Sparks A B, Morin P J, Vogelstein B, Kinzler K W
Johns Hopkins Oncology Center, Baltimore, Maryland 21231, USA.
Cancer Res. 1998 Mar 15;58(6):1130-4.
Mutation of the adenomatous polyposis coli (APC) tumor suppressor gene initiates the majority of colorectal (CR) cancers. One consequence of this inactivation is constitutive activation of beta-catenin/Tcf-mediated transcription. To further explore the role of the APC/beta-catenin/Tcf pathway in CR tumorigenesis, we searched for mutations in genes implicated in this pathway in CR tumors lacking APC mutations. No mutations of the gamma-catenin (CTNNG1), GSK-3alpha (GSK3A), or GSK-3beta (GSK3B) genes were detected. In contrast, mutations in the NH2-terminal regulatory domain of beta-catenin (CTNNB1) were found in 13 of 27 (48%) CR tumors lacking APC mutations. Mutations in the beta-catenin regulatory domain and APC were observed to be mutually exclusive, consistent with their equivalent effects on beta-catenin stability and Tcf transactivation. In addition, we found that CTNNB1 mutations can occur in the early, adenomatous stage of CR neoplasia, as has been observed previously with APC mutations. These results suggest that CTNNB1 mutations can uniquely substitute for APC mutations in CR tumors and that beta-catenin signaling plays a critical role in CR tumorigenesis.
腺瘤性结肠息肉病（APC）肿瘤抑制基因的突变引发了大多数结直肠癌（CR）。这种失活的一个后果是β-连环蛋白/Tcf介导的转录的组成性激活。为了进一步探索APC/β-连环蛋白/Tcf通路在CR肿瘤发生中的作用，我们在缺乏APC突变的CR肿瘤中寻找该通路相关基因的突变。未检测到γ-连环蛋白（CTNNG1）、糖原合成酶激酶-3α（GSK3A）或糖原合成酶激酶-3β（GSK3B）基因的突变。相反，在27个缺乏APC突变的CR肿瘤中的13个（48%）中发现了β-连环蛋白（CTNNB1）氨基末端调节域的突变。观察到β-连环蛋白调节域和APC中的突变是相互排斥的，这与它们对β-连环蛋白稳定性和Tcf反式激活的等效作用一致。此外，我们发现CTNNB1突变可发生在CR肿瘤形成的早期腺瘤阶段，正如先前在APC突变中所观察到的那样。这些结果表明，CTNNB1突变可在CR肿瘤中独特地替代APC突变，并且β-连环蛋白信号传导在CR肿瘤发生中起关键作用。
