Where Birt–Hogg–Dubé meets Cowden Syndrome: mirrored genetic defects in two cases of syndromic oncocytic tumours

Pradella, Laura Maria; Lang, Martin; Kurelac, Ivana; Mariani, Elisa; Guerra, Flora; Zuntini, Roberta; Tallini, Giovanni; Mackay, Alan; Reis‐Filho, Jorge S.; Seri, Marco; Turchetti, Daniela; Gasparre, Giuseppe

doi:10.1038/ejhg.2013.8

Cited by 23 publications

(18 citation statements)

References 21 publications

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“…In such cases, however, somatic mutations of different genes were found, with an apparent correlation between the specific gene and the type of tumor developed [20,21]. In the present case, the markedly increased Akt phosphorylation detected in BC, if compared to normal tissue, led us to infer that a somatic event had cooperated in deregulating the PI3K/Akt/mTOR pathway and, presumably, in inducing carcinogenesis.…”

Section: Discussionmentioning

confidence: 56%

A novel deleterious PTEN mutation in a patient with early-onset bilateral breast cancer

et al. 2014

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BackgroundAn early age at Breast Cancer (BC) onset may be a hallmark of inherited predisposition, but BRCA1/2 mutations are only found in a minority of younger BC patients. Among the others, a fraction may carry mutations in rarer BC genes, such as TP53, STK11, CDH1 and PTEN. As the identification of women harboring such mutations allows for targeted risk-management, the knowledge of associated manifestations and an accurate clinical and family history evaluation are warranted.Case presentationWe describe the case of a woman who developed an infiltrating ductal carcinoma of the right breast at the age of 32, a contralateral BC at age 36 and another BC of the right breast at 40. When she was 39 years-old, during a dermatological examination, mucocutaneous features suggestive of Cowden Syndrome, a disorder associated to germ-line PTEN mutations, were noticed. PTEN genetic testing revealed the novel c.71A > T (p.Asp24Val) mutation, whose deleterious effect, suggested by conservation data and in silico tools, was definitely demonstrated by the incapacity of mutant PTEN to inhibit Akt phosphorylation when used to complement PTEN-null cells. In BC tissue, despite the absence of LOH or somatic mutations of PTEN, Akt phosphorylation was markedly increased in comparison to normal tissue, thus implying additional somatic events into the deregulation of the PI3K/Akt/mTOR pathway and, presumably, into carcinogenesis. Hence, known oncogenic mutations in PIK3CA (exons 10 and 21) and AKT1 (exon 2) were screened in tumor DNA with negative results, which suggests that the responsible somatic event(s) is a different, uncommon one.ConclusionThis case stresses the importance of clinical/genetic assessment of early-onset BC patients in order to identify mutation carriers, who are at high risk of new events, so requiring tailored management. Moreover, it revealed a novel PTEN mutation with pathogenic effect, pointing out, however, the need for further efforts to elucidate the molecular steps of PTEN-associated carcinogenesis.

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Section: Discussionmentioning

confidence: 56%

A novel deleterious PTEN mutation in a patient with early-onset bilateral breast cancer

et al. 2014

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“…A number of other clinical features have been reported in BHD patients including lipomas 12,13,16,19 , parathyroid adenomas 12,19 , thyroid nodules 19 and cancer 17,22 , and parotid oncocytomas 16,17 ,36,37,38 , but whether these are incidental findings or true phenotypic features of BHD syndrome is unclear.…”

Section: Clinical Manifestations Of Bhd Syndromementioning

confidence: 99%

Molecular genetics and clinical features of Birt–Hogg–Dubé syndrome

2015

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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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“…It is controversial whether colon polyps and colon cancer are associated with BHD syndrome . Because oncocytoma of parotid grand and thyroid cancers have been reported in BHD patients, a cervical surveillance of BHD patients might be considered …”

Section: Clinical Features Of Bhd Syndromementioning

confidence: 99%

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

Hasumi

et al. 2015

Int J of Urology

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Abbreviations & Acronyms AMPK = adenosine monophosphate-activated protein kinase BHD syndrome = Birt-Hogg -Dub e syndrome FLCN = folliculin FNIP1 = folliculininteracting protein 1 FNIP2 = folliculininteracting protein 2 HOCT = hybrid oncocytic/ chromophobe tumors mTOR = mammalian target of rapamycin mTORC1 = mammalian target of rapamycin complex 1 VHL = von Hippel-Lindau Abstract: Birt-Hogg-Dub e 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-Dub e 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 BirtHogg-Dub e syndrome patients. The folliculin gene (FLCN) that is responsible for BirtHogg-Dub e 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-Dub e 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.Key words: Birt-Hogg-Dub e syndrome, folliculin, kidney cancer, mitochondria, mTORC1.In 1977, three Canadian physicians, Birt, Hogg and Dub e, reported kindred with skin nodules that they named fibrofolliculoma.1 In 1999, the development of lung cysts and renal tumors in this kindred were reported, and this disorder was thereafter called BHD syndrome.2 In 2002, FLCN was identified as a novel tumor suppressor gene responsible for BHD syndrome, and a genetic test of FLCN is used as a diagnostic tool for BHD syndrome.3 Among the clinical triad of BHD syndrome, the management of kidney cancer is a key for the overall survival of BHD patients. Although FLCN was a totally novel protein with unknown function and no known domains at the time of discovery, recent studies using murine models have uncovered important roles for FLCN in cell metabolism. [4][5][6][7][8][9][10] In the present review article, we describe the clinical features and management of BHD syndrome, as well ...

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Where Birt–Hogg–Dubé meets Cowden Syndrome: mirrored genetic defects in two cases of syndromic oncocytic tumours

Cited by 23 publications

References 21 publications

A novel deleterious PTEN mutation in a patient with early-onset bilateral breast cancer

A novel deleterious PTEN mutation in a patient with early-onset bilateral breast cancer

Molecular genetics and clinical features of Birt–Hogg–Dubé syndrome

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

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