van Engeland Manon, Roemen Guido M J M, Brink Mirian, Pachen Marco M M, Weijenberg Matty P, de Bruïne Adriaan P, Arends Jan-Willem, van den Brandt Piet A, de Goeij Anton F P M, Herman James G
Department of Pathology, University Maastricht, P.O. Box 616 6200 MD Maastricht, The Netherlands.
Oncogene. 2002 May 23;21(23):3792-5. doi: 10.1038/sj.onc.1205466.
Human cancer is characterized by genetic and epigenetic alterations. In this study we provide evidence for the interruption of Ras signaling in sporadic colorectal cancer (CRC) by either genetic activation of the K-ras oncogene or epigenetic silencing of the putative tumor suppressor gene RASSF1A. Paraffin embedded tumor tissue samples from 222 sporadic CRC patients were analysed for K-ras codon 12 and codon 13 activating mutations and RASSF1A promoter hypermethylation. Overall, K-ras mutations were observed in 87 of 222 (39%) and RASSF1A methylation was observed in 45 of 222 (20%) of CRCs. Mutation of K-ras alone was detected in 76 of 222 (34%) CRCs. RASSF1A promoter methylation with wild-type K-ras was observed in 34 of 222 (15%) CRCs. In 101 of 222 (46%) CRCs neither K-ras mutations nor RASSF1A methylation was observed and 11 of 222 (5%) CRCs showed both K-ras mutations and RASSF1A methylation. These data show that the majority of the studied CRCs with K-ras mutations lack RASSF1A promoter methylation, an event which occurs predominantly in K-ras wild-type CRCs (P=0.023, Chi-square test).
人类癌症的特征是基因和表观遗传改变。在本研究中，我们提供证据表明，在散发性结直肠癌（CRC）中，K-ras癌基因的基因激活或假定的肿瘤抑制基因RASSF1A的表观遗传沉默会中断Ras信号传导。对来自222例散发性CRC患者的石蜡包埋肿瘤组织样本进行分析，以检测K-ras密码子12和密码子13的激活突变以及RASSF1A启动子高甲基化。总体而言，在222例CRC中的87例（39%）中观察到K-ras突变，在222例中的45例（20%）中观察到RASSF1A甲基化。在222例CRC中的76例（34%）中仅检测到K-ras突变。在222例CRC中的34例（15%）中观察到RASSF1A启动子甲基化且K-ras为野生型。在222例CRC中的101例（46%）中既未观察到K-ras突变也未观察到RASSF1A甲基化，在222例CRC中的11例（5%）中同时出现K-ras突变和RASSF1A甲基化。这些数据表明，大多数具有K-ras突变的研究性CRC缺乏RASSF1A启动子甲基化，这一事件主要发生在K-ras野生型CRC中（P = 0.023，卡方检验）。
