Birt–Hogg–Dubé gene mutations in human endometrial carcinomas with microsatellite instability
Birt–Hogg–Dubé gene mutations in human endometrial carcinomas with microsatellite instability
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DOI：
10.1002/path.1992
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发表时间：
2006-07
期刊：
影响因子：
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通讯作者：
H. Fujii;W. Jiang;Toshiharu Matsumoto;K. Miyai;K. Sashara;N. Ohtsuji;O. Hino
中科院分区：
文献类型：
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作者：
H. Fujii;W. Jiang;Toshiharu Matsumoto;K. Miyai;K. Sashara;N. Ohtsuji;O. Hino
Birt-Hogg-Dubé（BHD）综合征是一种罕见的常染色体显性遗传性遗传性皮肤病，其特征是称为纤维毛囊瘤的良性错构瘤性皮肤病变，以及发生肺囊肿/气胸和各种形式肾细胞癌的风险增加。许多患者在BHD基因外显子11的高变多聚（C）8序列中存在插入/缺失突变。据报道，该突变热点也是微卫星不稳定性（MSI）散发性结直肠癌突变的靶点。为了验证BHD基因也是散发性子宫内膜癌微卫星不稳定性突变靶点的假设，对139例散发性子宫内膜癌进行了MSI状态和BHD基因第11外显子中poly（C）8区以及其他编码外显子突变的筛查。还评估了BAX基因的poly（G）8序列、MSH 6的poly（C）8序列和hMLH 1的甲基化状态。139例病例中有39例（28%）显示MSI。在39例BHD的MSI病例中，有5例（12.8%）检测到poly（C）8链的突变。其中，1例在外显子4中显示出额外的突变，可能满足肿瘤抑制基因的两次击中假设。39例MSI中10例（25.6%）检测到BAX基因突变。4例肿瘤同时显示BAX和BHD突变，两种基因突变之间存在显著正相关。未发现BHD状态与MSH 6突变或hMLH 1甲基化之间存在关联。当对多个病灶进行显微解剖并单独筛查突变时，在5例病例中的3例中，BHD突变在BAX基因突变后的肿瘤进展过程中被发现。综上所述，这些发现表明BHD基因是MSI子宫内膜癌的靶基因。然而，其突变频率低于BAX，并且BHD突变倾向于在另一个MSI靶基因BAX中获得突变后的肿瘤进展期间发生。版权所有© 2006大不列颠及爱尔兰病理学会。出版社：John Wiley & Sons，Ltd
Birt–Hogg–Dubé (BHD) syndrome is a rare form of autosomal dominantly inherited genodermatosis characterized by benign hamartomatous skin lesions named fibrofolliculomas, and an increased risk for developing pulmonary cyst/pneumothorax and various forms of renal cell carcinoma. Many of the patients harbour insertion/deletion mutations in the hypermutable poly(C)8 tract in exon 11 of the BHD gene. This mutational hot spot is also reported to be a target of mutation in microsatellite instability (MSI) sporadic colorectal cancer. To test the hypothesis that the BHD gene is also a mutational target in sporadic endometrial carcinoma with microsatellite instability, 139 cases of sporadic endometrial carcinoma were screened for MSI status, and mutations of the poly(C)8 tract in exon 11 as well as other coding exons of the BHD gene. The poly(G)8 tract of the BAX gene, the poly(C)8 tract of MSH6, and methylation status of hMLH1 were also assessed. Thirty‐nine of 139 cases (28%) showed MSI. Mutations in the poly(C)8 tract of BHD were detected in five of the 39 MSI cases (12.8%). Of these, one showed additional mutation in exon 4, possibly satisfying the two‐hit hypothesis of tumour suppressor genes. BAX gene mutation was detected in ten of the 39 MSI cases (25.6%). Four tumours showed both BAX and BHD mutations, and a significant positive association was found between mutations of the two genes. No association was found between BHD status and MSH6 mutation or hMLH1 methylation. When multiple foci were microdissected and individually screened for mutation, BHD mutations were shown to have been acquired during tumour progression, after mutation of the BAX gene, in three of five cases. Taken together, these findings show that the BHD gene is a target gene in MSI endometrial carcinoma. However, its mutational frequency is lower than that of BAX, and BHD mutation tends to occur during neoplastic progression after the acquisition of mutations in another MSI target gene, BAX. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.