Molecular genetics and clinical features of Birt-Hogg-Dubé syndrome.
Molecular genetics and clinical features of Birt-Hogg-Dubé syndrome.
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DOI：
10.1038/nrurol.2015.206
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发表时间：
2015-10
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--
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中科院分区：
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Birt-Hogg-Dubé（BHD）综合征是一种遗传性肾癌综合征，其中受影响的个体有发生良性皮肤纤维毛囊瘤、双侧肺囊肿和自发性气胸以及肾肿瘤的风险。在BHD综合征中发生的双侧多灶性肾肿瘤最常见的是混合嗜酸细胞肿瘤和嫌色细胞肾癌，但也可能出现其他组织学类型。17号染色体上FLCN基因的种系突变是BHD综合征的原因。BHD相关的肾肿瘤显示野生型FLCN等位基因通过体细胞突变或染色体丢失而失活，证实FLCN是一种符合经典二次打击模型的肿瘤抑制基因。FLCN与两种新的蛋白质FNIP 1和FNIP 2相互作用，并与mTOR的负调节因子AMPK相互作用。对FLCN缺陷细胞和动物模型的研究支持FLCN在调节AKT-mTOR通路中的作用。新出现的证据将FLCN与许多对细胞稳态重要的其他分子途径和细胞过程联系起来，这些分子途径和细胞过程在癌症中经常被失调，包括调节TFE 3/TFEB转录活性、通过Rag GTPases的氨基酸依赖性mTOR激活、TGF-β信号传导、PGC 1 α驱动的线粒体生物发生和自噬。目前，手术干预是BHD相关肾肿瘤的唯一治疗方法。对FLCN通路的进一步了解将有望导致这种疾病的有效治疗形式的发展。
Birt-Hogg-Dubé (BHD) syndrome is an inherited renal cancer syndrome in which affected individuals are at risk to develop benign, cutaneous fibrofolliculomas, bilateral pulmonary cysts and spontaneous pneumothoraces, and kidney tumors. Bilateral multifocal renal tumors that develop in BHD syndrome are most frequently hybrid oncocytic tumors and chromophobe renal carcinoma, but may present with other histologies. Germline mutations in the FLCN gene on chromosome 17 are responsible for BHD syndrome. BHD-associated renal tumors show inactivation of the wild-type FLCN allele by somatic mutation or chromosomal loss, confirming that FLCN is a tumor suppressor gene that fits the classic two-hit model. FLCN interacts with two novel proteins, FNIP1 and FNIP2, and with AMPK, a negative regulator of mTOR. Studies with FLCN-deficient cell and animal models support a role for FLCN in modulating the AKT-mTOR pathway. Emerging evidence links FLCN with a number of other molecular pathways and cellular processes important for cell homeostasis that are frequently deregulated in cancer, including regulation of TFE3/TFEB transcriptional activity, amino acid-dependent mTOR activation through Rag GTPases, TGF-β signaling, PGC1α-driven mitochondrial biogenesis, and autophagy. Currently, surgical intervention is the only therapy available for BHD-associated renal tumors. Further understanding of the FLCN pathway will hopefully lead to the development of effective forms of therapy for this disease.
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