Frequent alteration of MLL3 frameshift mutations in microsatellite deficient colorectal cancer.
Frequent alteration of MLL3 frameshift mutations in microsatellite deficient colorectal cancer.
复制标题
微卫星缺乏结直肠癌中MLL3帧速率突变的频繁改变。
DOI：
10.1371/journal.pone.0023320
复制
发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Issa JP
中科院分区：
文献类型：
--
作者：
Watanabe Y;Castoro RJ;Kim HS;North B;Oikawa R;Hiraishi T;Ahmed SS;Chung W;Cho MY;Toyota M;Itoh F;Estecio MR;Shen L;Jelinek J;Issa JP
MLL3 是一种组蛋白 3-赖氨酸 4 甲基转移酶，具有肿瘤抑制特性，属于在肿瘤形成中可能发生改变的染色质调节基因家族。 MLL3 突变是在结直肠癌的全基因组分析中发现的，但尚未得到单独研究的证实。我们使用 126 例结直肠癌病例分析了 MLL3 编码区和启动子甲基化的突变。我们发现了 MLL3 的两种亚型，DNA 测序揭示了影响结直肠癌细胞中 MLL3 两种亚型的移码和其他突变，以及分析的 134 个原代结直肠样本中的 19 个 (14%)。此外，移码突变在结直肠癌细胞系和原发性肿瘤中微卫星不稳定性（31%）的病例中更为常见。 MLL3 最大的亚型是从 CpG 岛相关启动子转录而来，该启动子与 22 号染色体上的假基因 (psiTPTE22) 具有高度同源性。通过同时测量两个基因座的检测，我们发现正常结肠中存在显着的年龄相关甲基化（从小于 25 岁的个体中的 21% 到 70 岁以上个体中的 56%，R = 0.88，p<0.001），并且在 CRC 细胞系和原发性肿瘤中频繁出现高甲基化 (83%)。接下来，我们分别研究了这两个基因座，发现与年龄和癌症相关的甲基化仅是假基因 CpG 岛的特性，而 MLL3 基因座未甲基化。我们发现，CRC 细胞和原发肿瘤中 MLL3 的移码突变在微卫星不稳定的病例中更为常见。此外，我们还发现MLL3基因的CpG岛相关启动子在CRC细胞以及原发肿瘤和正常结肠中没有DNA甲基化，并且该区域具有与年龄相关的DNA甲基化的假基因（psiTPTE22）高度同源。
MLL3 is a histone 3- lysine 4 methyltransferase with tumor-suppressor properties that belongs to a family of chromatin regulator genes potentially altered in neoplasia. Mutations in MLL3 were found in a whole genome analysis of colorectal cancer but have not been confirmed by a separate study. We analyzed mutations of coding region and promoter methylation in MLL3 using 126 cases of colorectal cancer. We found two isoforms of MLL3 and DNA sequencing revealed frameshift and other mutations affecting both isoforms of MLL3 in colorectal cancer cells and 19 of 134 (14%) primary colorectal samples analyzed. Moreover, frameshift mutations were more common in cases with microsatellite instability (31%) both in CRC cell lines and primary tumors. The largest isoform of MLL3 is transcribed from a CpG island-associated promoter that has highly homology with a pseudo-gene on chromosome 22 (psiTPTE22). Using an assay which measured both loci simultaneously we found prominent age related methylation in normal colon (from 21% in individuals less than 25 years old to 56% in individuals older than 70, R = 0.88, p<0.001) and frequent hypermethylation (83%) in both CRC cell lines and primary tumors. We next studied the two loci separately and found that age and cancer related methylation was solely a property of the pseudogene CpG island and that the MLL3 loci was unmethylated. We found that frameshift mutations of MLL3 in both CRC cells and primary tumor that were more common in cases with microsatellite instability. Moreover, we have shown CpG island-associated promoter of MLL3 gene has no DNA methylation in CRC cells but also primary tumor and normal colon, and this region has a highly homologous of pseudo gene (psiTPTE22) that was age relate DNA methylation.
登录
查看更多内容
影响因子：
5.3
作者：
Chen, HM;Rossier, C;Antonarakis, SE
通讯作者：
Antonarakis, SE
DOI：
10.1073/pnas.92.21.9737
发表时间：
1995-10-10
影响因子：
11.1
作者：
SAHA, V;CHAPLIN, T;YOUNG, BD
通讯作者：
YOUNG, BD
影响因子：
29.4
作者：
Watanabe Y;Kim HS;Castoro RJ;Chung W;Estecio MR;Kondo K;Guo Y;Ahmed SS;Toyota M;Itoh F;Suk KT;Cho MY;Shen L;Jelinek J;Issa JP
通讯作者：
Issa JP
影响因子：
7
作者：
Wang, G;Maher, E;Makrigiorgos, GM
通讯作者：
Makrigiorgos, GM
影响因子：
6.4
作者：
Liang, Qiaoyi;Ding, Jiayi;Zheng, Shu
通讯作者：
Zheng, Shu