Identification and characterization of Birt-Hogg-Dube associated renal carcinoma
Identification and characterization of Birt-Hogg-Dube associated renal carcinoma
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DOI：
10.1002/path.2139
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发表时间：
2007-04-01
影响因子：
7.3
通讯作者：
Kishida, T.
中科院分区：
文献类型：
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作者：
Murakami, T.;Sano, F.;Kishida, T.
Birt-Hogg-Dube(BHD)基因与BHD综合征有关，BHD综合征是一种罕见的常染色体显性遗传病，其特征是良性毛囊肿瘤、自发性气胸和肾脏肿瘤，组织学各不相同。为了阐明它在肾肿瘤的发生发展中的作用，我们用SSCP-测序分析了100例不同组织亚型的散发性肾肿瘤的BHD突变。我们在外显子11的C8热点(c.1733insC)中发现了一个胚系插入突变，该突变与肾脏肿瘤的发生有很强的相关性。生殖系突变的患者患有孤立性肾细胞癌(RCC)，但没有任何其他BHD表现或家族史。肿瘤显示不同的细胞形态，主要是嗜酸性细胞和局灶性透明细胞的混合体，具有管状乳头状结构。在该肿瘤中，两个BHD等位基因都被胚系突变失活，并伴有杂合性丢失，实时定量聚合酶链式反应(RQ-PCR)检测到的BHD mRNA的量很低。RQ-PCR检测发现肾肿瘤亚型/肾单位节段特异性基因表达相对较高，表达相对较高的α-甲基酰辅酶A消旋酶(AMACR)和KIT癌基因，而相对较低的碳酸酐酶IX(CA9)、水通道蛋白1(AQP1)、CLDN7(CLDN7)、小白蛋白(PVALB)、氯通道KB(CLCNKB)和11-β-羟基类固醇脱氢酶2(HSD11B2)的表达特征不同。根据这8个基因的表达，对88个肾脏肿瘤进行进一步的聚类分析，将肿瘤细分为接近嗜酸细胞瘤和嫌色RCC，后者被认为是远端肾单位相关的肿瘤。这些数据表明，BHD的体细胞突变在日本患者中相对罕见。这项研究中发现的BHD突变的肾癌在形态和基因表达特征上都表现出不同的生物学特征，似乎偏离了我们目前对肾脏肿瘤分类的理解。版权所有(C)2007年大不列颠和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
The Birt-Hogg-Dube (BHD) gene is responsible for BHD syndrome, a rare autosomal dominant disease, characterized by benign hair follicle tumours, spontaneous pneumothorax and renal neoplasms with diverse histology. To elucidate its involvement in the development of renal neoplasms, we examined a total of 100 sporadic renal tumours with various histological subtypes for BHD mutation by SSCP-sequencing analyses. We found one germline insertion mutation in the C8 hotspot of exon 11 (c.1733insC), which is known to have a strong association with renal tumour occurrence. The germline-mutated patient suffered from solitary renal cell carcinoma (RCC) but did not have any other BHD manifestations or family history. The tumour revealed heterogeneous cytomorphology, mainly a mixture of eosinophilic and focally clear cells with tubulopapillary architecture. In this tumour, both BHD alleles were inactivated by germline mutation concomitant with loss of heterozygosity, and the amount of BHD mRNA detected by real-time quantitative PCR (RQ-PCR) was very low. Renal tumour subtype/nephron segment-specific gene expression detected by RQ-PCR demonstrated that the tumour expressed relatively high amounts of alpha-methylacyl-CoA racemase (AMACR) and the KIT oncogene, but relatively low amounts of carbonic anhydrase IX (CA9), aquaporin 1 (AQP1), claudin 7 (CLDN7), parvalbumin (PVALB), chloride channel Kb (CLCNKB) and 11-beta-hydroxysteroid dehydrogenase 2 (HSD11B2), suggesting diverse mRNA signatures. Further clustering analysis of 88 renal tumours based on expression of these eight genes sub-classified the tumour as close to oncocytomas and chromophobe RCCs, which are considered distal nephron-associated tumours. These data suggest that somatic mutation of BHD is relatively rare in Japanese patients. The BHD-mutated RCC identified in this study, which exhibits heterogeneous biological features in both morphology and gene expression signatures, seems to deviate from our current understanding of renal tumour classification. Copyright (c) 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.