FLCN

Gene Summary

Gene:FLCN; folliculin
Aliases: BHD, FLCL, DENND8B
Location:17p11.2
Summary:This gene is located within the Smith-Magenis syndrome region on chromosome 17. Mutations in this gene are associated with Birt-Hogg-Dube syndrome, which is characterized by fibrofolliculomas, renal tumors, lung cysts, and pneumothorax. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:folliculin
Source:NCBIAccessed: 30 August, 2019

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • X-Ray Computed Tomography
  • Cancer Gene Expression Regulation
  • Proteins
  • Pneumothorax
  • Adolescents
  • Wnt Signaling Pathway
  • Proto-Oncogene Proteins
  • Pedigree
  • Uterine Cancer
  • Adenoma, Oxyphilic
  • Chromosome 17
  • Genetic Predisposition
  • Renal Cell Carcinoma
  • Base Sequence
  • Birt-Hogg-Dube Syndrome
  • Mutation
  • Breast Cancer
  • Kidney Cancer
  • DNA Mutational Analysis
  • Lung
  • Lung Diseases
  • Tumor Suppressor Gene
  • Skin Diseases
  • Skin Cancer
  • TOR Serine-Threonine Kinases
  • Germ-Line Mutation
  • Differential Diagnosis
  • Kidney
  • Cysts
  • Hereditary Neoplastic Syndromes
  • Exons
  • Fibroma
  • Salivary Glands
  • Prostate Cancer
  • Rats, Mutant Strains
  • Uniparental Disomy
  • Genetic Testing
  • Signal Transduction
  • Tumor Suppressor Proteins
  • Phenotype
  • Ultrasonography, Prenatal
  • Twins, Monozygotic
Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: FLCN (cancer-related)

Qian L, Su W, Wang Y, et al.
Synthesis and characterization of gold nanoparticles from aqueous leaf extract of Alternanthera sessilis and its anticancer activity on cervical cancer cells (HeLa).
Artif Cells Nanomed Biotechnol. 2019; 47(1):1173-1180 [PubMed] Related Publications
Cervical cancer is the third most common highest mortality in women worldwide. The use of standard chemotherapeutic drugs against cervical cancer patients received several side effects. Therefore, we focused phytoconsituents-mediated synthesis of gold nanoparticles (AuNPs) considered as greatest attention in the treatment of cervical cancer. In this present study, we reported that green synthesis of AuNPs by using with Alternanthera Sessilis aqueous extract. Synthesis of AuNPs were characterized by UV visible spectroscopy, energy dispersive X-ray (EDX), selected area diffraction pattern (SAED), Fourier transform infrared spectroscopy (FTIR), high-resolution transmission electron microscopy (HR-TEM) and atomic force microscope. Synthesized AuNPs confirmed by the UV absorption maximum at 535 and crystal structure of gold AuNPs was further confirmed by EDX and SAED. TEM and atomic force microscopy images show the size and morphological distribution of nanoparticles. FTIR analysis was confirmed the hydroxyl groups, amine and alkaline groups of biomolecules are present in the AuNPs. Moreover, AuNPs induce cytotoxicity in cervical cancer cells and also induce apoptosis through modulating intrinsic apoptotic mechanisms in cervical cancer cells. This green synthesis of AuNPs from Alternanthera sessilis approach was easy, large scaled up and eco-friendly.

Furuya M, Nakatani Y
Pathology of Birt-Hogg-Dubé syndrome: A special reference of pulmonary manifestations in a Japanese population with a comprehensive analysis and review.
Pathol Int. 2019; 69(1):1-12 [PubMed] Related Publications
Birt-Hogg-Dubé (BHD) syndrome is a rare genetic disorder characterized by cutaneous fibrofolliculomas, pulmonary cysts and renal cell carcinomas. Affected individuals inherit germline mutations in the folliculin gene (FLCN). Approximately 150 pathogenic FLCN variants have been identified worldwide. Many Japanese probands of BHD syndrome were first identified by pulmonologists and/or radiologists during treatment of pneumothoraces. Lung specimens obtained through video-assisted thoracoscopic surgery (VATS) have characteristic features unique to BHD syndrome; however, pathologists often miss key findings and diagnose patients with "bullae/blebs". The pleural and subpleural cysts of BHD syndrome-associated lung diseases are often modified by tissue remodeling and can be difficult to distinguish from emphysematous bullae/blebs. Intraparenchymal unruptured cysts tend to retain distinctive features that are different from other cystic lung diseases. Here, we review the clinicopathological findings of BHD syndrome in a Japanese population based on data from 200 probands diagnosed by genetic testing and a total of 520 symptomatic family members identified through BHD-NET Japan (http://www.bhd-net.jp/). Detailed morphology of pulmonary cysts obtained from VATS and autopsied lung specimens are described, and pathological clues for differentiating miscellaneous cystic lung disorders are discussed.

