Objectives: To clarify the role of the KLF6 (Kruppel-like factor 6) locus in multistep colorectal carcinogenesis, we analyzed loss of heterozygosity (LOH) at 10p15 (KLF6 locus) and mutations of the KLF6gene in 298 colorectal tumors at various pathological stages of sporadic and familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC) patients. Methods: 10p15 LOH was analyzed using KLF6M1 and KLF6M2, and KLF6 gene mutation was analyzed using PCR-SSCP and sequencing. Results: It was found that the frequencies of LOH (sum of M1 and M2) were 4% in adenomas, 0% in intramucosal carcinomas, 35% in invasive carcinomas, and 33% in liver metastases in sporadic cases. Invasive carcinomas from FAP patients showed only 6% LOH, and invasive carcinomas from HNPCC patients exhibited 0% LOH. Mutation analysis of the KLF6 gene in 298 colorectal tumors detected no somatic mutations. Conclusions: The present data suggest that LOH of the KLF6 locus at chromosome 10p15 contributes to the invasion step from an intramucosal carcinoma to an invasive carcinoma specifically in sporadic colorectal carcinogenesis, but is rarely involved in the carcinogenesis of FAP and HNPCC cases. Moreover, the absence of somatic mutations suggests the uncertainty of the KLF6 gene as a classical tumor suppressor gene at the lost 10p15 region in colorectal carcinogenesis.

Keywords:
10p15 loss of heterozygosity, KLF6 mutation, Colorectal tumor, Sporadic adenomatous polyposis, Familial adenomatous polyposis, Hereditary nonpolyposis colorectal cancer
1.
Fearon ER, Vogelstein BA: Genetic model for colorectal tumorigenesis. Cell 1990;61:759–767.
2.
Miyaki M, Tanaka K, Kikuchi-Yanoshita R, Muraoka M, Konishi M: Familial polyposis: recent advances. Crit Rev Oncol Hematol 1995;19:1–31.
3.
Aaltonen LA, Peltomäki P, Leach FS, Sistonen P, Pykkänen L, Mecklin J-P, Järvinen H, Powell SM, Jen J, Hamilton SR, Petersen GM, Kinzler KW, Vogelstein B, de la Chapelle A: Clue to the pathogenesis of familial colorectal cancer. Science 1993;260:812–816.
4.
Reeves HL, Narla G, Ogunbiyi O, Haq AI, Katz A, Benzeno S, Hod E, Harpaz N, Goldberg S, Tal-Kremer S, Eng FJ, Arthur MJP, Martigenetti JA, Friedman SL: Kruppel-like factor 6 (KLF6) is a tumor-suppressor gene frequently inactivated in colorectal cancer. Gastroenterology 2004;126:1090–1103.
5.
Narla G, Heath KE, Reeves HL, Li D, Giono LE, Kimmelman AC, Glucksman MJ, Narla J, Eng FJ, Chan AM, Ferrari AC, Martignetti JA, Friedman SL: KLF6, a candidate tumor suppressor gene mutated in prostate cancer. Science 2001;294:2563–2566.
6.
Cho YG, Kim CJ, Park CH, Yang YM, Kim SY, Nam SW, Lee SH, Yoo NJ, Lee JY, Park WS: Genetic alterations of the KLF6 gene in gastric cancer. Oncogene 2005;24:4588–4590.
7.
Kremer-Tal S, Reeves HL, Narla G, Thung SN, Schwartz M, Difeo A, Katz A, Bruix J, Bioulac-Sage P, Martignetti JA, Friedman SL: Frequent inactivation of the tumor suppressor Kruppel-like factor 6 (KLF6) in hepatocellular carcinoma. Hepatology 2004;40:1047–1052.
8.
Jeng YM, Hsu H-C: KLF6, a putative tumor suppressor gene, is mutated in astrocytic gliomas. Int J Cancer 2003;105:625–629.
9.
Benzeno S, Narla G, Allina J, Ceng GZ, Reeves HL, Banck MS, Odin JA, Diehl JA, Germain D, Friedman SL: Cyclin-dependent kinase inhibition by the KLF6 tumor suppressor protein through interaction with Cyclin D1. Cancer Res 2004;64:3885–3891.
10.
Lievre A, Landi B, Cote J-F, Veyrie N, Zucman-Rossi J, Berger A, Laurent-Puig P: Absence of mutation in the putative tumor-suppressor gene KLF6 in colorectal cancers. Oncogene 2005;24:7253–7256.
11.
Kikuchi-Yanoshita R, Konishi M, Ito S, Seki M, Tanaka K, Maeda Y, Iino H, Fukayama M, Koike M, Mori T, Sakuraba H, Fukunari H, Iwama T, Miyaki M: Genetic changes of both p53 alleles associated with the conversion from colorectal adenoma to early carcinoma in familial adenomatous polyposis and non-familial adenomatous polyposis patients. Cancer Res 1992;52:3965–3971.
12.
Miyaki M, Konishi M, Kikuchi-Yanoshita R, Enomoto M, Igari T, Tanaka K, Muraoka M, Takahashi H, Amada Y, Fukayama M, Meda Y, Iwama T, Mishima Y, Mori T, Koike M: Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors. Cancer Res 1994;54:3011–3020.
13.
Miyaki M, Iijima T, Yasuno M, Kita Y, Hishima T, Kuroki T, Mori T: High incidence of protein-truncating mutations of the p53 gene in liver metastases of colorectal carcinomas. Oncogene 2002;21:6689–6693.
14.
Miyaki M, Iijima T, Kimura J, Yasuno M, Mori T, Hayashi Y, Koike M, Shitara N, Iwama T, Kuroki T: Frequent mutation of β-catenin and APC genes in primary colorectal tumors from patients with hereditary nonpolyposis colorectal cancer. Cancer Res 1999;59:4506–4509.
15.
Boyault S, Herault A, Balabaud C, Zucman-Rossi J: Absence of KLF6 gene mutations in 71 hepatocellular carcinomas. Hepatology 2005;41:681–682.
16.
Williams C, Ponten F, Moberg C, Söderkvist P, Uhlen M, Ponten J, Sibon G, Lundeberg J: A high frequency of sequence alterations is due to formalin fixation of archival specimens. Am J Pathol 1999;155:1467–1471.
17.
Soengas MS, Capodieci P, Polsky D, Mora J, Esteller M, Opitz-Araya X, McCombie R, Herman JG, Gerald WL, Lazebnik YA, Cordon-Cardo C, Lowe SW: Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature 2001;409:207–211.
18.
Kimmelman AC, Qiao RF, Narla G, Banno A, Lau N, Bos PD, Rodriguez NN, Liang B, Guha A, Martignetti JA, Friedman SL, Chan AM: Suppression of glioblastoma tumorigenicity by the Kruppel-like transcription factor KLF6. Oncogene 2004;23:5077–5083.
19.
Li D, Yea S, Dolios G, Martignetti JA, Narla G, Wang R, Walsh MJ, Friedman SL: Regulation of Krüppel-like factor 6 tumor suppressor activity by acetylation. Cancer Res 2005;65:9216–9225.
© 2006 S. Karger AG, Basel
2007
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.