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Review
. 2016 Mar;23(3):204-10.
doi: 10.1111/iju.13015. Epub 2015 Nov 25.

Birt-Hogg-Dubé syndrome: Clinical and molecular aspects of recently identified kidney cancer syndrome

Hisashi Hasumi  1 , Masaya Baba  2 , Yukiko Hasumi  3 , Mitsuko Furuya  4 , Masahiro Yao  1
Affiliations
Review

Birt-Hogg-Dubé syndrome: Clinical and molecular aspects of recently identified kidney cancer syndrome

Hisashi Hasumi et al. Int J Urol. 2016 Mar.

Abstract

Birt-Hogg-Dubé syndrome is an autosomal dominantly inherited disease that predisposes patients to develop fibrofolliculoma, lung cysts and bilateral multifocal renal tumors, histologically hybrid oncocytic/chromophobe tumors, chromophobe renal cell carcinoma, oncocytoma, papillary renal cell carcinoma and clear cell renal cell carcinoma. The predominant forms of Birt-Hogg-Dubé syndrome-associated renal tumors, hybrid oncocytic/chromophobe tumors and chromophobe renal cell carcinoma are typically less aggressive, and a therapeutic principle for these tumors is a surgical removal with nephron-sparing. The timing of surgery is the most critical element for postoperative renal function, which is one of the important prognostic factors for Birt-Hogg-Dubé syndrome patients. The folliculin gene (FLCN) that is responsible for Birt-Hogg-Dubé syndrome was isolated as a novel tumor suppressor for kidney cancer. Recent studies using murine models for FLCN, a protein encoded by the FLCN gene, and its two binding partners, folliculin-interacting protein 1 (FNIP1) and folliculin-interacting protein 2 (FNIP2), have uncovered important roles for FLCN, FNIP1 and FNIP2 in cell metabolism, which include AMP-activated protein kinase-mediated energy sensing, Ppargc1a-driven mitochondrial oxidative phosphorylation and mTORC1-dependent cell proliferation. Birt-Hogg-Dubé syndrome is a hereditary hamartoma syndrome, which is triggered by metabolic alterations under a functional loss of FLCN/FNIP1/FNIP2 complex, a critical regulator of kidney cell proliferation rate; a mechanistic insight into the FLCN/FNIP1/FNIP2 pathway could provide us a basis for developing new therapeutics for kidney cancer.

Keywords: Birt-Hogg-Dubé syndrome; folliculin; kidney cancer; mTORC1; mitochondria.

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