Mitochondrial DNA mutations distinguish bilateral multifocal renal oncocytomas from familial Birt-Hogg-Dubé tumors.
Mitochondrial DNA mutations distinguish bilateral multifocal renal oncocytomas from familial Birt-Hogg-Dubé tumors.
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DOI：
10.1038/modpathol.2015.101
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发表时间：
2015-11
期刊：
影响因子：
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通讯作者：
Linehan WM
中科院分区：
文献类型：
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作者：
Lang M;Vocke CD;Merino MJ;Schmidt LS;Linehan WM
嗜酸细胞瘤大多是良性肿瘤，其特征在于有缺陷的线粒体的积累，并且在散发的情况下，与破坏性线粒体DNA（mtDNA）突变相关。然而，mtDNA突变在Birt-Hogg-Dubé（BHD）患者肾肿瘤和其他具有明显遗传成分的肾嗜酸细胞瘤中的作用迄今尚未研究。在这里，我们的特点线粒体基因组在不同的肾脏肿瘤和调查的可能性，采用线粒体DNA测序分析活检标本，以帮助嗜酸细胞瘤的鉴别诊断。对25例双侧和多灶性（BMF）肾嗜酸细胞瘤、30例来自BHD患者的肾肿瘤和36例不同组织学的非嗜酸细胞肾肿瘤以及肾肿瘤活检样本中的全线粒体基因组进行测序。BMF嗜酸细胞瘤的mtDNA测序显示，所有肿瘤都携带破坏性突变，这损害了NADH-泛醌氧化还原酶的组装。来自给定BMF嗜酸细胞瘤患者的多个肿瘤主要具有相同的体细胞突变，并且这些患者的肾脏显示弥漫性嗜酸细胞增多。相反，BHD综合征患者的肾嗜酸细胞瘤和不同组织学类型的肾肿瘤未显示破坏性mtDNA突变。此外，我们证明了在活检标本中扩增和测序整个mtDNA是可行的，并且这些序列是肿瘤DNA的代表。这些结果表明，影响呼吸链复合体I的致病性mtDNA突变与非BHD相关性肾肿瘤中的嗜酸细胞瘤表型密切相关，并且活检组织的mtDNA序列可预测肿瘤基因型。这项工作支持呼吸链复合物中mtDNA突变作为肾嗜酸细胞瘤诊断标志物的作用。
Oncocytomas are mostly benign tumors characterized by accumulation of defective mitochondria, and in sporadic cases, are associated with disruptive mitochondrial DNA (mtDNA) mutations. However, the role mtDNA mutations play in renal tumors of Birt-Hogg-Dubé (BHD) patients and other renal oncocytomas with an apparent genetic component has not been investigated to date. Here we characterize the mitochondrial genome in different renal tumors and investigate the possibility of employing mtDNA sequencing analyses of biopsy specimens to aid in the differential diagnosis of oncocytomas. The entire mitochondrial genome was sequenced in 25 samples of bilateral and multifocal (BMF) renal oncocytomas, 30 renal tumors from BHD patients and 36 non-oncocytic renal tumors of different histologies as well as in biopsy samples of kidney tumors. mtDNA sequencing in BMF oncocytomas revealed that all tumors carry disruptive mutations, which impair the assembly of the NADH-ubiquinone oxidoreductase. Multiple tumors from a given BMF oncocytoma patient mainly harbor the same somatic mutation and the kidneys of these patients display diffuse oncocytosis. In contrast, renal oncocytomas of patients with BHD syndrome and renal tumors with different histologies do not show disruptive mtDNA mutations. Moreover, we demonstrate that it is feasible to amplify and sequence the entire mtDNA in biopsy specimens, and that these sequences are representative of the tumor DNA. These results show that pathogenic mtDNA mutations affecting complex I of the respiratory chain are strongly correlated with the oncocytoma phenotype in non-BHD-related renal tumors and that mtDNA sequences from biopsies are predictive of the tumor genotype. This work supports a role for mtDNA mutations in respiratory chain complexes as diagnostic markers for renal oncocytomas.