Die Rolle epigenetischer Veränderungen in kolorektalen Karzinomen und ihren Vorläuferläsionen

Zusammenfassung

Das kolorektale Karzinom stellt den dritthäufigsten malignen Tumor weltweit dar mit einer Inzidenz von 570 000 pro Jahr. Anhand der molekularen Veränderungen können (sporadische) kolorektale Karzinome in zwei unterschiedliche Phänotypen unterteilt werden. Der genetische Phänotyp, der ca. 50 – 70 % aller sporadischen kolorektalen Karzinome ausmacht, ist charakterisiert durch eine chromosomale Instabiliät (CIN) mit der klassischen Adenom-Karzinom-Sequenz, hervorgerufen durch Alterationen im APC-βCatenin-Weg mit p53-Mutationen, SMAD-Genveränderungen und LOH (loss of heterozygosity) auf 5q, 17 p 18q. Demgegenüber steht der CpG Island-Methylatorphänotyp (CIMP + ), der eine epigenetische Inaktivierung von Tumorsuppressorgenen aufweist, die bei familiären Karzinomsyndromen typischerweise Keimbahnmutationen aufweisen wie z. B. Rb, VHL, hMLH1, p16 oder BRCA. Häufig gehen kolorektale Karzinome vom CIMP + -Typ mit einer Mikrosatelliteninstabilität (MSI + ) einher infolge einer Promotormethylierung des Mismatch-Repair-Gens hMLH1. Weiterhin sind sie vermehrt im proximalen rechtsseitigen Kolon lokalisiert und nicht selten High-Grade-Karzinome mit muzinöser oder siegelringzelliger Differenzierung.

Abstract

Colorectal carcinomas are the third most common malignant tumours worldwide with an incidence of 570,000 per year. According to their molecular mechanisms, sporadic colorectal carcinomas can be divided into two different phenotypes. The genetic phenotype, 50 to 70 % of all sporadic colorectal carcinomas, is characterised by a chromosomal instability (CIN) with the classical adenoma-carcinoma sequence due to alteration of the APC-βcatenin pathway with p53 mutations, SMAD alterations and LOH (loss of heterozygositiy) of 5q, 17 p 18q. On the other, the CpG island methylator phenotype (CIMP + ) was described with an epigenetic inactivation of tumour suppressor genes that are typically inactivated by germline mutations in familiar cancer syndromes, e. g., Rb, VHL, hMLH1, p16 or BRCA. Colorectal carcinomas of the CIMP + type often show a high microsatellite instability (MSI + ) caused by aberrant promoter methylation of the missmatch repair gene hMLH1. Further CIMP + are located in the proximal right-side colon and show a poor grading with mucinous or signet-cell differentiation.

