A de novo FLCN mutation in a patient with spontaneous pneumothorax and renal cancer; a clinical and molecular evaluation

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• 作者：Fred H. Menko ; Paul C. Johannesma ; R. Jeroen A. van Moorselaar…
• 关键词：Birt–Hogg–Dubé syndrome ; Folliculin ; de novo mutation ; Pneumothorax ; Renal cancer
• 刊名：Familial Cancer
• 出版年：2013
• 出版时间：September 2013
• 年：2013
• 卷：12
• 期：3
• 页码：373-379
• 全文大小：876KB
• 参考文献：1. Birt AR, Hogg GR, Dubé WJ (1977) Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol 113:1674-677 CrossRef
  2. Roth JS, Rabinowitz AD, Benson M (1993) Bilateral renal cell carcinoma in the Birt–Hogg–Dubé syndrome. J Am Acad Dermatol 29:1055-056 CrossRef
  3. Zbar B, Alvord WG, Glenn G et al (2002) Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt–Hogg–Dubé syndrome. Cancer Epidemiol Biomark Prev 11:393-00
  4. Nickerson ML, Warren MB, Toro JR et al (2002) Mutations in a novel gene lead to kidney tumours, lung wall defects, and benign tumours of the hair follicle in patients with the Birt–Hogg–Dubé syndrome. Cancer Cell 2:157-64 CrossRef
  5. Graham RB, Nolasco M, Peterlin B et al (2005) Nonsense mutations in folliculin presenting as isolated familial spontaneous pneumothorax in adults. Am J Respir Crit Care Med 172:39-4 CrossRef
  6. Painter JN, Tapanainen HA, Somer M et al (2005) 4-bp deletion in the Birt–Hogg–Dubé gene ( / FLCN) causes dominantly inherited spontaneous pneumothorax. Am J Hum Genet 76:522-27 CrossRef
  7. Woodward ER, Ricketts C, Killick P et al (2008) Familial non-VHL clear cell (conventional) renal cell carcinoma: clinical features, segregation analysis, and mutation analysis of / FLCN. Clin Cancer Res 14:5925-930 CrossRef
  8. Schmidt LS, Nickerson ML, Warren MB et al (2005) Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt–Hogg–Dubé syndrome. Am J Hum Genet 76:1023-033 CrossRef
  9. Toro JR, Wei MH, Glenn GM et al (2008) 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 45:321-31 CrossRef
  10. Benhammou JN, Vocke CD, Santani A et al (2011) Identification of intragenic deletions and duplication in the / FLCN gene in Birt–Hogg–Dubé syndrome. Genes Chromosomes Cancer 50:466-77 CrossRef
  11. Wei MH, Blake PW, Shevchenko J, Toro JR (2009) The folliculin mutation database: an online database of mutations associated with Birt–Hogg–Dubé syndrome. Hum Mutat 30:E880–E890 CrossRef
  12. Lim DH, Rehal PK, Nahorski MS et al (2010) A new locus-specific database (LSDB) for mutations in the folliculin (FLCN) gene. Hum Mutat 1:E1043–E1051 CrossRef
  13. van Steensel MA, van Geel M, Badeloe S et al (2009) Molecular pathways involved in hair follicle tumor formation: all about mammalian target of rapamycin? Exp Dermatol 18:185-91 CrossRef
  14. Hasumi Y, Baba M, Ajima R et al (2009) Homozygous loss of BHD causes early embryonic lethality and kidney tumor development with activation of mTORC1 and mTORC2. Proc Natl Acad Sci USA 106:18722-8727 CrossRef
  15. Nookala RK, Langemeyer L, Pacitto A et al (2012) Crystal structure of folliculin reveals a hidDENN function in genetically inherited renal cancer. Open Biol 2:120071 CrossRef
  16. Menko FH, van Steensel MA, Giraud S et al (2009) European BHD Consortium. Birt–Hogg–Dubé syndrome: diagnosis and management. Lancet Oncol 10:1199-206 CrossRef
  17. Win AK, Jenkins MA, Buchanan DD et al (2011) Determining the frequency of de novo germline mutations in DNA mismatch repair genes. J Med Genet 48:530-34 CrossRef
  18. Aretz S, Uhlhaas S, Caspari R (2004) Frequency and parental origin of de novo APC mutations in familial adenomatous poly-posis. Eur J Hum Genet 12:52-8 CrossRef
  19. Preston RS, Phil A, Claessens T et al (2011) Absence of the Birt–Hogg–Dubé gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility. Oncogene 30:1159-173 CrossRef
  20. Leter EM, Koopmans AK, Gille JJ et al (2008) Birt–Hogg–Dubé syndrome: clinical and genetic studies of 20 families. J Invest Dermatol 128:45-9 CrossRef
  21. Houweling AC, Gijezen LM, Jonker MA et al (2011) Renal cancer and pneumothorax risk in Birt–Hogg–Dubé syndrome; an analysis of 115 / FLCN mutation carriers from 35 BHD families. Br J Cancer 105:1912-919 CrossRef
  22. Noppen M (2010) Spontaneous pneumothorax: epidemiology, pathophysiology and cause. Eur Respir Rev 19:217-19 CrossRef
  23. Grundy S, Bentley A, Tschopp J-M (2012) Primary spontaneous pneumothorax: a diffuse disease of the pleura. Respiration 83:185-89 CrossRef
  24. Toro JR, Pautler SE, Stewart L et al (2007) Lung cysts, spontaneous pneumothorax, and genetic associations in 89 families with Birt–Hogg–Dubé syndrome. Am J Respir Crit Care Med 175:1044-053 CrossRef
  25. Fr?hlich BA, Zeitz C, Mátyás G et al (2008) Novel mutations in the folliculin gene associated with spontaneous pneumothorax. Eur Respir J 32:1316-320 CrossRef
  26. Kluger N, Giraud S, Coupier I et al (2010) Birt–Hogg–Dubé syndrome: clinical and genetic studies of 10 French families. Br J Dermatol 162:527-37 CrossRef
  27. Butnor KJ, Guinee DG Jr (2006) Pleuropulmonary pathology in Birt–Hogg–Dubé syndrome. Am J Surg Pathol 30:395-99 CrossRef
  28. Ayo DS, Aughenbaugh GL, Yi ES et al (2007) Cystic lung disease in Birt–Hogg–Dubé syndrome. Chest 132:679-84 CrossRef
  29. Koga S, Furuya M, Takahashi Y et al (2009) Lung cysts in Birt–Hogg–Dubé syndrome: histopathological characteristics and aberrant sequence repeats. Pathol Int 59:720-28 CrossRef
  30. Furuya M, Tanaka R, Koga S et al (2012) Pulmonary cysts of Birt–Hogg–Dubé syndrome: a clinicopathological and immunohistochemical study of 9 families. Am J Surg Pathol 36:589-00 CrossRef
  31. Vocke CD, Yang Y, Pavlovich CP et al (2005) High frequency of somatic frameshift BHD gene mutations in Birt–Hogg–Dubé-associated renal tumors. J Natl Cancer Inst 97:931-35 CrossRef
  
