BHD-associated kidney cancer exhibits unique molecular characteristics and a wide variety of variants in chromatin remodeling genes
BHD-associated kidney cancer exhibits unique molecular characteristics and a wide variety of variants in chromatin remodeling genes
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DOI：
10.1093/hmg/ddy181
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发表时间：
2018-08-01
影响因子：
3.5
通讯作者：
Yao, Masahiro
中科院分区：
文献类型：
--
作者：
Hasumi, Hisashi;Furuya, Mitsuko;Yao, Masahiro
Birt-Hogg-Dube （BHD）综合征是一种遗传性肾癌综合征，患者易患肾癌、皮肤纤维滤泡瘤和肺囊肿。其相关基因FLCN是肾癌的抑癌基因，通过调控线粒体氧化代谢在能量稳态中发挥重要作用。然而，flcn缺乏导致肾肿瘤发生的过程尚不清楚。为了阐明bhd相关肾癌的分子发病机制，我们使用新一代测序技术进行了全外显子组测序分析，并使用液相色谱-质谱联用和气相色谱-质谱联用进行了代谢物分析。bhd相关肾癌的全外显子组测序分析显示，bhd相关肾癌的拷贝数变异与已经报道的散发性病例有很大不同。在体细胞变异分析中，bhd相关肾癌中很少有常见的变异；然而，染色质重塑基因的变异在bhd相关的肾癌中经常被观察到（17/29,59%）。bhd相关肾癌的代谢物分析显示，在flcn缺乏的情况下，代谢重编程可能会导致氧化还原调节上调，这可能会中和呼吸能力增加的线粒体产生的活性氧。bhd相关性肾癌表现出与散发性肾癌完全不同的独特分子特征，为flcn缺乏下的肿瘤发生机制提供了新的认识，也为开发新的肾癌治疗方法奠定了基础。
Birt-Hogg-Dube (BHD) syndrome is a hereditary kidney cancer syndrome, which predisposes patients to develop kidney cancer, cutaneous fibrofolliculomas and pulmonary cysts. The responsible gene FLCN is a tumor suppressor for kidney cancer, which plays an important role in energy homeostasis through the regulation of mitochondrial oxidative metabolism. However, the process by which FLCN-deficiency leads to renal tumorigenesis is unclear. In order to clarify molecular pathogenesis of BHD-associated kidney cancer, we conducted whole-exome sequencing analysis using next-generation sequencing technology as well as metabolite analysis using liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry. Whole-exome sequencing analysis of BHD-associated kidney cancer revealed that copy number variations of BHD-associated kidney cancer are considerably different from those already reported in sporadic cases. In somatic variant analysis, very few variants were commonly observed in BHD-associated kidney cancer; however, variants in chromatin remodeling genes were frequently observed in BHD-associated kidney cancer (17/29 tumors, 59%). Metabolite analysis of BHD-associated kidney cancer revealed metabolic reprogramming toward upregulated redox regulation which may neutralize reactive oxygen species potentially produced from mitochondria with increased respiratory capacity under FLCN-deficiency. BHD-associated kidney cancer displays unique molecular characteristics that are completely different from sporadic kidney cancer, providing mechanistic insight into tumorigenesis under FLCN-deficiency as well as a foundation for development of novel therapeutics for kidney cancer.