Genetic and epigenetic aberrations occurring in colorectal tumors associated with serrated pathway.
Genetic and epigenetic aberrations occurring in colorectal tumors associated with serrated pathway.
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DOI：
10.1002/ijc.29903
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发表时间：
2016-04-01
影响因子：
6.4
通讯作者：
Kaneda A
中科院分区：
文献类型：
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作者：
Sakai E;Fukuyo M;Ohata K;Matsusaka K;Doi N;Mano Y;Takane K;Abe H;Yagi K;Matsuhashi N;Fukushima J;Fukayama M;Akagi K;Aburatani H;Nakajima A;Kaneda A
为了阐明结直肠癌（CRC）锯齿状通路中的分子改变，我们对无蒂锯齿状腺瘤/息肉（SSA/P）、传统锯齿状腺瘤（TSA）和高甲基化CRC进行了表观遗传学和遗传学分析。使用焦磷酸测序定量分析了我们先前研究中建立的6个第1组和14个第2组标记物的甲基化水平。随后，我们对126个候选驱动基因进行了靶向外显子测序分析，并检查了与癌症发展相关的分子改变。SSA/P显示第1组和第2组标志物的高甲基化水平，BRAF突变频繁，发生在近端结肠，这是高甲基化CRC的特征。但是TSA显示第1组标记物的甲基化水平较低，BRAF突变频率较低，并且发生在远端结肠。SSA/P，而不是TSA，因此被认为是高甲基化CRC的前体。高甲基化CRC的某些基因的甲基化水平甚至更高，例如，MLH 1，比SSA/P，和非同义突变（p < 0.0001）和插入/缺失（p = 0.002）的体细胞突变的显着频率。MLH 1甲基化的SSA/P显示MLH 1的甲基化水平低于高甲基化的CRC，并且很少伴随MLH 1表达的沉默。MLH 1甲基化和MLH 1未甲基化SSA/P之间的突变频率没有差异，表明SSA/P中MLH 1甲基化可能不足以获得超突变表型。错配修复基因突变，例如，与腺瘤相比，MSH 3和MSH 6以及PI 3 K、WNT、TGF-β和BMP信号传导中的基因（但不参与TP 53信号传导）显著参与了高甲基化CRC，这表明在锯齿状通路中废除这些基因的重要性。 有什么新消息吗？ 结直肠癌（CRC）发展的锯齿状途径的特征在于存在锯齿状结肠隐窝和高甲基化表观基因型。然而，并非所有锯齿状病变都会引起CRC。在这里，只有无蒂锯齿状腺瘤/息肉，一种潜在的恶性锯齿状息肉亚型，被确定为高甲基化CRC的前体。此外，MLH 1的表达，沉默先前被链接到微卫星不稳定性在CRC中，被发现保存在大多数锯齿状腺瘤/息肉样本。研究结果表明，锯齿状结直肠癌超突变表型的获得可能取决于广泛的MLH 1甲基化和其他错配修复基因的突变。
To clarify molecular alterations in serrated pathway of colorectal cancer (CRC), we performed epigenetic and genetic analyses in sessile serrated adenoma/polyps (SSA/P), traditional serrated adenomas (TSAs) and high‐methylation CRC. The methylation levels of six Group‐1 and 14 Group‐2 markers, established in our previous studies, were analyzed quantitatively using pyrosequencing. Subsequently, we performed targeted exon sequencing analyses of 126 candidate driver genes and examined molecular alterations that are associated with cancer development. SSA/P showed high methylation levels of both Group‐1 and Group‐2 markers, frequent BRAF mutation and occurrence in proximal colon, which were features of high‐methylation CRC. But TSA showed low‐methylation levels of Group‐1 markers, less frequent BRAF mutation and occurrence at distal colon. SSA/P, but not TSA, is thus considered to be precursor of high‐methylation CRC. High‐methylation CRC had even higher methylation levels of some genes, e.g., MLH1, than SSA/P, and significant frequency of somatic mutations in nonsynonymous mutations (p < 0.0001) and insertion/deletions (p = 0.002). MLH1‐methylated SSA/P showed lower methylation level of MLH1 compared with high‐methylation CRC, and rarely accompanied silencing of MLH1 expression. The mutation frequencies were not different between MLH1‐methylated and MLH1‐unmethylated SSA/P, suggesting that MLH1 methylation might be insufficient in SSA/P to acquire a hypermutation phenotype. Mutations of mismatch repair genes, e.g., MSH3 and MSH6, and genes in PI3K, WNT, TGF‐β and BMP signaling (but not in TP53 signaling) were significantly involved in high‐methylation CRC compared with adenoma, suggesting importance of abrogation of these genes in serrated pathway. What's new? The serrated pathway of colorectal cancer (CRC) development is characterized by the presence of saw‐toothed colonic crypts and by a high‐methylation epigenotype. Not all serrated lesions, however, give rise to CRC. Here, only sessile serrated adenoma/polyps, a potentially malignant serrated polyp subtype, were identified as precursors of high‐methylation CRC. Moreover, MLH1 expression, silencing of which previously was linked to microsatellite instability in CRC, was found to be preserved in most serrated adenoma/polyp samples. The findings suggest that the acquisition of a hypermutation phenotype in serrated CRC likely depends on extensive MLH1 methylation and mutation of additional mismatch repair genes.