Highlights
- •We report the case of a patient with Birt-Hogg-Dubé syndrome showing the renal tumor-only phenotype.
- •Targeted sequencing of FLCN revealed a novel germline missense mutation (c.602A>C, p.Gln201Pro).
- •Protein analyses revealed that the FLCN missense mutation is pathogenic.
- •Whole-genome sequencing of one of the renal tumors identified another frameshift mutation in FLCN, suggesting a “second hit” mutation for tumorigenesis.
- •Our literature review suggested the relationship between missense mutations and the renal tumor-only phenotype.
Abstract
Birt-Hogg-Dubé syndrome is an autosomal dominant disease caused by germline mutations
in the folliculin gene (FLCN), characterized by skin fibrofolliculomas, pulmonary cysts, and multiple renal tumors.
We report the case of a 51-year-old woman with multiple bilateral renal tumors resected
by bilateral open partial nephrectomy. Following pathological diagnosis of hybrid
oncocytic/chromophobe tumors, targeted next-generation sequencing of FLCN of the patient's blood revealed a novel missense mutation (c.602A>C, p.Gln201Pro)
in exon 6. Sanger sequencing revealed that this mutation was heterozygous. In silico prediction programs consistently indicated the mutation as pathogenic. Western blot
analysis and immunohistochemistry revealed suppressed FLCN expression and the upregulation
of glycoprotein nonmetastatic B, a downstream target negatively regulated by FLCN,
in the tumor tissue, suggesting that the mutation resulted in reduction of functional
FLCN expression. Whole-genome sequencing of one of the tumors identified another frameshift
mutation in exon 4, suggesting a “second hit” leading to tumorigenesis. We recommend
that gene sequencing should be considered in patients with multiple renal tumors to
identify their genetic predisposition to renal tumors.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Cancer GeneticsAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Birt-Hogg-Dubé syndrome.Clin Chest Med. 2016; 37: 475-486
- Birt-Hogg-Dubé syndrome: clinical and molecular aspects of recently identified kidney cancer syndrome.Int J Urol. 2016; 23: 204-210
- Renal cancer and pneumothorax risk in Birt-Hogg-Dubé syndrome; an analysis of 115 FLCN mutation carriers from 35 BHD families.Br J Cancer. 2011; 105: 1912-1919
- Renal cell tumour characteristics in patients with the Birt-Hogg-Dubé cancer susceptibility syndrome: a retrospective, multicentre study.Orphanet J Rare Dis. 2014; 9: 163
- The UOK 257 cell line: a novel model for studies of the human Birt-Hogg-Dubé gene pathway.Cancer Genet Cytogenet. 2008; 180: 100-109
- Systematic chemical screening identifies disulfiram as a repurposed drug that enhances sensitivity to cisplatin in bladder cancer: a summary of preclinical studies.Br J Cancer. 2019; 121: 1027-1038
- Inactivation of the FLCN tumor suppressor gene induces TFE3 transcriptional activity by increasing its nuclear localization.PLoS One. 2010; 5: e15793
- BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports.J Med Genet. 2008; 45: 321-331
- Two Japanese cases of birt-hogg-dubé syndrome with pulmonary cysts, fibrofolliculomas, and renal cell carcinomas.Case Rep Dermatol. 2014; 6: 20-28
- Clinical and genetic characteristics of chinese patients with Birt-Hogg-Dubé syndrome.Orphanet J Rare Dis. 2017; 12: 104
- Birt-Hogg-Dubé syndrome in Korean: clinicoradiologic features and long term follow-up.Korean J Intern Med. 2019; 34: 830-840
- Distinctive expression patterns of glycoprotein non-metastatic B and folliculin in renal tumors in patients with Birt-Hogg-Dubé syndrome.Cancer Sci. 2015; 106: 315-323
- Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome.Cancer Cell. 2002; 2: 157-164
- H255Y and K508R missense mutations in tumour suppressor folliculin (FLCN) promote kidney cell proliferation.Hum Mol Genet. 2017; 26: 354-366
- Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome.Am J Hum Genet. 2005; 76: 1023-1033
- A systematic review assessing the existence of pneumothorax-only variants of FLCN. Implications for lifelong surveillance of renal tumours.Eur J Hum Genet. 2021; 29: 1595-1600
- Folliculin-interacting proteins Fnip1 and Fnip2 play critical roles in kidney tumor suppression in cooperation with Flcn.Proc Natl Acad Sci U S A. 2015; 112: E1624-E1631
- Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling.Proc Natl Acad Sci U S A. 2006; 103: 15552-15557
- Folliculin variants linked to Birt-Hogg-Dubé syndrome are targeted for proteasomal degradation.PLoS Genet. 2020; 16e1009187
- Genome-wide uniparental disomy and copy number variations in renal cell carcinomas associated with Birt-Hogg-Dubé syndrome.Am J Pathol. 2016; 186: 337-346
- High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dubé-associated renal tumors.J Natl Cancer Inst. 2005; 97: 931-935
Article Info
Publication History
Published online: June 05, 2022
Accepted:
June 4,
2022
Received in revised form:
April 30,
2022
Received:
March 3,
2022
Identification
Copyright
© 2022 Elsevier Inc. All rights reserved.