Bashanfer SAA, Saleem M, Heidenreich O, et al.
Disruption of MAPK1 expression in the ERK signalling pathway and the RUNX1‑RUNX1T1 fusion gene attenuate the differentiation and proliferation and induces the growth arrest in t(8;21) leukaemia cells.
Oncol Rep. 2019; 41(3):2027-2040 [PubMed] Related Publications
The t(8;21) translocation is one of the most frequent chromosome abnormalities associated with acute myeloid leukaemia (AML). This abberation deregulates numerous molecular pathways including the ERK signalling pathway among others. Therefore, the aim of the present study was to investigate the gene expression patterns following siRNA‑mediated suppression of RUNX1‑RUNX1T1 and MAPK1 in Kasumi‑1 and SKNO‑1 cells and to determine the differentially expressed genes in enriched biological pathways. BeadChip microarray and gene ontology analysis revealed that RUNX1‑RUNX1T1 and MAPK1 suppression reduced the proliferation rate of the t(8;21) cells with deregulated expression of several classical positive regulator genes that are otherwise known to enhance cell proliferation. RUNX1‑RUNX1T1 suppression exerted an anti‑apoptotic effect through the overexpression of BCL2, BIRC3 and CFLAR genes, while MAPK1 suppression induced apopotosis in t(8;21) cells by the apoptotic mitochondrial changes stimulated by the activity of upregulated TP53 and TNFSF10, and downregulated JUN gene. RUNX1‑RUNX1T1 suppression supported myeloid differentiation by the differential expression of CEBPA, CEBPE, ID2, JMJD6, IKZF1, CBFB, KIT and CDK6, while MAPK1 depletion inhibited the differentiation of t(8;21) cells by elevated expression of ADA and downregulation of JUN. RUNX1‑RUNX1T1 and MAPK1 depletion induced cell cycle arrest at the G0/G1 phase. Accumulation of cells in the G1 phase was largely the result of downregulated expression of TBRG4, CCNE2, FOXO4, CDK6, ING4, IL8, MAD2L1 and CCNG2 in the case of RUNX1‑RUNX1T1 depletion and increased expression of RASSF1, FBXO6, DADD45A and P53 in the case of MAPK1 depletion. Taken together, the current results demonstrate that MAPK1 promotes myeloid cell proliferation and differentiation simultaneously by cell cycle progression while suppresing apoptosis.

Kim SH, Park WS, Chung J
Tumour heterogeneity in triplet-paired metastatic tumour tissues in metastatic renal cell carcinoma: concordance analysis of target gene sequencing data.
J Clin Pathol. 2019; 72(2):152-156 [PubMed] Related Publications
AIMS: The aim of the present study was to determine the concordant correlation in the expression of 88 target genes from triple-paired metastatic tissues in individual patients with metastatic renal carcinoma (mRCC) using a target gene sequencing (TGS) approach.
METHODS: Between 2002 and 2017, a total of 350 triple-paired metastatic tissue samples from 262 patients with mRCC obtained from either nephrectomy or metastasectomy were used for TGS of 88 candidate genes. After quality check, 243 tissue samples from 81 patients were finally applied to TGS. The concordance of triple-paired tissues was analysed with the 88 TGS panels using bioinformatics tools.
RESULTS: Among 81 patients, alterations were observed in 42 (51.9%) for any of the 88 mRCC panel genes; however, no pathogenic gene was detected in 38 (39.5%) . Concordance >95% for altered gene expression among the three tissues was reported in 12 (28.6%) patients, while concordance >95% within two tissues was reported in 30 (71.4%); concordance <50% was reported in the remaining eight patients. Considering several types of genetic alterations, including deletions, insertions, missense and nonsense mutations, and splice variants, genes most frequently detected with genetic alterations in the patients with mRCC were
CONCLUSIONS: The study provides reference information on the genetic alterations at various organ sites and the multi-heterogeneity of mRCC tissues. The concordance of pathogenic gene alterations within tissues was not high, and approximately half of the patients showed no pathogenic gene alterations at all.

Kumar MS, Adki KM
Marine natural products for multi-targeted cancer treatment: A future insight.
Biomed Pharmacother. 2018; 105:233-245 [PubMed] Related Publications
Cancer is world's second largest alarming disease, which involves abnormal cell growth and have potential to spread to other parts of the body. Most of the available anticancer drugs are designed to act on specific targets by altering the activity of involved transporters and genes. As cancer cells exhibit complex cellular machinery, the regeneration of cancer tissues and chemo resistance towards the therapy has been the main obstacle in cancer treatment. This fact encourages the researchers to explore the multitargeted use of existing medicines to overcome the shortcomings of chemotherapy for alternative and safer treatment strategies. Recent developments in genomics-proteomics and an understanding of the molecular pharmacology of cancer have also challenged researchers to come up with target-based drugs. The literature supports the evidence of natural compounds exhibiting antioxidant, antimitotic, anti-inflammatory, antibiotic as well as anticancer activity. In this review, we have selected marine sponges as a prolific source of bioactive compounds which can be explored for their possible use in cancer and have tried to link their role in cancer pathway. To prove this, we revisited the literature for the selection of cancer genes for the multitargeted use of existing drugs and natural products. We used Cytoscape network analysis and Search tool for retrieval of interacting genes/ proteins (STRING) to study the possible interactions to show the links between the antioxidants, antibiotics, anti-inflammatory and antimitotic agents and their targets for their possible use in cancer. We included total 78 pathways, their genes and natural compounds from the above four pharmacological classes used in cancer treatment for multitargeted approach. Based on the Cytoscape network analysis results, we shortlist 22 genes based on their average shortest path length connecting one node to all other nodes in a network. These selected genes are CDKN2A, FH, VHL, STK11, SUFU, RB1, MEN1, HRPT2, EXT1, 2, CDK4, p14, p16, TSC1, 2, AXIN2, SDBH C, D, NF1, 2, BHD, PTCH, GPC3, CYLD and WT1. The selected genes were analysed using STRING for their protein-protein interactions. Based on the above findings, we propose the selected genes to be considered as major targets and are suggested to be studied for discovering marine natural products as drug lead in cancer treatment.

