Schlosshauer P W, Pirog E C, Levine R L, Ellenson L H
Department of Pathology, Joan and Sanford I. Weill Medical College of Cornell University, New York, USA.
Mod Pathol. 2000 Oct;13(10):1066-71. doi: 10.1038/modpathol.3880196.
Despite recent studies, the molecular genetic events responsible for the development of uterine endometrioid carcinoma (UEC) remain incompletely characterized. Mutations in the beta-catenin (CTNNB1) gene have been recently reported in a small percentage of UECs and in the endometrioid variant of ovarian carcinoma suggesting that the Wnt signal transduction pathway is involved in the development of female genital tract tumors with endometrioid morphology. The Wnt pathway is a critical pathway in the development of colorectal cancer (CRC) with mutations occurring in the beta-catenin (CTNNB1) or adenomatous polyposis coli (APC) genes in 10 to 15% and 85% of cases, respectively. Because UEC and CRC share other molecular genetic alterations and histologic features and previous studies of UEC have not reported an analysis of the APC gene, we chose to further elucidate the role of the Wnt pathway in UEC. To this end, we analyzed 32 cases of UEC for mutations of the CTNNB1 and APC genes. Mutations of CTNNB1 were present in six of 32 (18%) cases: four grade 1 carcinomas, one grade 2, and one grade 3 carcinoma. Five missense mutations were identified, three involving Ser/Thr phosphorylation sites and two adjacent to a Ser phosphorylation site. One case contained a deletion encompassing codons 34 to 37, which includes a Ser phosphorylation site. No mutations resulting in truncation of the APC protein were found. Our results support a role for the Wnt signaling pathway via mutation of CTNNB1, but not APC, in the development of a subset of UECs.
尽管近期有相关研究，但导致子宫内膜样癌（UEC）发生的分子遗传学事件仍未完全明确。最近报道称，一小部分UEC以及卵巢癌的子宫内膜样变体中存在β-连环蛋白（CTNNB1）基因突变，这表明Wnt信号转导通路参与了具有子宫内膜样形态的女性生殖道肿瘤的发生发展。Wnt通路是结直肠癌（CRC）发生发展中的关键通路，分别有10%至15%和85%的病例中β-连环蛋白（CTNNB1）基因或腺瘤性息肉病 coli（APC）基因发生突变。由于UEC和CRC具有其他共同的分子遗传学改变和组织学特征，且既往关于UEC的研究未报道过对APC基因的分析，我们选择进一步阐明Wnt通路在UEC中的作用。为此，我们分析了32例UEC的CTNNB1和APC基因的突变情况。32例中有6例（18%）存在CTNNB1突变：4例1级癌、1例2级癌和1例3级癌。鉴定出5个错义突变，其中3个涉及丝氨酸/苏氨酸磷酸化位点，2个位于丝氨酸磷酸化位点附近。1例包含一个缺失，涵盖密码子34至37，其中包括一个丝氨酸磷酸化位点。未发现导致APC蛋白截短的突变。我们的结果支持Wnt信号通路通过CTNNB1而非APC突变在一部分UEC发生发展中发挥作用。
