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Carcinogenesis Advance Access first published online on December 20, 2006
This version published online on December 26, 2006
Carcinogenesis, doi:10.1093/carcin/bgl246
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Genetic and epigenetic profiling in early colorectal tumors and prediction of invasive potential in pT1 (early invasive) colorectal cancers

Katsuhiko Nosho1, Hiroyuki Yamamoto1, Taiga Takahashi1, Masashi Mikami1, Hiroaki Taniguchi1, Nobuki Miyamoto1, Yasushi Adachi1, Yoshiaki Arimura1, Fumio Itoh2, Kohzoh Imai3 and Yasuhisa Shinomura1

1 First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan
2 Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University, Kawasaki, Japan
3 Sapporo Medical University, Sapporo, Japan

Correspondence: Katsuhiko Nosho, First Department of Internal Medicine, Sapporo Medical University, S.-1, W.-16, Chuo-ku, Sapporo 060-8543, Japan. Phone: +81-11-611-2111 ext. 3211; Fax: +81-11-611-2282; E-mail: nosho{at}sapmed.ac.jp

Morphologically, early colorectal tumors are divided into two groups, protruded-type tumors and flat-type tumors. Although some studies have shown genetic alterations in protruded-type tumors, little is known about genetic and epigenetic alterations in flat-type tumors, as well as pT1 (early invasive) colorectal cancers (CRCs). In the current study, we compared the frequencies of genetic and epigenetic alterations of the RAS-RAF and Wnt signaling pathways in flat-type and protruded-type tumors. In addition, we investigated the relationship between those alterations and invasive potential of pT1 CRCs. Methylations of RASSF2, MGMT, WIF-1, EPHB2, CDKN2A and MLH1 were detected in 44.3%, 30.3%, 81.4%, 7.5%, 43.6% and 13.4% of the 307 early colorectal tumors, respectively. Mutations of KRAS, BRAF, PIK3CA and ß-catenin were detected in 25.4%, 4.6%, 1.6% and 9.4% of those tumors, respectively. Methylations of MGMT, WIF-1 and CDKN2A were detected in significantly higher percentages of protruded-type tumors than in flat-type tumors. Mutation of at least one gene was detected in a significantly higher percentage of flat-type tumors than in protruded-type tumors. RASSF2 methylation was correlated significantly with KRAS, BRAF or PIK3CA mutation. Multiple logistic analysis showed that lymphatic invasion and RASSF2 methylation with KRAS, BRAF or PIK3CA mutation were independent risk factors for venous invasion in pT1 CRCs. In conclusion, since genetic alterations of these pathways have frequently occurred in flat-type tumors, flat-type tumors seem to have a distinct genetic profile different from that of protruded-type tumors. RASSF2 methylation with oncogenic activation is a promising biomarker for predicting invasive potential of pT1 CRCs.

Key Words: RASSF2 • KRAS • pT1 colorectal cancer • colorectal adenoma • MethyLight

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S. Ogino, A. Hazra, G. J. Tranah, G. J. Kirkner, T. Kawasaki, K. Nosho, M. Ohnishi, Y. Suemoto, J. A. Meyerhardt, D. J. Hunter, et al.
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