Genetic and epigenetic alterations of netrin-1 receptors in gastric cancer with chromosomal instability.
Genetic and epigenetic alterations of netrin-1 receptors in gastric cancer with chromosomal instability.
复制标题
DOI：
10.1186/s13148-015-0096-y
复制
发表时间：
2015
影响因子：
5.7
通讯作者：
Fujiwara T
中科院分区：
文献类型：
--
作者：
Toda K;Nagasaka T;Umeda Y;Tanaka T;Kawai T;Fuji T;Taniguchi F;Yasui K;Kubota N;Takehara Y;Tazawa H;Kagawa S;Sun DS;Nishida N;Goel A;Fujiwara T
在许多癌症中，Netrin-1依赖受体DCC和UNC5C的基因表达经常下调。我们推测DCC和UNC5C的下调在胃肿瘤的发生中具有重要的生长调节功能。本研究对98例日本散发性胃癌及相应的正常胃粘膜标本进行了一系列DCC和UNC5C的遗传学和表观遗传学分析。用杂合性缺失(LOH)分析和微卫星不稳定性(MSI)分析分别确定染色体不稳定性(CIN)和微卫星不稳定性(MSI)表型。胃癌组织中DCC和UNC5C启动子甲基化水平分别为45%(44/98)和32%(31/98)，正常胃粘膜组织中分别为9%(9/105)和5%(5/105)。总体而言，70%(83例信息性病例中的58例)和51%(79例信息性病例中的40例)的胃癌分别存在DCC和UNC5C基因的LOH或异常甲基化。总体而言，77%的胃癌(66例信息性病例中的51例)在这两种依赖受体上显示出累积缺陷，并与染色体不稳定性显著相关。在97%的CIN阳性胃癌和55.0%的CIN阴性胃癌中，DCC和UNC5C均失活。网织蛋白受体缺陷是胃癌的常见特征。DCC的改变在早期阶段就很明显，并且随着疾病的进展而升级，提示Netrin-1受体的累积改变在胃癌的进展中是一个晚期事件，并强调了这一生长调控通路在胃癌发生中的重要性。本文的在线版本(doi：10.1186/s13148.0150096-y)包含补充材料，授权用户可以使用。
The gene expressions of netrin-1 dependence receptors, DCC and UNC5C, are frequently downregulated in many cancers. We hypothesized that downregulation of DCC and UNC5C has an important growth regulatory function in gastric tumorigenesis. In the present study, a series of genetic and epigenetic analyses for DCC and UNC5C were performed in a Japanese cohort of 98 sporadic gastric cancers and corresponding normal gastric mucosa specimens. Loss of heterozygosity (LOH) analyses and microsatellite instability (MSI) analysis was applied to determine chromosomal instability (CIN) and MSI phenotypes, respectively. More than 5 % methylation in the DCC and UNC5C promoters were found in 45 % (44/98) and 32 % (31/98) gastric cancers, respectively, and in 9 % (9/105) and 5 % (5/105) normal gastric mucosa, respectively. Overall, 70 % (58 of 83 informative cases) and 51 % (40 of 79 informative cases) of gastric cancers harbored either LOH or aberrant methylation in the DCC and UNC5C genes, respectively. In total, 77 % (51 of 66 informative cases) of gastric cancers showed cumulative defects in these two dependence receptors and were significantly associated with chromosomal instability. Both DCC and UNC5C were inactivated in 97 % of CIN-positive gastric cancers and in 55 % of CIN-negative gastric cancers. Defect in netrin receptors is a common feature in gastric cancers. DCC alterations are apparent in the early stages, and UNC5C alterations escalate with the progression of the disease, suggesting that the cumulative alterations of netrin-1 receptors was a late event in gastric cancer progression and emphasizing the importance of this growth regulatory pathway in gastric carcinogenesis. The online version of this article (doi:10.1186/s13148-015-0096-y) contains supplementary material, which is available to authorized users.