Bläker H, Helmchen B, Bönisch A, Aulmann S, Penzel R, Otto H F, Rieker R J
Institute of Pathology, University of Heidelberg, Germany.
Scand J Gastroenterol. 2004 Aug;39(8):748-53. doi: 10.1080/00365520410005847.
Adenocarcinomas of the small and the large intestine share risk factors and morphological features but both tumor types seem to follow different genetic pathways. The aim of this study on small intestinal carcinomas was to analyze alternative mechanisms of activation of pathways that are typically affected in colorectal cancer.
Twenty-one sporadic carcinomas were investigated for mutations in KRAS, BRAF, the beta-catenin gene CTNNB1, and the mutational cluster region of APC. Immunohistochemical analysis was performed with a monoclonal antibody for beta-catenin, the transcriptionally active downstream component of wnt signaling.
Oncogene mutations were found in 13 (62%) small intestinal adenocarcinomas. Twelve tumors displayed a KRAS mutation, and a novel BRAF mutation at codon 603/604 was seen in one carcinoma without KRAS mutation. One tumor harbored a CTNNB1 mutation consisting of an insertion of 247 nucleotides deriving from chromosome 9. APC mutations were identified in 2 tumors. Immunohistochemistry demonstrated nuclear accumulation of beta-catenin in 5 carcinomas. These carcinomas included the tumor with a CTNNB1 mutation but not those with APC mutations.
Our data show frequent activation of the RAS-RAF-MAPK pathway through mutations of either KRAS or, infrequently, BRAF. Activation of the wnt pathway through accumulation of beta-catenin may have a role in a subset of small intestinal adenocarcinomas but in contrast to colorectal carcinoma, accumulation of beta-catenin is generally not caused by inactivating APC or activating CTNNB1 mutations.
小肠腺癌和大肠腺癌具有共同的风险因素和形态学特征，但这两种肿瘤类型似乎遵循不同的遗传途径。本项关于小肠癌的研究旨在分析在结直肠癌中通常受影响的通路的激活替代机制。
对21例散发性癌进行KRAS、BRAF、β-连环蛋白基因CTNNB1以及APC突变簇区域的突变检测。使用针对β-连环蛋白（Wnt信号转导的转录活性下游成分）的单克隆抗体进行免疫组织化学分析。
在13例（62%）小肠腺癌中发现了癌基因突变。12例肿瘤显示KRAS突变，在1例无KRAS突变的癌中发现了一个新的第603/604密码子BRAF突变。1例肿瘤存在CTNNB1突变，由来自9号染色体的247个核苷酸插入组成。在2例肿瘤中鉴定出APC突变。免疫组织化学显示5例癌中β-连环蛋白核内积聚。这些癌包括具有CTNNB1突变的肿瘤，但不包括具有APC突变的肿瘤。
我们的数据显示，通过KRAS突变或偶尔的BRAF突变，RAS-RAF-MAPK通路频繁激活。β-连环蛋白积聚导致的Wnt通路激活可能在一部分小肠腺癌中起作用，但与结直肠癌不同，β-连环蛋白积聚通常不是由APC失活或CTNNB1激活突变引起的。
