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Correspondence |

Multiple Desmoplastic Melanomas in Birt-Hogg-Dubé Syndrome and a Proposed Signaling Link Between Folliculin, the mTOR Pathway, and Melanoma Susceptibility

Raymond A. Cocciolone, MBBS; Kerry A. Crotty, MBBS; Lesley Andrews, MBBS; Nikolas K. Haass, MD, PhD; Fergal J. Moloney, MD
Arch Dermatol. 2010;146(11):1316-1318. doi:10.1001/archdermatol.2010.333.
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Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal dominant disorder characterized by the development of cutaneous and systemic tumors.1 The BHD gene (OMIM 135150) codes for the protein folliculin, which is expressed in multiple tissues including kidney, lung, and skin.1 Folliculin is thought to play a role in tumor suppression exerting an inhibitory effect on the growth-promoting mammalian target of rapamycin (mTOR) pathway.2 Mutations observed within the BHD gene in BHDS lead to the expression of inactive folliculin, ultimately resulting in mTOR pathway activation.3 Unregulated mTOR activation promotes cell growth and proliferation, as observed in melanoma pathogenesis.3,4

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Figure 2

The putative interaction of the folliculin/FNIP1/FNIP2/AMPK complex with the mammalian target of rapamycin (mTOR) pathway in melanoma. The BHD mutation in Birt-Hogg-Dubé syndrome leads to folliculin inactivation and thus to mTOR activation and may therefore play an additional role in tumor promotion. Rapamycin and its analogs inhibit mTOR and may compensate for the inactive folliculin/FNIP1/FNIP2/AMPK complex. AKT indicates proto-oncogene serine-threonine protein kinase; AMPK, adenosine monophosphate–activated protein kinase; FNIP, folliculin interacting protein; MAPK, mitogen-activated protein kinase; mTORC1, mTOR/raptor complex; mTORC2, mTOR/rictor complex; PI3K, phosphatidylinositol 3-kinase; Rheb, GTP-binding protein Ras homolog enriched in brain; TSC1/2, tuberous sclerosis complex 1/2.

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Figure 1

Clinical and histopathologic images. A, Multiple small skin-colored papules on the nose and cheek. Note site of prior melanoma excision and grafting on right cheek. B, Photomicrograph of fibrofolliculoma exhibiting an expanded follicular structure with internal strands of epithelium surrounded by loose connective tissue with an increase in fibroblasts (hematoxylin-eosin, original magnification ×4). C, Featureless nodule on left shoulder; histologic analysis showed a desmoplastic melanoma with a Breslow thickness of 2.4 mm.

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