Furuya M, Kobayashi H, Baba M, et al.
Splice-site mutation causing partial retention of intron in the FLCN gene in Birt-Hogg-Dubé syndrome: a case report.
BMC Med Genomics. 2018; 11(1):42 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder caused by germline mutations in the folliculin gene (FLCN). Nearly 150 pathogenic mutations have been identified in FLCN. The most frequent pattern is a frameshift mutation within a coding exon. In addition, splice-site mutations have been reported, and previous studies have confirmed exon skipping in several cases. However, it is poorly understood whether there are any splice-site mutations that cause translation of intron regions in FLCN.
CASE PRESENTATION: A 59-year-old Japanese patient with multiple pulmonary cysts and pneumothorax was hospitalized due to dyspnea. BHD was suspected and genetic testing was performed. The patient exhibited the splice-site mutation of FLCN in the 5' end of intron 9 (c.1062 + 1G > A). Total mRNA was extracted from pulmonary cysts, and RT-PCR assessment and sequence analyses were done. Two distinct bands were generated; one was wild-type and the other was a larger-sized mutant. Sequence analysis of the latter transcript revealed the insertion of 130 base pairs of intron 9 from the beginning of the splice-site between exons 9 and 10.
CONCLUSION: To our knowledge, this is the first report of distinct intron insertion using a BHD patient's diseased tissue-derived mRNA. The present case suggests that a splice-site mutation can lead to exon skipping as well as intron reading mRNA. The splicing process may be dependent in part on whether the donor or acceptor site is affected.

Maher ER
Hereditary renal cell carcinoma syndromes: diagnosis, surveillance and management.
World J Urol. 2018; 36(12):1891-1898 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Genetic factors have been implicated in the pathogenesis of renal cell carcinoma (RCC), with around 3% of cases having a family history. A greater knowledge of the genetics of inherited RCC has the potential to translate into novel therapeutic targets for sporadic RCC.
METHODS: A literature review was performed summarising the current knowledge on hereditary RCC diagnosis, surveillance and management.
RESULTS: Familial RCC is usually inherited in an autosomal dominant manner, although inherited RCC may present without a relevant family history. A number of familial RCC syndromes have been identified. Familial non-syndromic RCC is suspected when ≥ 2 relatives are affected in the absence of syndromic features, although clear diagnostic criteria are lacking. Young age at onset and bilateral/multicentric tumours are recognised characteristics which should prompt molecular genetic analysis. Surveillance in individuals at risk of inherited RCC aims to prevent morbidity and mortality via early detection of tumours. Though screening and management guidelines for some inherited RCC syndromes (e.g. von Hippel-Lindau disease, Birt-Hogg-Dube syndrome, hereditary leiomyomatosis) are well defined for rare cause of inherited RCC (e.g. germline BAP1 mutations), there is limited information regarding the lifetime RCC risks and the most appropriate screening modalities.
CONCLUSION: Increasing knowledge of the natural history and genetic basis has led to characterisation and tailored management of hereditary RCC syndromes. International data sharing of inherited RCC gene variant information may enable evidence-based improvements in the diagnosis, surveillance protocols and management of these rare conditions.

Sattler EC, Steinlein OK
Delayed diagnosis of Birt-Hogg-Dubé syndrome due to marked intrafamilial clinical variability: a case report.
BMC Med Genet. 2018; 19(1):45 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Birt-Hogg-Dubé syndrome is a genetic syndrome caused by mutations in the FLCN gene. The main symptoms are lung bullae and pneumothorax, benign and malignant kidney tumors, and facial fibrofolliculoma. The risk of pneumothorax is considerable between ages 20-40 years, but decreases markedly after this age range and first-time pneumothorax after age 50 years is rare. Fibrofolliculomas usually occur between ages 35 and 45 years, while the risk for kidney cancer increases steadily with age, starting in young adulthood. However, we demonstrate here that within the same family patients might develop symptoms significantly before or after the usual age range, obscuring the typical clinical pattern and delaying diagnosis.
CASE PRESENTATION: The 43 year old index patient had a history of lung bullae and recurrent pneumothoraces starting 14 years earlier. His father (age 83 years) and one of the paternal uncles experienced their first pneumothorax unusually late after the age of 60 years. The uncle subsequently had four more pneumothoraces, and was diagnosed with kidney in his early 70s. Considerable differences in age of onset were also observed with regard to facial fibrofolliculomas that both paternal uncles developed very early around age 20 years, but which the father only started to show in his eighth decade. Birt-Hogg-Dubé syndrome was finally diagnosed when the index patient started to develop fibrofolliculomas within the typical age range.
CONCLUSIONS: The family described here illustrates that Birt-Hogg-Dubé syndrome can be difficult to recognize, if presenting with considerable intrafamilial clinical variability. With a life-time kidney cancer risk of about 14-35% the consequences of delayed diagnosis might be grave for the affected family members. The possibility of Birt-Hogg-Dubé syndrome should therefore be taken into consideration in apparently sporadic patients presenting with lung bullae and pneumothorax.

Steinlein OK, Ertl-Wagner B, Ruzicka T, Sattler EC
Birt-Hogg-Dubé syndrome: an underdiagnosed genetic tumor syndrome.
J Dtsch Dermatol Ges. 2018; 16(3):278-283 [PubMed] Related Publications
Birt-Hogg-Dubé syndrome (BHD, also referred to as Hornstein-Knickenberg syndrome) is an autosomal dominant tumor syndrome caused by mutations in the FLCN gene located on chromosome 17. Depending on their age, patients with BHD may exhibit various clinical signs and symptoms. Disease severity can vary greatly among members of the same family. Early symptoms include basal lung cysts, which can lead to recurrent spontaneous pneumothoraces. The majority of patients (> 90 %) develop multiple fibrofolliculomas, especially on the face and upper trunk, in the second or third decade of life. Given the 12-34 % lifetime risk of developing benign or malignant renal tumors, targeted screening programs are prognostically crucial. While these renal tumors may belong to various histological subtypes, common variants include multifocal - sometimes bilateral - chromophobe and oncocytic hybrid tumors. Early diagnosis and adequate long-term care of families with BHD require interdisciplinary cooperation.

