BRAF mutation in endometrial carcinoma and hyperplasia:: Correlation with KRAS and p53 mutations and mismatch repair protein expression
BRAF mutation in endometrial carcinoma and hyperplasia:: Correlation with KRAS and p53 mutations and mismatch repair protein expression
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DOI：
10.1158/1078-0432.ccr-04-2670
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发表时间：
2005-09-01
影响因子：
11.5
通讯作者：
Konishi, I
中科院分区：
文献类型：
--
作者：
Feng, YZ;Shiozawa, T;Konishi, I
目的：虽然子宫内膜癌中有几个基因异常的报道，但其遗传学改变尚未完全阐明。最近的研究表明，在几种恶性肿瘤中，BRAF基因的频繁激活突变是丝裂原活化蛋白激酶途径中Ras蛋白的效应子。然而，BRAF突变在子宫内膜癌中的患病率和意义尚不清楚。实验设计：我们研究了BRAF突变的外显子11和15在97例子宫内膜癌（类子宫内膜样型，78;非类子宫内膜样型，19），9例子宫内膜不典型增生，20例正常子宫内膜直接测序。结果：97例胃癌和9例增生组织中，BRAF基因突变20例（21%），1例（11%），突变部位多为未报道的位点。20例正常子宫内膜和21例肿瘤病灶旁正常子宫内膜均无BRAF突变。BRAF突变的患病率在不同分期、组织学亚型或分级之间没有明显差异。KRAS和p53突变分别为18例（19%）和22例（23%），hMLH 1和hMSH 2阳性分别为65例（67%）和92例（95%）。BRAF突变是更频繁地发现在hMLH 1阴性的情况下（12的32，41%）比hMLH 1阳性的情况下（7的65，11%; P = 0.008），这表明它是与一个异常的错配修复function.Conclusions：这些研究结果表明，BRAF基因突变部分参与子宫内膜的恶性转化。
Purpose: Although several gene abnormalities have been reported in endometrial carcinoma, the genetic alterations have not fully been elucidated. Recent studies have revealed frequent activating mutations of the gene for BRAF an effector of Ras protein in the mitogen-activated protein kinase pathway, in several malignancies. However, the prevalence and significance of BRAF mutations in endometrial carcinoma remain unclear.Experimental Design: We examined BRAF mutations in exons 11 and 15 in 97 cases of endometrial carcinoma (endometrioid type, 78; nonendometrioid type, 19), 9 cases of atypical endometrial hyperplasia, and 20 cases of normal endometrium by direct sequencing. In addition, mutations of KRAS and p53 and the immunohistochemical expression of hMLH1 and hMSH2 were also examined,Results: Of the 97 carcinomas and 9 hyperplasias, 20 (21%) and 1 (11%) had BRAF mutations, most of them at previously unreported sites. Twenty samples of normal endometriurn and 21 samples of normal endometrium obtained from sites adjacent to neoplastic lesions had no BRAF mutations. There was no apparent difference in the prevalence of BRAF mutation among stages, histologic subtypes, or grades. Mutations of KRAS and p53 were found in 18 (19%) and 22 (23%) cases, and 65 (67%) and 92 (95%) cases showed positive immunostaining for hMLH1 and hMSH2, respectively. BRAF mutation was more frequently found in hMLH1-negative cases (12 of 32, 41%) than in hMLH1-positive cases (7 of 65, 11%; P = 0.008), suggesting that it is associated with an abnormal mismatch repair function.Conclusions: These findings suggest that mutations of the BRAF gene are partly involved in the malignant transformation of the endometrium.