Carcinogenesis Advance Access originally published online on December 20, 2006
Carcinogenesis 2007 28(6):1364-1370; doi:10.1093/carcin/bgl246
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Genetic and epigenetic profiling in early colorectal tumors and prediction of invasive potential in pT1 (early invasive) colorectal cancers
First Department of Internal Medicine, Sapporo Medical University, S-1, W-16, Chuo-ku, Sapporo 060-8543, Japan
1 Division of Gastroenterology and Hepatology, Department of Internal Medicine, St Marianna University, Kawasaki 216-8511, Japan
2 Sapporo Medical University, Sapporo 060-8543, Japan
* To whom correspondence should be addressed. Tel: +81 11 611 2111 ext. 3211; Fax: +81 11 611 2282; Email: 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, O-6-methylguanine-DNA methyltransferase (MGMT), Wnt inhibitory factor-1 (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, catalytic subunit alpha of phosphatidylinositol 3'-kinase (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.
Abbreviations: CRC, colorectal cancer; MGMT, O-6-methylguanine-DNA methyltransferase; MSI-H, high-frequency microsatellite instability; MSI, microsatellite instability; MSP, methylation-specific polymerase chain reaction; PCR, polymerase chain reaction; PI3K, phosphatidylinositol 3'-kinase; PIK3CA, catalytic subunit alpha of phosphatidylinositol 3'-kinase; WIF-1, Wnt inhibitory factor-1
Received July 29, 2006; revised December 5, 2006; accepted December 5, 2006.
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