Hou X, Zhou Y, Peng Y, et al.
Birt-Hogg-Dubé syndrome in two Chinese families with mutations in the FLCN gene.
BMC Med Genet. 2018; 19(1):14 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Birt-Hogg-Dubé syndrome is an autosomal dominant hereditary condition caused by mutations in the folliculin-encoding gene FLCN (NM_144997). It is associated with skin lesions such as fibrofolliculoma, acrochordon and trichodiscoma; pulmonary lesions including spontaneous pneumothorax and pulmonary cysts and renal cancer.
METHODS: Genomic DNA was extracted from peripheral venous blood samples of the propositi and their family members. Genetic analysis was performed by whole exome sequencing and Sanger sequencing aiming at corresponding exons in FLCN gene to explore the genetic mutations of these two families.
RESULTS: In this study, we performed genetic analysis by whole exome sequencing and Sanger sequencing aiming at corresponding exons in FLCN gene to explore the genetic mutations in two Chinese families. Patients from family 1 mostly suffered from pneumothorax and pulmonary cysts, several of whom also mentioned skin lesions or kidney lesions. While in family 2, only thoracic lesions were found in the patients, without any other clinical manifestations. Two FLCN mutations have been identified: One is an insertion mutation (c.1579_1580insA/p.R527Xfs on exon 14) previously reported in three Asian families (one mainland family and two Taiwanese families); while the other is a firstly reviewed mutation in Asian population (c.649C > T / p.Gln217X on exon 7) that ever been detected in a French family.
CONCLUSIONS: Overall, The detection of these two mutations expands the spectrum of FLCN mutations and will provide insight into genetic diagnosis and counseling of Birt-Hogg-Dubé syndrome.

Bock K, Lohse Z, Madsen PH, Hilberg O
Birt-Hogg-Dubé syndrome: spontaneous pneumothorax as a first symptom.
BMJ Case Rep. 2018; 2018 [PubMed] Related Publications
Birt-Hogg-Dubé syndrome (BHDS) is a rare hereditary autosomal dominant condition characterised by benign cutaneous lesions, lung cysts, increased risk of spontaneous pneumothorax and renal cancer. It shows great heterogenous presentation within and between affected families. We report a case of a Danish female patient with recurrent pneumothoraces as the first symptom of BHDS. Over the years, she developed skin changes, and a family history of skin changes, pneumothoraces and renal cancer was discovered. BHDS was suspected, a genetic analysis was performed and a pathogenic variation c.1285delC in FLCN gene was detected in the patient. As we stated the diagnosis BHDS, we discovered several undiagnosed family members all of them now entering a lifelong follow-up programme with abdominal imaging because of the increased risk of developing renal cancer. BHDS should be known to oncologists, dermatologists and pulmonologists as the patients most often present to these medical disciplines.

Callari M, Batra AS, Batra RN, et al.
Computational approach to discriminate human and mouse sequences in patient-derived tumour xenografts.
BMC Genomics. 2018; 19(1):19 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Patient-Derived Tumour Xenografts (PDTXs) have emerged as the pre-clinical models that best represent clinical tumour diversity and intra-tumour heterogeneity. The molecular characterization of PDTXs using High-Throughput Sequencing (HTS) is essential; however, the presence of mouse stroma is challenging for HTS data analysis. Indeed, the high homology between the two genomes results in a proportion of mouse reads being mapped as human.
RESULTS: In this study we generated Whole Exome Sequencing (WES), Reduced Representation Bisulfite Sequencing (RRBS) and RNA sequencing (RNA-seq) data from samples with known mixtures of mouse and human DNA or RNA and from a cohort of human breast cancers and their derived PDTXs. We show that using an In silico Combined human-mouse Reference Genome (ICRG) for alignment discriminates between human and mouse reads with up to 99.9% accuracy and decreases the number of false positive somatic mutations caused by misalignment by >99.9%. We also derived a model to estimate the human DNA content in independent PDTX samples. For RNA-seq and RRBS data analysis, the use of the ICRG allows dissecting computationally the transcriptome and methylome of human tumour cells and mouse stroma. In a direct comparison with previously reported approaches, our method showed similar or higher accuracy while requiring significantly less computing time.
CONCLUSIONS: The computational pipeline we describe here is a valuable tool for the molecular analysis of PDTXs as well as any other mixture of DNA or RNA species.

Brown S, Brennan P, Rajan N
Inherited skin tumour syndromes.
Clin Med (Lond). 2017; 17(6):562-567 [PubMed] Free Access to Full Article Related Publications
This article provides an overview of selected genetic skin conditions where multiple inherited cutaneous tumours are a central feature. Skin tumours that arise from skin structures such as hair, sweat glands and sebaceous glands are called skin appendage tumours. These tumours are uncommon, but can have important implications for patient care. Certain appendageal tumours, particularly when multiple lesions are seen, may indicate an underlying genetic condition. These tumours may not display clinical features that allow a secure diagnosis to be made, necessitating biopsy and dermatopathological assessment. Coupled with robust clinical assessment, biopsy findings can guide genetic testing as, increasingly, the causative genes are known for these conditions. Here we review illustrative examples of appendageal tumours and relevant advances made in genetic discovery, and suggest when referral to a geneticist may need to be considered.

