Coding Microsatellite Instability Analysis in Microsatellite Unstable Small Intestinal Adenocarcinomas Identifies MARCKS as a Common Target of Inactivation
Coding Microsatellite Instability Analysis in Microsatellite Unstable Small Intestinal Adenocarcinomas Identifies MARCKS as a Common Target of Inactivation
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DOI：
10.1002/mc.20587
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发表时间：
2010-02-01
影响因子：
4.6
通讯作者：
Blaeker, Hendrik
中科院分区：
文献类型：
--
作者：
Michel, Sara;Kloor, Matthias;Blaeker, Hendrik
大约 15% 的小肠腺癌表现出 DNA 错配修复 (MMR) 失活，并表现出高水平的微卫星不稳定性 (MSI-H)。 MSI-H 肿瘤的进展是由于影响编码微卫星（编码微卫星不稳定性，cMSI）的突变导致的，这可能导致编码蛋白的功能失活，并为受影响的细胞提供选择性生长优势。为了研究小肠癌发生过程中的 cMSI 选择，对 56 例腺癌进行了 MSI 检测。鉴定出 11 种 MSI-H 癌 (19.6%)，并对 24 个潜在肿瘤相关基因进行 cMSI 分析。突变频率与结直肠癌（CRC）中观察到的相似。除了 TGF beta R2、ACVR2 和 AIM2 中出现高频率的 cMSI 之外，我们在 1 1 个肿瘤中的 10 个 (91%) 中检测到了 MARCKS 突变，其中双等位基因突变的比例为 30%。由于对肠道中 MARCKS 的表达知之甚少，我们分析了 31 种癌症中的 MARCKS 蛋白表达。在非肿瘤性粘膜中，发现 MARCKS 沿着隐窝-绒毛轴以浓度梯度表达。与 cMSI 诱导的 MARCKS 功能失活一致，11 例 MSI-H 腺癌中有 8 例显示该蛋白局部或完全缺失。在微卫星稳定 (MSS) 小肠腺癌中，20 个肿瘤中有 2 个 (10%) 出现 MARCKS 表达缺失。总之，我们在此提出了 MSI-H 小肠腺癌的 cMSI 谱，将 MARCKS 识别为常见的突变靶点。 MARCKS 蛋白表达的缺失表明 MARCKS 失活在小肠腺癌的发病机制中发挥着重要作用。 (C) 2009 Wiley-Liss, Inc.
Approximately 15% of small intestinal adenocarcinomas show inactivation of DNA-mismatch repair (MMR) and display high-level microsatellite instability (MSI-H). MSI-H tumors progress as a result of mutations affecting coding microsatellites (coding microsatellite instability, cMSI) that may result in a functional inactivation of the encoded proteins and provide a selective growth advantage for the affected cell. To investigate the cMSI selection in small intestinal carcinogenesis 56 adenocarcinomas were tested for MSI. Eleven MSI-H carcinomas (19.6%) were identified and subjected to cMSI analysis in 24 potentially tumor relevant genes. Mutation frequencies were similar to those observed in colorectal cancer (CRC). Beside high frequencies of cMSI in TGF beta R2, ACVR2, and AIM2 we detected MARCKS mutations in 10 out of 1 1 (91%) tumors with a 30% share of biallelic mutations. Since little is known about MARCKS expression in the intestine, we analyzed MARCKS protein expression in 31 carcinomas. In non-neoplastic mucosa, MARCKS was found to be expressed with a concentration gradient along the crypt-villus axis. In line with cMSI induced functional inactivation of MARCKS, 8 out of 11 MSI-H adenocarcinomas showed regional or complete loss of the protein. In microsatellite stable (MSS) small bowel adenocarcinoma, loss of MARCKS expression was seen in 2 out of 20 tumors (10%). In conclusion, we herein present a cMSI profile of MSI-H small intestinal adenocarcinomas identifying MARCKS as a frequent target of mutation. Loss of MARCKS protein expression suggests a significant role of MARCKS inactivation in the pathogenesis of small intestinal adenocarcinomas. (C) 2009 Wiley-Liss, Inc.