Genetic and epigenetic profiling in early colorectal tumors and prediction of invasive potential in pT1 (early invasive) colorectal cancers
Genetic and epigenetic profiling in early colorectal tumors and prediction of invasive potential in pT1 (early invasive) colorectal cancers
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DOI：
10.1093/carcin/bgl246
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发表时间：
2007-06-01
期刊：
影响因子：
4.7
通讯作者：
Shinomura, Yasuhisa
中科院分区：
文献类型：
--
作者：
Nosho, Katsuhiko;Yamamoto, Hiroyuki;Shinomura, Yasuhisa
从形态学上，早期结直肠肿瘤分为两类：突出型肿瘤和扁平型肿瘤。尽管一些研究表明突出型肿瘤存在遗传改变，但对于扁平型肿瘤以及 pT1（早期浸润性）结直肠癌 (CRC) 的遗传和表观遗传改变知之甚少。在当前的研究中，我们比较了扁平型和突出型肿瘤中 RAS-RAF 和 Wnt 信号通路的遗传和表观遗传改变的频率。此外，我们还研究了这些改变与 pT1 CRC 侵袭潜力之间的关系。在 307 个早期结直肠肿瘤中，分别有 44.3%、30.3%、81.4%、7.5%、43.6% 和 13.4% 检测到 RASSF2、O-6-甲基鸟嘌呤-DNA 甲基转移酶 (MGMT)、Wnt 抑制因子-1 (WIF-1)、EPHB2、CDKN2A 和 MLH1 甲基化。分别在 25.4%、4.6%、1.6% 和 9.4% 的肿瘤中检测到 KRAS、BRAF、磷脂酰肌醇 3'-激酶 (PIK3CA) 催化亚基 α 和 β-连环蛋白突变。突出型肿瘤中检测到的 MGMT、WIF-1 和 CDKN2A 甲基化比例显着高于扁平型肿瘤。在平坦型肿瘤中检测到至少一种基因突变的比例显着高于在突出型肿瘤中。 RASSF2 甲基化与 KRAS、BRAF 或 PIK3CA 突变显着相关。多重logistic分析显示，淋巴管侵犯和RASSF2甲基化伴KRAS、BRAF或PIK3CA突变是pT1 CRC静脉侵犯的独立危险因素。总之，由于这些途径的遗传改变经常发生在扁平型肿瘤中，因此扁平型肿瘤似乎具有与突出型肿瘤不同的独特遗传特征。具有致癌激活作用的 RASSF2 甲基化是预测 pT1 CRC 侵袭潜力的有前途的生物标志物。
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 beta-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.