Miyoshi Y, Iwao K, Nawa G, Yoshikawa H, Ochi T, Nakamura Y
Department of Medical Genetics, Osaka University Medical School, Suita-shi, Japan.
Oncol Res. 1998;10(11-12):591-4.
Mutations in the APC gene contribute to development of sporadic desmoid tumors as well as to the hereditary tumors that usually accompany familial adenomatous polyposis (FAP). Adenomatous polyposis coli (APC) mutations cause an intracellular accumulation of beta-catenin that results in abnormal signaling in the wnt/wingless pathway. Mutations of the beta-catenin gene itself have also been noted in several types of tumors. In this study we screened the beta-catenin gene in 13 sporadic desmoid tumors for alterations in exon 3, which encodes several serine/threonine residues that are targets for phosphorylation by GSK-3beta. Somatic substitutions at codons 41 (threonine) and 45 (serine) were identified in seven independent tumors, respectively. Although no APC mutations were detected among the remaining six tumors, we found accumulation of beta-catenin by Western blotting analysis in one such tumor for which frozen tissues were available. Our results have suggested that possible involvement of beta-catenin activation by beta-catenin gene mutation or alteration of other factor(s) can contribute to desmoid tumorigenesis.
APC基因的突变会导致散发性硬纤维瘤的发生，以及通常伴随家族性腺瘤性息肉病（FAP）的遗传性肿瘤。腺瘤性息肉病 coli（APC）突变会导致β-连环蛋白在细胞内积累，从而导致wnt/wingless信号通路异常。在几种肿瘤类型中也发现了β-连环蛋白基因本身的突变。在本研究中，我们在13例散发性硬纤维瘤中筛选了β-连环蛋白基因的第3外显子的改变，该外显子编码几个丝氨酸/苏氨酸残基，这些残基是GSK-3β磷酸化的靶点。分别在7个独立的肿瘤中鉴定出密码子41（苏氨酸）和45（丝氨酸）的体细胞替代。尽管在其余6个肿瘤中未检测到APC突变，但我们通过蛋白质印迹分析在一个有冷冻组织的此类肿瘤中发现了β-连环蛋白的积累。我们的结果表明，β-连环蛋白基因突变或其他因素改变可能导致β-连环蛋白激活，从而促成硬纤维瘤的发生。
