p16INK4a promoter methylation and 9p21 allelic loss in colorectal carcinomas:: relation with immunohistochemical p16INK4a expression and with tumor budding
p16INK4a promoter methylation and 9p21 allelic loss in colorectal carcinomas:: relation with immunohistochemical p16INK4a expression and with tumor budding
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DOI：
10.1016/j.humpath.2006.01.005
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发表时间：
2006-05-01
期刊：
影响因子：
3.3
通讯作者：
Nizze, H
中科院分区：
文献类型：
--
作者：
Prall, F;Ostwald, C;Nizze, H
在结直肠癌中，已知p16（INK4a）失活通过等位基因丢失和启动子甲基化发生，但突变很少。p16（INK4a）在肿瘤芽中上调，并且随后的增殖停止可能是肿瘤芽生的先决条件。57结直肠癌从一个连续的系列进行了研究。使用组织匀浆的DNA，p16（INK4a）启动子甲基化被认为是在17 57肿瘤甲基化特异性聚合酶链反应，这可以证实使用DNA从激光捕获显微切割材料在这些情况下的16。17例肿瘤中6例出现启动子甲基化，免疫组化p16（INK4a）表达完全缺失。免疫组化p16（INK4a）表达的定量显示，与没有p16（INK4a）启动子甲基化的病例相比，其余病例的表达频率在统计学上较低。9例p21等位基因丢失，但p16（INK4a）表达未降低。p16（INK4a）在肿瘤芽中的表达对肿瘤出芽程度的线性回归，如在泛细胞角蛋白免疫染色上计数的，没有显示出相关性。p16（INK4a）基因启动子甲基化可完全抑制p16（INK4a）在结直肠癌中的表达。然而，在许多情况下，它对p16（INK4a）表达有明显的但仅是调节性的影响。可能的是，甲基化是杂合的，和/或结直肠癌中的嵌合体，和/或甲基化不是完全稳定的，但可以在癌细胞复制周期之间丢失。p16（INK4a）的上调似乎不是肿瘤出芽的严格要求，因此，缺乏相关性。(c)2006年爱思唯尔公司All rights reserved.
In colorectal carcinomas, p16(INK4a) inactivation is known to occur by allelic loss and by promoter methylation, but mutations are rare. p16(INK4a) is up-regulated in tumor buds, and the consequent shutdown of proliferation may be a prerequisite for tumor budding. Fifty-seven colorectal carcinomas from a consecutive series were investigated. Using DNA from tissue homogenates, p16(INK4a) promoter methylation was seen in 17 of 57 tumors by methylation-specific polymerase chain reaction, and this could be confirmed using DNA from laser-capture microdissected material in 16 of these cases. A total loss of immunohistochemical p16(INK4a) expression was seen in 6 of 17 tumors with promoter methylation. Quantification of immunohistochemical p16(INK4a) expression for the remaining I I cases revealed statistically lower frequencies of expression as compared with cases without p16(INK4a) promoter methylation. 9p21 allelic loss was observed in 9 cases, but p16(INK4a) expression in these carcinomas was not reduced. Attempted linear regression of p16(INK4a) expression in tumor buds on the degree of tumor budding, as counted on pan-cytokeratin immunostains, did not show a correlation. p16(INK4a) promoter methylation can completely abrogate p16(INK4a) expression in colorectal carcinomas. In many cases, however, it has an appreciable but only modulatory influence on p16(INK4a) expression. Possibly, methylations are heterozygous, and/or mosaic in colorectal carcinomas and/or methylations are not totally stable but can be lost between carcinoma cell replication cycles. Up-regulation of p16(INK4a) does not seem to be a strict requirement for tumor budding, hence, the absence of a correlation. (c) 2006 Elsevier Inc. All rights reserved.