Schlüsselwörter

Kolorektales Karzinom - Adenom - Promotormethylierung - CIN - CIMP

Key words

colorectal carcinoma - adenoma - promotor methylation - CIN - CIMP

Literatur

• 1 Aaltonen L A, Peltomaki P, Leach F S. et al . Clues to the pathogenesis of familial colorectal cancer.  Science. 1993;  260 812-816
• 2 Bai A HC, Tong J HM, To K F. et al . Promoter methylation of tumor-related genes in the progression of colorectal neoplasia.  Int J Cancer. 2004;  112 846-853
• 3 Baylin S B, Esteller M, Rountree M R. et al . Aberrant pattern of DNA methylation, chromatin formation and gene expression in cancer.  Hum Mol Genet. 2001;  10 687-692
• 4 Bird A, Wolffe A P. Methylation-induced repression- belts, braces and chromation.  Cell. 1999;  99 451-454
• 5 Dong S M, Lee E J, Park C K. et al . Progressive methylation during the serrated neoplasia pathway of the colorectum.  Mod Pathol. 2005;  18 170-178
• 6 Ehrlich M. DNA hypomethylation and cancer. Natick DNA Alteratins in Cancer: Genetic and Epigenetic Changes Natick; Eaton Publishing 2000: 273-291
• 7 Engeland van M, Roemen G MJM, Brink M. et al . K-ras and RASSF1A promoter methylation in colorectal cancer.  Oncogene. 2002;  21 3792-3795
• 8 Esteller M, Tortola S, Toyota M. et al . Hypermethylation-associated inactivation of p14ARF is independent pf p16INK4a methylation and mutational status.  Cancer Res. 2000;  60 129-133
• 9 Esteller M, Hamilton S R, Buger P C. et al . Inactivation of the DNA repair gene O 6-methylguanine-DNA methyltransferase by promoter methylation is a common event in primary human neoplasia.  Cancer Res. 1999;  59 793-797
• 10 Esteller M, Toyota M, Sanchez-Cespedes M. et al . Inactivation of the DNA repair gene O 6-methylguanine-DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis.  Cancer Res. 2000;  60 2368-2371
• 11 Esteller M, Risques R A, Toyota M. et al . Promoter hypermethylation of the DNA repair O 6-methylguanine-DNA methyltransferase is associated with the presence of G:C to A:T transition mutations in p53 in human colorectal tumorigenesis.  Cancer Res. 2001;  61 4689-4692
• 12 Fodde R, Kuipers J, Rosenberg C. et al . Mutations in the APC tumour suppressor gene cause chromosomal instability.  Nat Cell Biol. 2001;  3 433-438
• 13 Hall M, Peters G. Genetic alterations of cyclins, cyclin-dependent kinases and Cdk inhibitors in human cancer.  Adv Cancer Res. 1996;  68 67-108
• 14 Hendrich B, Bird A. Mammalian methyltransferases and methyl CpG-binding domains: proteins involved in DNA methylation.  Curr Top Microbiol Immunol. 2000;  249 55-74
• 15 Hibi K, Nakayama H, Koike M. et al . Colorectal cancers with both p16 and p14 methylation show invasive characteristics.  Jpn J Cancer Res. 2002;  93 883-887
• 16 Jass J R. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features.  Histopathology. 2007;  50 113-130
• 17 Karpf A R, Jones D A. Reactivating the expression of methylation silenced genes in human cancers.  Oncogene. 2002;  35 5496-5503
• 18 Kim H C, Roh S A, GA I H. et al . CpG island methylation as an early event during adenoma progression in carcinogenesis of sporadic colorectal cancer.  J Gastroenterol Hepatol. 2005;  20 1920-1926
• 19 Lee S, Hwang K S, Lee H J. et al . Aberrant CpG island hypermethylation of multiple genes in colorectal colorectal neoplasia.  Lab Invest. 2004;  84 884-893
• 20 Liggett W H, Sidransky Jr D. Role of the p16 tumor suppressor gene in cancer.  J Clin Oncol. 1998;  16 1197-1206
• 21 Lind G E, Thorstensen L, Lovig T. et al . A CpG island hypermethylation profile of primary colorectal carcinomas and colon cancer cell lines.  Mol Cancer. 2004;  3 28
• 22 Mäkinen M J. Colorectal serrated adenocarcinoma.  Histopathology. 2007;  50 131-150
• 23 Raveh T, Kimchi A. DAP kinase – a proapoptotic gene that functions as a tumor suppressor.  Exp Cell Res. 2001;  264 185-192
• 24 Shivakumar L, Minna J D, Sakamaki T. et al . The RASSF1A tumor suppressor blocks cell cycle progression and inhibits cyclin D 1 accumulation.  Mol Cell Biol. 2002;  22 4309-4318
• 25 Song M S, Song S J, Ayad N G. et al . The tumour suppressor RASSF1A regulates mitosis by inhibiting the APC-Cdc20 complex.  Nat Cell Biol. 2004;  6 129-137
• 26 Sato F, Harpaz N, Shibata D. et al . Hypermethylation of the p14ARF gene in ulcerative colitis-associated colorectal carcinogenesis.  Cancer Res. 2002;  62 1148-1151
• 27 Thibodeau S N, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon.  Science. 1993;  260 816-819
• 28 Toyota M, Ahuja N, Ohe-Toyota M. et al . CpG island methylator phenotype in colorectal cancer.  Proc Natl Acad Sci USA. 1999;  96 8681-8686
• 29 Vogelstein B, Fearon E R, Hamilton S R. et al . Genetic alterations during colorectal-tumor development.  N Engl J Med. 1988;  19 525-532
• 30 Whitehall V LJ, Walsh M D, Young J. et al . Methylation of O-6-methylguanine DNA methyltransferase characterizes a subset of colorectal cancer with low-level DNA microsatellite instability.  Cancer Res. 2001;  61 827-830