Daccord C, Nicod LP, Lazor R
Cystic Lung Disease in Genetic Syndromes with Deficient Tumor Suppressor Gene Function.
Respiration. 2017; 94(6):467-485 [PubMed] Related Publications
Cystic lung diseases constitute a distinct group of rare lung disorders, among which two result from monogenic defects affecting tumor suppressor genes: lymphangioleiomyomatosis, either sporadic or associated with tuberous sclerosis complex, and Birt-Hogg-Dubé syndrome. These disorders have similarities in their clinical expression, including occurrence in young adults, multiple pulmonary cysts, recurrent pneumothorax, skin hamartomas, and renal tumors. However, they markedly differ in their gender distribution, pathogenesis, disease course, and prognosis. Our knowledge on these two rare conditions is rapidly expanding. Management of lymphangioleiomyomatosis has substantially improved in the past decade with the understanding of its pathogenic mechanisms, the discovery of an effective therapy, and development of large cohorts and international guidelines. Birt-Hogg-Dubé syndrome has been described more recently and still awaits deeper understanding of its pathophysiology.

Iwabuchi C, Ebana H, Ishiko A, et al.
Skin lesions of Birt-Hogg-Dubé syndrome: Clinical and histopathological findings in 31 Japanese patients who presented with pneumothorax and/or multiple lung cysts.
J Dermatol Sci. 2018; 89(1):77-84 [PubMed] Related Publications
BACKGROUND: Birt-Hogg-Dubé syndrome (BHDS) (OMIM #135150) is an autosomal dominant disease, characterized by fibrofolliculomas (FFs) of the skin, pulmonary cysts with/without pneumothorax, and renal tumors. The prevalence of skin manifestations reported for Japanese BHDS patients is lower (<30%) compared with that of Western countries (75∼90%), which appear to be underestimated.
OBJECTIVE: To precisely examine the prevalence of skin lesions with dermoscopy and histopathology with reference to genetic analyses.
METHODS: We studied 31 patients (47.0±13.2years old, range 15-71) consisting of 26 unrelated families consecutively from May 2013 to June 2015 specifically for skin-colored papules on their faces and cervicothoracic regions. Patients initially suspected of BHDS from multiple pulmonary cysts that resulted in pneumothorax (30/31; 96.8%) received dermoscopic examinations and skin biopsies if applicable. The diagnosis of BHDS was established by folliculin (FLCN) genetic testing, and the results were compared to the histopathological findings of FFs or trichodiscomas (TDs).
RESULTS: FLCN germline mutation was demonstrated in 25/26 (96.2%) unrelated families tested and 28/29 patients (96.6%) tested. Skin lesions were recognized in 26/31 patients (83.9%); skin biopsies were performed in 23 patients of whom FFs and/or TDs were histologically demonstrated in 17 (73.9%). Although our study population included patients whose skin manifestations were evaluated prior to or after FLCN genetic testing, skin lesions were clearly prevalent and recognizable irrespective of whether genetic testing was or wasn't done. When examined with dermoscopy, distinct FFs appeared as well-demarcated areas of pallor with central follicular openings in 13 of 15 FF-bearing patients (86.7%); however, those manifestations were not recognized for TD.
CONCLUSIONS: Skin lesions appear to be more prevalent than previously reported (<30% vs.73.9%) in Japanese BHDS patients. Dermoscopy is a useful diagnostic aid for finding FFs.

Eble JN, Delahunt B
Emerging entities in renal cell neoplasia: thyroid-like follicular renal cell carcinoma and multifocal oncocytoma-like tumours associated with oncocytosis.
Pathology. 2018; 50(1):24-36 [PubMed] Related Publications
The list of accepted entities of renal cell neoplasia has burgeoned since the turn of the century through recognition of rare tumour types and the discovery of genetic mutations driving renal neoplasia syndromes. This growth has not finished and in this report we present examples of each of these types which were not included in the 2016 World Health Organization classification of renal neoplasia, but are candidates for inclusion in the next edition of the classification. Thyroid-like follicular renal cell carcinoma is a rare tumour type with a distinctive microscopic appearance resembling follicles of the thyroid gland. Thirty-nine cases have been described and the findings have been reasonably consistent. Oncocytoma-like tumours associated with oncocytosis arise as a result of somatic mutations in the mitochondrial genome. The differential diagnosis is mainly with the renal lesions of the Birt-Hogg-Dubé syndrome, which is the result of germline mutations in the folliculin gene. Patients with oncocytoma-like tumours associated with oncocytosis are at great risk of developing renal failure as the proliferating lesions replace the renal parenchyma. Oncocytoma-like tumours have never been found to metastasise.

Oliveira RC, Tavares E, Sousa V, Figueiredo A
Birt-Hogg-Dubé syndrome: awareness is important!
BMJ Case Rep. 2017; 2017 [PubMed] Related Publications
Birt-Hogg-Dubé (BHD) is a rare syndrome of inherited renal cell carcinomas, characterised by cutaneous lesions and pulmonary cysts and pneumothorax in a vast majority of the patients. Awareness of this syndrome is important in order to refer patients for genetic counselling and personalised follow-up as soon as possible. We describe a case of a 30-year-old female referred to our institution due to incidental discovery of solid bilateral renal masses. Renal biopsies were consistent with chromophobe tumour, and bilateral nephrectomy was performed. Gross examination revealed deformed kidneys with 28 brown and solid lesions, size variable between 0.1 and 6 cm, histologically corresponding to renal cell carcinomas, chromophobe type. Genetic test was required that showed a c.573delGAinsT frameshift mutation in heterozigosity at the folliculin gene, consistent with BHD diagnosis.

