Colorectal carcinomas with CpG island methylator phenotype 1 frequently contain mutations in chromatin regulators.
Colorectal carcinomas with CpG island methylator phenotype 1 frequently contain mutations in chromatin regulators.
复制标题
DOI：
10.1053/j.gastro.2013.10.060
复制
发表时间：
2014-02
期刊：
影响因子：
29.4
通讯作者：
Estécio MR
中科院分区：
文献类型：
--
作者：
Tahara T;Yamamoto E;Madireddi P;Suzuki H;Maruyama R;Chung W;Garriga J;Jelinek J;Yamano HO;Sugai T;Kondo Y;Toyota M;Issa JP;Estécio MR
以DNA甲基化异常为特征的结直肠癌亚型称为CpG岛甲基化表型(CIMP)1、CIMP2或CIMP阴性。CIMP1结直肠癌的发病机制及其对患者预后和治疗反应的影响不同于其他结直肠癌。我们试图确定与CIMP1癌相关的遗传性体细胞改变。我们检测了来自3个三级医疗中心接受手术或结肠镜检查的100例原发癌、10例腺瘤和邻近正常粘膜的基因组DNA样本。我们对16个大肠肿瘤及其邻近的正常组织进行了外显子组测序。与已知的CRC体细胞改变的广泛比较允许分离CIMP1-排他性改变。所选基因突变的流行率是从一个独立的队列中确定的。我们发现，调控染色质的基因在CIMP1癌中发生突变；CHD7和CHD8的突变率最高，这两个基因编码依赖于染色域螺旋酶/三磷酸腺苷的染色质重塑家族成员。在9例CIMP1癌中有5例检测到这2个基因的体细胞突变。患病率筛查显示，CHD7和CHD8的非沉默突变在CIMP1肿瘤中的发生率(18/42[43%])显著高于CIMP2(3/34[9%]；P<；0.01)或CIMP阴性肿瘤(2/34[6%]；P<；.001)。与所有基因相比，CIMP1标记与CHD7的结合增加。CHD7突变的Charge综合征(涉及中枢神经系统、眼睛、耳朵、鼻子和纵隔器官的先天性畸形)患者的基因改变也在CHD7突变的CRC中改变。染色质重塑的异常可能与CIMP1CRCs的发生有关。当根据表观遗传状态对这些肿瘤进行分类时，可以更好地了解癌细胞的生物学决定因素。
Subgroups of colorectal carcinomas (CRCs) characterized by DNA methylation anomalies are termed CpG island methylator phenotype (CIMP)1, CIMP2, or CIMP-negative. The pathogenesis of CIMP1 colorectal carcinomas, and their effects on patients’ prognoses and responses to treatment, differ from those of other CRCs. We sought to identify genetic somatic alterations associated with CIMP1 CRCs. We examined genomic DNA samples from 100 primary CRCs, 10 adenomas, and adjacent normal-appearing mucosae from patients undergoing surgery or colonoscopy at 3 tertiary medical centers. We performed exome sequencing of 16 colorectal tumors and their adjacent normal tissues. Extensive comparison with known somatic alterations in CRCs allowed segregation of CIMP1-exclusive alterations. The prevalence of mutations in selected genes was determined from an independent cohort. We found that genes that regulate chromatin were mutated in CIMP1 CRCs; the highest rates of mutation were observed in CHD7 and CHD8, which encode members of the chromodomain helicase/adenosine triphosphate—dependent chromatin remodeling family. Somaticmutations in these 2 genes were detected in 5 of 9 CIMP1 CRCs. A prevalence screen showed that nonsilencing mutations in CHD7 and CHD8 occurred significantly more frequently in CIMP1 tumors (18 of 42 [43%]) than in CIMP2 (3 of 34 [9%]; P < .01) or CIMP-negative tumors (2 of 34 [6%]; P < .001). CIMP1 markers had increased binding by CHD7, compared with all genes. Genes altered in patients with CHARGE syndrome (congenital malformations involving the central nervous system, eye, ear, nose, and mediastinal organs) who had CHD7 mutations were also altered in CRCs with mutations in CHD7. Aberrations in chromatin remodeling could contribute to the development of CIMP1 CRCs. A better understanding of the biological determinants of CRCs can be achieved when these tumors are categorized according to their epigenetic status.
登录
查看更多内容
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
29.4
作者：
Jover R;Nguyen TP;Pérez-Carbonell L;Zapater P;Payá A;Alenda C;Rojas E;Cubiella J;Balaguer F;Morillas JD;Clofent J;Bujanda L;Reñé JM;Bessa X;Xicola RM;Nicolás-Pérez D;Castells A;Andreu M;Llor X;Boland CR;Goel A
通讯作者：
Goel A
DOI：
10.1073/pnas.0704652104
发表时间：
2007-11-20
影响因子：
11.1
作者：
Shen, Lanlan;Toyota, Minoru;Issa, Jean-Pierre J.
通讯作者：
Issa, Jean-Pierre J.
影响因子：
7
作者：
Hinoue, Toshinori;Weisenberger, Daniel J.;Laird, Peter W.
通讯作者：
Laird, Peter W.
影响因子：
16
作者：
Ishihara, Ko;Oshimura, Mitsuo;Nakao, Mitsuyoshi
通讯作者：
Nakao, Mitsuyoshi