Löhr Matthias, Klöppel Günter, Maisonneuve Patrick, Lowenfels Albert B, Lüttges Jutta
Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
Neoplasia. 2005 Jan;7(1):17-23. doi: 10.1593/neo.04445.
Molecular analyses have demonstrated mutations in the K-ras gene at codon 12 in the majority of pancreatic ductal adenocarcinomas (PDACs). In order to determine whether the K-ras mutation rate increases parallel to the grade of dysplasia in duct lesions, we performed a meta-analysis of the studies published between 1988 and 2003 that provide information on K-ras mutations in hyperplastic and dysplastic duct lesions in the pancreas. The described duct lesions were reclassified according to the nomenclature for pancreatic intraepithelial neoplasia (PanIN), and the molecular methods for detecting K-ras were reviewed. In PanIN lesions from pancreata of patients with PDAC, there was a stepwise increase in K-ras mutations that correlated with the grade of dysplasia of the PanIN lesion. K-ras mutations were found in 36%, 44%, and 87% of PanIN-1a, 1b, and 2-3 lesions, respectively (trend statistic P <.001). Mutation-enriched polymerase chain reaction (PCR) resulted in higher rates of K-ras mutations in PanIN than plain PCR did. The incidence of K-ras mutations in PanIN lesions associated with chronic pancreatitis (CP) or normal pancreas was low (around 10%). In CP, K-ras mutations were only found after a disease duration of 3 years. The correlation of the incidence of K-ras mutations with the grade of dysplasia in PanIN and the occurrence of these mutations in CP with a duration of more than 3 years underlines the importance of this genetic change for the development of PDAC.
分子分析表明，大多数胰腺导管腺癌（PDAC）的K-ras基因第12密码子存在突变。为了确定K-ras突变率是否与导管病变的发育异常程度平行增加，我们对1988年至2003年间发表的研究进行了荟萃分析，这些研究提供了胰腺增生性和发育异常性导管病变中K-ras突变的信息。根据胰腺上皮内瘤变（PanIN）的命名法对所描述的导管病变进行重新分类，并对检测K-ras的分子方法进行了综述。在PDAC患者胰腺的PanIN病变中，K-ras突变呈逐步增加，与PanIN病变的发育异常程度相关。在PanIN-1a、1b和2-3级病变中，K-ras突变的发生率分别为36%、44%和87%（趋势统计P<.001）。与普通聚合酶链反应（PCR）相比，突变富集PCR导致PanIN中K-ras突变率更高。与慢性胰腺炎（CP）或正常胰腺相关的PanIN病变中K-ras突变的发生率较低（约10%）。在CP中，仅在病程3年后才发现K-ras突变。K-ras突变发生率与PanIN发育异常程度的相关性以及这些突变在病程超过3年的CP中的发生情况强调了这种基因变化对PDAC发生发展的重要性。