• 作者单位：Fred H. Menko (1)
  Paul C. Johannesma (2)
  R. Jeroen A. van Moorselaar (3)
  Rinze Reinhard (4)
  Jan Hein van Waesberghe (4)
  Erik Thunnissen (5)
  Arjan C. Houweling (1)
  Edward M. Leter (1)
  Quinten Waisfisz (1)
  Martijn B. van Doorn (6)
  Theo M. Starink (6)
  Pieter E. Postmus (2)
  Barry J. Coull (7)
  Maurice A. M. van Steensel (7) (8)
  Johan J. P. Gille (1)
  
  1. Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands
  2. Department of Pulmonology, VU University Medical Center, Amsterdam, The Netherlands
  3. Department of Urology, VU University Medical Center, Amsterdam, The Netherlands
  4. Department of Radiology, VU University Medical Center, Amsterdam, The Netherlands
  5. Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
  6. Department of Dermatology, VU University Medical Center, Amsterdam, The Netherlands
  7. Department of Dermatology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands
  8. Department of Clinical Genetics, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands
  
• ISSN：1573-7292

文摘

Birt–Hogg–Dubé syndrome (BHD) is an autosomal dominant condition due to germline FLCN (folliculin) mutations, characterized by skin fibrofolliculomas, lung cysts, pneumothorax and renal cancer. We identified a de novo FLCN mutation, c.499C>T (p.Gln167X), in a patient who presented with spontaneous pneumothorax. Subsequently, typical skin features and asymptomatic renal cancer were diagnosed. Probably, de novo FLCN mutations are rare. However, they may be under-diagnosed if BHD is not considered in sporadic patients who present with one or more of the syndromic features. Genetic and immunohistochemical analysis of the renal tumour indicated features compatible with a tumour suppressor role of FLCN. The finding that mutant FLCN was expressed in the tumour might indicate residual functionality of mutant FLCN, a notion which will be explored in future studies.