Slavin T, Neuhausen SL, Rybak C, et al.
Genetic Gastric Cancer Susceptibility in the International Clinical Cancer Genomics Community Research Network.
Cancer Genet. 2017; 216-217:111-119 [PubMed] Free Access to Full Article Related Publications
Few susceptibility genes for gastric cancer have been identified. We sought to identify germline susceptibility genes from participants with gastric cancer from an international hereditary cancer research network. Adults with gastric cancer of any histology, and with a germline DNA sample (n = 51), were retrospectively selected. For those without previously identified germline mutations (n = 43), sequencing was performed for 706 candidate genes. Twenty pathogenic or likely pathogenic variants were identified among 18 participants. Eight of the 18 participants had previous positive clinical testing, including six with CDH1 pathogenic or likely pathogenic variants, and two with pathogenic MSH2 and TP53 variants. Of the remaining 10, six were in BRCA1 DNA damage response pathway genes (ATM, ATR, BRCA2, BRIP1, FANCC, TP53), other variants were identified in CTNNA1, FLCN, SBDS, and GNAS. Participants identified with pathogenic or likely pathogenic variants were younger at gastric cancer diagnosis than those without, 39.1 versus 48.0 years, and over 50% had a close family member with gastric cancer (p-values < 0.0001). In conclusion, many participants were identified with mutations in clinically-actionable genes. Age of onset and family history of gastric cancer were mutation status predictors. Our findings support multigene panels in identifying gastric cancer predisposition.

Schmidt LS, Linehan WM
FLCN: The causative gene for Birt-Hogg-Dubé syndrome.
Gene. 2018; 640:28-42 [PubMed] Free Access to Full Article Related Publications
Germline mutations in the novel tumor suppressor gene FLCN are responsible for the autosomal dominant inherited disorder Birt-Hogg-Dubé (BHD) syndrome that predisposes to fibrofolliculomas, lung cysts and spontaneous pneumothorax, and an increased risk for developing kidney tumors. Although the encoded protein, folliculin (FLCN), has no sequence homology to known functional domains, x-ray crystallographic studies have shown that the C-terminus of FLCN has structural similarity to DENN (differentially expressed in normal cells and neoplasia) domain proteins that act as guanine nucleotide exchange factors (GEFs) for small Rab GTPases. FLCN forms a complex with folliculin interacting proteins 1 and 2 (FNIP1, FNIP2) and with 5' AMP-activated protein kinase (AMPK). This review summarizes FLCN functional studies which support a role for FLCN in diverse metabolic pathways and cellular processes that include modulation of the mTOR pathway, regulation of PGC1α and mitochondrial biogenesis, cell-cell adhesion and RhoA signaling, control of TFE3/TFEB transcriptional activity, amino acid-dependent activation of mTORC1 on lysosomes through Rag GTPases, and regulation of autophagy. Ongoing research efforts are focused on clarifying the primary FLCN-associated pathway(s) that drives the development of fibrofolliculomas, lung cysts and kidney tumors in BHD patients carrying germline FLCN mutations.

Gómez Rivas J, Carrión DM, Alonso Y Gregorio S, et al.
A novel heterozygous mutation in the Birt-Hogg-Dubé Syndrome.
Arch Esp Urol. 2017; 70(7):675-678 [PubMed] Related Publications
OBJETIVE: Our aim is to present a novel mutation of the Birt-Hogg-Dubé Syndrome.
METHODS: We present a case report of a 70-year-old male with three solid nodulary lesions of 4, 2.6, and 3 cm each in the right kidney, and two lesions of 1.5 and 1.3 cm in the left kidney.
RESULTS: Needle biopsy was performed. The pathological analysis of right kidney lesions revealed a renal tumor suggestive of chromophobe renal cell carcinoma and medullar tumor with zones that suggested oncocytosis. Genetic test results were positive for a novel heterozygous mutation c.1198G>A; p.V400I in exon 11 of the FLCN gene.
CONCLUSION: In patients presenting with bilateral multifocal renal tumors of oncocytic hybrid histology, Birt- Hogg-Dubé syndrome should be the first diagnosis in mind. The mutation found in this patient has not been previously described in the literature in the context of BHD.

Slade L, Pulinilkunnil T
The MiTF/TFE Family of Transcription Factors: Master Regulators of Organelle Signaling, Metabolism, and Stress Adaptation.
Mol Cancer Res. 2017; 15(12):1637-1643 [PubMed] Related Publications
The microphthalmia family (MITF, TFEB, TFE3, and TFEC) of transcription factors is emerging as global regulators of cancer cell survival and energy metabolism, both through the promotion of lysosomal genes as well as newly characterized targets, such as oxidative metabolism and the oxidative stress response. In addition, MiT/TFE factors can regulate lysosomal signaling, which includes the mTORC1 and Wnt/β-catenin pathways, which are both substantial contributors to oncogenic signaling. This review describes recent discoveries in MiT/TFE research and how they impact multiple cancer subtypes. Furthermore, the literature relating to TFE-fusion proteins in cancers and the potential mechanisms through which these genomic rearrangements promote tumorigenesis is reviewed. Likewise, the emerging function of the Folliculin (FLCN) tumor suppressor in negatively regulating the MiT/TFE family and how loss of this pathway promotes cancer is examined. Recent reports are also presented that relate to the role of MiT/TFE-driven lysosomal biogenesis in sustaining cancer cell metabolism and signaling in nutrient-limiting conditions. Finally, a discussion is provided on the future directions and unanswered questions in the field. In summary, the research surrounding the MiT/TFE family indicates that these transcription factors are promising therapeutic targets and biomarkers for cancers that thrive in stressful niches.

