Comparison of microsatellite instability, CpG island methylation phenotype, BRAF and KRAS status in serrated polyps and traditional adenomas indicates separate pathways to distinct colorectal carcinoma end points
Comparison of microsatellite instability, CpG island methylation phenotype, BRAF and KRAS status in serrated polyps and traditional adenomas indicates separate pathways to distinct colorectal carcinoma end points
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DOI：
10.1097/01.pas.0000213313.36306.85
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发表时间：
2006-12-01
影响因子：
5.6
通讯作者：
Farraye, Francis A.
中科院分区：
文献类型：
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作者：
O'Brien, Michael J.;Yang, Shi;Farraye, Francis A.
本研究的目的是比较BRAF和KRAS， CpG岛甲基化表型（CIMP）和微卫星不稳定性（MSI）状态在每个组织学类别，包括终末癌残余腺瘤，锯齿状息肉瘤途径和传统（非锯齿状）腺瘤-癌序列。从选定的样品中提取脱氧核糖核酸（DNA），用标记物hMLH1、MGMT、MINT1、MINT2、p16和MS1检测BRAF（(V600E)）、KRAS2密码子12、13和CIMP，用BAT25和BAT26检测。BRAF（V600E）突变存在于82%的锯齿状癌（SCas）、62%的锯齿状腺瘤（SAs）、83%的异常增生的锯齿状息肉（SPAPs-syn）。无梗锯齿状腺瘤[SSA])， 76%的微泡锯齿状息肉（MVSPs），在传统腺瘤-癌序列的任何组织学分类中均未发现。KRAS2突变在43%的杯状细胞锯齿状息肉（GCSP）、13%的mvsp、7%的SPAPs和24%的SAs中发现；26%的大传统腺瘤（lTAs）与小传统腺瘤（sTAs）相比（0/30;P < 0.005）， 37.3%的传统癌（TCa）。CIMP-H（> 1标记物阳性）在SPAP、SA和SCa中出现的频率明显高于MVSP (P < 0.05)；CIMP-H存在于10%的sta中，但在lTA （44.4%, OR 7.2, P = 0.007）和TCa （38.9%, OR 5.8, P = 0.007）中更为常见。与lTAs[0%]和TCAs[3.4%]相比，较高的CIMP水平（4个或更多标记物阳性）在锯齿状通路的高级类别（SAs[31%]和SCas[30%]）中更为常见（or 12.2; P = 0.02）。MSI-H仅在SCas的腺癌成分（9/11）或相邻的sa中被鉴定出来（3/7）。研究结果表明，BRAF（(V600E)）突变是起源于增生性息肉（MVSP）的锯齿状息肉通路的特异性标记，其潜在终点为MSI癌。CIMP-High （CIMP-H）在该序列中发育较早，MSI-H发育较晚。这些数据提供了第二种锯齿状通路的不太完整的图像，由SAs中的KRAS2突变确定，但表明锯齿状瘤变途径的两个迭代的进展阶段是分开的，与传统的腺瘤-癌序列不同。
The aim of this study was to compare BRAF and KRAS, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI) status in each of the histologic categories, including end-point carcinomas with residual adenoma, of the serrated polyp neoplasia pathway and the traditional (nonserrated) adenoma-carcinoma sequence. Deoxyribonucleic acid (DNA) was extracted from the selected samples and assayed for BRAF((V600E)), KRAS2 codon12, 13, CIMP using markers hMLH1, MGMT, MINT1, MINT2, p16, and MS1 using an assay for BAT25 and BAT26. A BRAF((V600E)) mutation was present in 82% of serrated carcinomas (SCas), 62% of serrated adenomas (SAs), 83% of serrated polyps with abnormal proliferation (SPAPs-syn. sessile serrated adenoma [SSA]), 76% of microvesicular serrated polyps (MVSPs), and was not found in any of the histologic categories of the traditional adenoma-carcinoma sequence. KRAS2 mutations were found in 43% of the goblet cell serrated polyp (GCSP) category, 13% of MVSPs, 7% of SPAPs, and 24% of SAs; in 26% of large traditional adenoma (lTAs) compared with small traditional adenomas (sTAs) (0/30; P < 0.005) and in 37.3% of traditional carcinomas (TCa). CIMP-H ( > 1 marker positive) was significantly more frequent in SPAP, SA, and SCa compared with MVSP (P < 0.05); CIMP-H was present in 10% of sTAs but was found more frequently in lTA (44.4%; OR 7.2; P = 0.007) and TCa (38.9%; OR 5.8; P = 0.007). Higher CIMP levels (4 or more markers positive) were significantly more frequent in advanced categories of the serrated pathway (SAs [31%] and SCas [30%]) compared with lTAs [0%] and TCAs [3.4%] (OR 12.2; P = 0.02). MSI-H was identified only in the adenocarcinoma component of SCas (9/11) or in the contiguous SAs (3/7). The findings indicate that a BRAF((V600E)) mutation is a specific marker for a serrated polyp pathway that has its origin in a hyperplastic polyp (MVSP) and a potential end point as MSI carcinoma. CIMP-High (CIMP-H) develops early in this sequence and MSI-H develops late. The data provided a less complete picture of a second serrated pathway, identified by a KRAS2 mutation in SAs, but showed that the progressive stages of both iterations of the serrated neoplasia pathway are separate and distinct from those of the traditional adenoma-carcinoma sequence.