Genetics and epigenetics of small bowel adenocarcinoma: the interactions of CIN, MSI, and CIMP
Genetics and epigenetics of small bowel adenocarcinoma: the interactions of CIN, MSI, and CIMP
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DOI：
10.1038/modpathol.2010.223
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发表时间：
2011-04-01
期刊：
影响因子：
7.5
通讯作者：
Blaeker, Hendrik
中科院分区：
文献类型：
--
作者：
Warth, Arne;Kloor, Matthias;Blaeker, Hendrik
肿瘤遗传学和表观遗传学的表征允许根据分子途径对肿瘤实体进行分层，并可能揭示肿瘤发生过程中不同类型 DNA 改变的相互作用。小肠腺癌很罕见，迄今为止，尚未在这种肿瘤类型中研究基因组不稳定性和表观遗传学的相互关系。因此，我们使用比较基因组杂交分析了 37 个具有已知微卫星不稳定性和 KRAS 状态的原发性小肠癌的染色体不稳定性，通过甲基化特异性聚合酶链反应分析是否存在异常甲基化（CpG 岛甲基化表型），以及 BRAF 突变。在 37 个肿瘤中的 22 个 (59%) 中检测到染色体不稳定性（9 个微卫星不稳定癌中的 3 个，28 个微卫星稳定癌中的 19 个）。九种癌（24%）是微卫星癌并且染色体稳定。在 16% 的染色体不稳定肿瘤和 44% 的微卫星不稳定癌以及微卫星和染色体稳定癌中发现了高水平 DNA 甲基化。 KRAS 在染色体不稳定、微卫星不稳定、微卫星和染色体稳定肿瘤中分别有 55%、0 和 10% 发生突变，而 BRAF 突变频率在染色体不稳定肿瘤中为 6%，在微卫星不稳定肿瘤和微卫星和染色体稳定肿瘤中为 22%。总之，在这项研究中，我们表明，小肠染色体不稳定癌与微卫星不稳定癌以及微卫星和染色体稳定肿瘤的区别在于高频率的 KRAS 突变、低频率的 CpG 岛甲基化表型和 BRAF 突变。在微卫星不稳定和微卫星和染色体稳定癌症中，CpG岛甲基化表型和BRAF/KRAS突变分布相似，表明肿瘤在其分子发病机制中起始或进展的共同机制。现代病理学(2011) 24, 564-570; doi：10.1038/modpathol.2010.223； 2011 年 2 月 4 日在线发布
Characterization of tumor genetics and epigenetics allows to stratify a tumor entity according to molecular pathways and may shed light on the interactions of different types of DNA alterations during tumorigenesis. Small intestinal adenocarcinoma is rare, and to date the interrelation of genomic instability and epigenetics has not been investigated in this tumor type. We therefore analyzed 37 primary small bowel carcinomas with known microsatellite instability and KRAS status for chromosomal instability using comparative genomic hybridization, for the presence of aberrant methylation (CpG island methylation phenotype) by methylation-specific polymerase chain reaction, and for BRAF mutations. Chromosomal instability was detected in 22 of 37 (59%) tumors (3 of 9 microsatellite instable, and 19 of 28 microsatellite stable carcinomas). Nine carcinomas (24%) were microsatellite and chromosomally stable. High-level DNA methylation was found in 16% of chromosomal instable tumors and in 44% of both microsatellite instable and microsatellite and chromosomally stable carcinomas. KRAS was mutated in 55, 0, and 10% of chromosomal instable, microsatellite instable, and microsatellite and chromosomally stable tumors, respectively whereas the frequencies of BRAF mutations were 6% for chromosomal instable and 22% for both microsatellite instable and microsatellite and chromosomally stable carcinomas. In conclusion, in this study we show that chromosomal instable carcinomas of the small intestine are distinguished from microsatellite instable and microsatellite and chromosomally stable tumors by a high frequency of KRAS mutations, low frequencies of CpG island methylation phenotype, and BRAF mutations. In microsatellite instable and microsatellite and chromosomally stable cancers, CpG island methylation phenotype and BRAF/KRAS mutations are similarly distributed, indicating common mechanisms of tumor initiation or progression in their molecular pathogenesis. Modern Pathology (2011) 24, 564-570; doi: 10.1038/modpathol.2010.223; published online 4 February 2011