Kayhan G, Yılmaz Demirci N, Turktas H, Ergun MA
Birt-Hogg-Dube Syndrome with a Novel Mutation in the FLCN Gene.
Genet Test Mol Biomarkers. 2017; 21(10):632-634 [PubMed] Related Publications
BACKGROUND: Birt-Hogg-Dube syndrome (BHDS) is an autosomal dominant disease characterized by hair follicle hamartomas, kidney tumors, and spontaneous pneumothorax; its cause is a heterozygous mutation in the FLCN gene. Colorectal polyps and carcinoma have also been reported in BHDS. FLCN mutations can be detected in patients with isolated primary spontaneous pneumothorax (PSP), so PSP may present as part of BHDS. The aim of this report is to enhance awareness that patients presenting with spontaneous PSP should be evaluated for FLCN mutations.
MATERIALS AND METHODS: A 44-year-old woman with PSP and her parents were analyzed for FLCN mutations. One of the patient's paternal aunts had a PSP and two of her paternal aunts had colon cancer diagnosed at early ages.
RESULTS: A novel in-frame deletion in the FLCN gene, c.932_933delCT (P311Rfs*78), was detected in the proband and in her unaffected father.
CONCLUSIONS: We recommend that molecular analysis of the FLCN gene be performed in patients with PSP and their families, and that mutation carriers be examined for kidney and colon tumors.

Nguyen KA, Syed JS, Espenschied CR, et al.
Advances in the diagnosis of hereditary kidney cancer: Initial results of a multigene panel test.
Cancer. 2017; 123(22):4363-4371 [PubMed] Related Publications
BACKGROUND: Panel testing has been recently introduced to evaluate hereditary cancer; however, limited information is available regarding its use in kidney cancer.
METHODS: The authors retrospectively reviewed test results and clinical data from patients who underwent targeted multigene panel testing of up to 19 genes associated with hereditary kidney cancer from 2013 to 2016. The frequency of positive (mutation/variant likely pathogenic), inconclusive (variant of unknown significance), and negative results was evaluated. A logistic regression analysis evaluated predictive factors for a positive test.
RESULTS: Patients (n = 1235) had a median age at diagnosis of 46 years, which was significantly younger than the US population of individuals with kidney cancer (P < .0001). Overall, 6.1%, 75.5%, and 18.4% of individuals had positive, negative, and inconclusive results, respectively. The most commonly altered genes included folliculin (FLCN) and fumarate hydratase (FH), which were altered in 1.8% and 1.3% of patients, respectively. Tuberous Sclerosis Complex 2 (TSC2), mesenchymal epithelial transition factor proto-oncogene (MET), and PMS1 homolog 2 (PMS2) had the highest rates of variants of unknown significance, which were identified in 2.7%, 2.2%, and 1.7% of patients, respectively. Early age of onset was the only factor that was identified as predictive of a positive test on multivariate analysis (odds ratio, 0.975; P = .0052) and may be the only identifying characteristic of low-penetrant syndromes, such as those associated with MITF (melanogenesis-associated transcription factor) mutations, which do not have singular histology or a family history of kidney cancer.
CONCLUSIONS: Panel tests may be particularly useful for patients who lack distinguishing clinical characteristics of known hereditary kidney cancer syndromes. The current results support the use of early age of onset for genetic counseling and/or testing. Cancer 2017;123:4363-71. © 2017 American Cancer Society.

Liu L, Yang K, Wang X, et al.
Detection of
Biomed Res Int. 2017; 2017:8751384 [PubMed] Free Access to Full Article Related Publications
Birt-Hogg-Dube syndrome (BHD, OMIM#135150) is a rare disease in clinic; it is characterized by skin fibrofolliculomas, pulmonary cysts with an increased risk of recurrent pneumothorax, renal cysts, and renal neoplasms. Previous studies have demonstrated that variants in

Tong Y, Schneider JA, Coda AB, et al.
Birt-Hogg-Dubé Syndrome: A Review of Dermatological Manifestations and Other Symptoms.
Am J Clin Dermatol. 2018; 19(1):87-101 [PubMed] Related Publications
Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant genodermatosis with malignant potential characterized by cutaneous and extracutaneous stigmata. Aberrations in the folliculin (FLCN) gene, which is located on chromosome 17, have been discovered in individuals with this condition. Over 150 unique mutations have been identified in BHD. The skin lesions associated with this condition include fibrofolliculomas, trichodiscomas, perifollicular fibromas, and acrochordons. Extracutaneous features of the syndrome typically include the lung (spontaneous pneumothorax and cysts) and the kidney (neoplasms). The only malignancies associated with BHD are renal cancers; however, other tumors have been observed in individuals with BHD. In this article, the skin lesions associated with this condition are reviewed, lung and renal manifestations associated with this syndrome are presented, and malignancies occurring in these patients are summarized.

Laviolette LA, Mermoud J, Calvo IA, et al.
Negative regulation of EGFR signalling by the human folliculin tumour suppressor protein.
Nat Commun. 2017; 8:15866 [PubMed] Free Access to Full Article Related Publications
Germline mutations in the Folliculin (FLCN) tumour suppressor gene result in fibrofolliculomas, lung cysts and renal cancers, but the precise mechanisms of tumour suppression by FLCN remain elusive. Here we identify Rab7A, a small GTPase important for endocytic trafficking, as a novel FLCN interacting protein and demonstrate that FLCN acts as a Rab7A GTPase-activating protein. FLCN

Schneider M, Dinkelborg K, Xiao X, et al.
Early onset renal cell carcinoma in an adolescent girl with germline FLCN exon 5 deletion.
Fam Cancer. 2018; 17(1):135-139 [PubMed] Related Publications
Birt-Hogg-Dube (BHD) disease is an autosomal dominant cancer syndrome characterized by benign skin tumors, renal cancer and spontaneous pneumothorax and is caused by mutations in the Folliculin (FLCN) gene. Benign skin tumors and pneumothorax occur in the majority of patients affected by BHD syndrome, but only 30-45% of them develop renal cell carcinoma (RCC) with a median age of diagnosis at 48. The earliest onset of RCC in a BHD patient has been reported at age 20. Here we report a case of a 14 year-old patient with germline FLCN mutation leading to an early-onset bulky RCC that could not be classified strictly according to existing histological types. Germline genetic testing revealed a deletion at FLCN exon 5. The father of the patient was identified as the asymptomatic carrier. We report the youngest patient with BHD-related RCC. This early onset presentation supports genetic testing of at-risk patients and initiation of imaging surveillance for RCC in early adolescence. In addition, future studies are necessary to understand the determinants of reduced penetrance in BHD disease.

