaretti W: Deletions at chromosome 1p by fluorescence in situ hybridization are an early event in human colorectal tumorigenesis. Gastroenterology 1996;111:102-107.
21.
Chung W, Kwabi-Addo B, Ittmann M, Jelinek J, Shen L, Yu Y, Issa JP: Identification of novel tumor markers in prostate, colon and breast cancer by unbiased methylation profiling. PLoS One 2008;3:e2079.
22.
Ebert MP, Tänzer M, Balluff B, Burgermeister E, Kretzschmar AK, Hughes DJ, Tetzner R, Lofton-Day C, Rosenberg R, Reinacher-Schick AC, Schulmann K, Tannapfel A, Hofheinz R, Röcken C, Keller G, Langer R, Specht K, Porschen R, Stöhlmacher-Williams J, Schuster T, Ströbel P, Schmid RM: TFAP2E-DKK4 and chemoresistance in colorectal cancer. N Engl J Med 2012;366:44-53.
23.
Yang B, Du Z, Gao YT, Lou C, Zhang SG, Bai T, Wang YJ, Song WQ: Methylation of Dickkopf-3 as a prognostic factor in cirrhosis-related hepatocellular carcinoma. World J Gastroenterol 2010;16:755-763.
24.
Eads CA, Lord RV, Wickramasinghe K, Long TI, Kurumboor SK, Bernstein L, Peters JH, DeMeester SR, DeMeester TR, Skinner KA, Laird PW: Epigenetic patterns in the progression of esophageal adenocarcinoma. Cancer Res 2001;61:3410-3418.
25.
Schmittgen TD, Livak KJ: Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 2008;3:1101-1108.
26.
Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN, Srivastava S: A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 1998;58:5248-5257.
27.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-247.
28.
Bardi G, Pandis N, Fenger C, Kronborg O, Bomme L, Heim S: Deletion of 1p36 as a primary chromosomal aberration in intestinal tumorigenesis. Cancer Res 1993;53:1895-1898.
29.
Bomme L, Bardi G, Pandis N, Fenger C, Kronborg O, Heim S: Clonal karyotypic abnormalities in colorectal adenomas: clues to the early genetic events in the adenoma-carcinoma sequence. Genes Chromosomes Cancer 1994;10:190-196.
30.
Giaretti W, Molinu S, Ceccarelli J, Prevosto C: Chromosomal instability, aneuploidy, and gene mutations in human sporadic colorectal adenomas. Cell Oncol 2004;26:301-305.
31.
Andre T, Quinaux E, Louvet C, Colin P, Gamelin E, Bouche O, Achille E, Piedbois P, Tubiana-Mathieu N, Boutan-Laroze A, Flesch M, Lledo G, Raoul Y, Debrix I, Buyse M, de Gramont A: Phase III study comparing a semimonthly with a monthly regimen of fluorouracil and leucovorin as adjuvant treatment for stage II and III colon cancer patients: final results of GERCOR C96.1. J Clin Oncol 2007;25:3732-3738.
32.
Twelves C, Wong A, Nowacki MP, Abt M, Burris H 3rd, Carrato A, Cassidy J, Cervantes A, Fagerberg J, Georgoulias V, Husseini F, Jodrell D, Koralewski P, Kroning H, Maroun J, Marschner N, McKendrick J, Pawlicki M, Rosso R, Schuller J, Seitz JF, Stabuc B, Tujakowski J, Van Hazel G, Zaluski J, Scheithauer W: Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 2005;352:2696-2704.
33.
Lembersky BC, Wieand HS, Petrelli NJ, O'Connell MJ, Colangelo LH, Smith RE, Seay TE, Giguere JK, Marshall ME, Jacobs AD, Colman LK, Soran A, Yothers G, Wolmark N: Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06. J Clin Oncol 2006;24:2059-2064.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.