Liu Y, Xu Z, Feng R, et al.
Clinical and genetic characteristics of chinese patients with Birt-Hogg-Dubé syndrome.
Orphanet J Rare Dis. 2017; 12(1):104 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder, the main manifestations of which are fibrofolliculomas, renal tumors, pulmonary cysts and recurrent pneumothorax. The known causative gene for BHD syndrome is the folliculin (FLCN) gene on chromosome 17p11.2. Studies of the FLCN mutation for BHD syndrome are less prevalent in Chinese populations than in Caucasian populations. Our study aims to investigate the genotype spectrum in a group of Chinese patients with BHD.
METHODS: We enrolled 51 patients with symptoms highly suggestive of BHD from January 2014 to February 2017. The FLCN gene was examined using PCR and Sanger sequencing in every patient, for those whose Sanger sequencing showed negative mutation results, multiplex ligation-dependent probe amplification (MLPA) testing was conducted to detect any losses of large segments.
MAIN RESULTS: Among the 51 patients, 27 had FLCN germline mutations. In total, 20 mutations were identified: 14 were novel mutations, including 3 splice acceptor site mutations, 2 different deletions, 6 nonsense mutations, 1 missense mutation, 1 small insertion, and 1 deletion of the whole exon 8.
CONCLUSIONS: We found a similar genotype spectrum but different mutant loci in Chinese patients with BHD compared with European and American patients, thus providing stronger evidence for the clinical molecular diagnosis of BHD in China. It suggests that mutation analysis of the FLCN gene should be systematically conducted in patients with cystic lung diseases.

Yap E, Norziha ZA, Simbun A, et al.
MicroRNAs that affect the Fanconi Anemia/BRCA pathway are downregulated in imatinib-resistant chronic myeloid leukemia patients without detectable BCR-ABL kinase domain mutations.
Leuk Res. 2017; 59:32-40 [PubMed] Related Publications
Chronic myeloid leukemia (CML) patients who do not achieve landmark responses following treatment with imatinib mesylate (IM) are considered IM-resistant. Although IM-resistance can be due to BCR-ABL kinase domain (KD) mutations, many IM-resistant patients do not have detectable BCR-ABL KD mutations. MicroRNAs (miRNAs) are short non-coding RNAs that control gene expression. To investigate the role of miRNAs in IM-resistance, we recruited 8 chronic phase CML patients with IM-resistance who tested negative for BCR-ABL KD mutations and 2 healthy normal controls. Using miRNA sequencing, we identified 54 differentially expressed miRNAs; 43 of them downregulated. The 3 most differentially downregulated miRNAs were miR-146a-5p, miR-99b-5p and miR-151a-5p. Using real-time quantitative reverse transcriptase-polymerase chain reaction, the expression patterns of the 3 miRNAs were validated on the same cohort of 8 patients in addition to 3 other IM-resistant CML patients. In-silico analysis showed that the predicted gene targets are ATRIP, ATR, WDR48, RAD51C and FANCA genes which are involved in the Fanconi Anemia/BRCA pathway. This pathway regulates DNA damage response (DDR) and influences disease response to chemotherapy. Thus it is conceivable that DDR constitutes a key component in IM-resistance. Further research is needed to elucidate miRNA modulation of the predicted gene targets.

Bartram MP, Mishra T, Reintjes N, et al.
Characterization of a splice-site mutation in the tumor suppressor gene FLCN associated with renal cancer.
BMC Med Genet. 2017; 18(1):53 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Renal cell carcinoma is among the most prevalent malignancies. It is generally sporadic. However, genetic studies of rare familial forms have led to the identification of mutations in causative genes such as VHL and FLCN. Mutations in the FLCN gene are the cause of Birt-Hogg-Dubé syndrome, a rare tumor syndrome which is characterized by the combination of renal cell carcinoma, pneumothorax and skin tumors.
METHODS: Using Sanger sequencing we identify a heterozygous splice-site mutation in FLCN in lymphocyte DNA of a patient suffering from renal cell carcinoma. Furthermore, both tumor DNA and DNA from a metastasis are analyzed regarding this mutation. The pathogenic effect of the sequence alteration is confirmed by minigene assays and the biochemical consequences on the protein are examined using TALEN-mediated transgenesis in cultured cells.
RESULTS: Here we describe an FLCN mutation in a 55-year-old patient who presented himself with progressive weight loss, bilateral kidney cysts and renal tumors. He and members of his family had a history of recurrent pneumothorax during the last few decades. Histology after tumor nephrectomy showed a mixed kidney cancer consisting of elements of a chromophobe renal cell carcinoma and dedifferentiated small cell carcinoma component. Subsequent FLCN sequencing identified an intronic c.1177-5_-3delCTC alteration that most likely affected the correct splicing of exon 11 of the FLCN gene. We demonstrate skipping of exon 11 to be the consequence of this mutation leading to a shift in the reading frame and the insertion of a premature stop codon. Interestingly, the truncated protein was still expressed both in cell culture and in tumor tissue, though it was strongly destabilized and its subcellular localization differed from wild-type FLCN. Both, altered protein stability and subcellular localization could be partly reversed by blocking proteasomal and lysosomal degradation.
CONCLUSIONS: Identification of disease-causing mutations in BHD syndrome requires the analysis of intronic sequences. However, biochemical validation of the consecutive alterations of the resulting protein is especially important in these cases. Functional characterization of the disease-causing mutations in BHD syndrome may guide further research for the development of novel diagnostic and therapeutic strategies.

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