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Breast cancer risk in neurofibromatosis type 1 is a function of the type of NF1 gene mutation: a new genotype-phenotype correlation
  1. Ian M Frayling1,2,
  2. Victor-Felix Mautner3,
  3. Rick van Minkelen4,
  4. Roope A Kallionpaa5,
  5. Safiye Aktaş6,
  6. Diana Baralle7,
  7. Shay Ben-Shachar8,
  8. Alison Callaway9,
  9. Harriet Cox10,
  10. Diana M Eccles7,
  11. Salah Ferkal11,
  12. Holly LaDuca12,
  13. Conxi Lázaro13,
  14. Mark T Rogers1,2,
  15. Aaron J Stuenkel12,
  16. Pia Summerour12,
  17. Ali Varan14,
  18. Yoon Sim Yap15,
  19. Ouidad Zehou16,
  20. Juha Peltonen5,
  21. D Gareth Evans17,18,
  22. Pierre Wolkenstein19,
  23. Meena Upadhyaya1
  1. 1 Inherited Tumour Syndromes Research Group, Institute of Cancer & Genetics, Cardiff University, Cardiff, UK
  2. 2 All-Wales Medical Genetics Service, Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK
  3. 3 Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  4. 4 Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
  5. 5 Department of Cell Biology and Anatomy, Turun Yliopisto, Turku, Finland
  6. 6 Dokuz Eylül Üniversitesi, Izmir, Turkey
  7. 7 Faculty of Medicine, University of Southampton, Southampton, UK
  8. 8 The Genetic Institute, Tel-Aviv Sourasky Medical Center, affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
  9. 9 Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury, UK
  10. 10 Institute of Cancer and Genetics, Cardiff University, Cardiff, UK
  11. 11 Service de Santé Publique, Hôpital Henri Mondor, Créteil, France
  12. 12 Clinical Diagnostics, Ambry Genetics Corp, Aliso Viejo, California, USA
  13. 13 Hereditary Cancer Program, Institut Català d’Oncologia, L’Hospitalet de Llobregat, Spain
  14. 14 Hacettepe Universitesi Onkoloji Enstitusu, Ankara, Turkey
  15. 15 Department of Medical Oncology, National Cancer Centre Singapore, Singapore
  16. 16 Hôpital Henri Mondor, APHP University Paris Est Créteil, Créteil, France
  17. 17 Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
  18. 18 Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK
  19. 19 Immunity Transplantation Infections, Hôpital Henri Mondor, APHP University Paris Est Créteil, Créteil, France
  1. Correspondence to Dr Ian M Frayling, Institute of Medical Genetics, University Hospital of Wales, Cardiff CF14 4XW, UK; FraylingIM{at}


Background Neurofibromatosis type 1 (NF1) predisposes to breast cancer (BC), but no genotype-phenotype correlations have been described.

Methods Constitutional NF1 mutations in 78 patients with NF1 with BC (NF1-BC) were compared with the NF1 Leiden Open Variation Database (n=3432).

Results No cases were observed with whole or partial gene deletions (HR 0.10; 95% CI 0.006 to 1.63; p=0.014, Fisher’s exact test). There were no gross relationships with mutation position. Forty-five (64.3%; HR 6.4–83) of the 70 different mutations were more frequent than expected (p<0.05), while 52 (74.3%; HR 5.3–83) were significant when adjusted for multiple comparisons (adjusted p≤0.125; Benjamini-Hochberg). Higher proportions of both nonsense and missense mutations were also observed (adjusted p=0.254; Benjamini-Hochberg). Ten of the 11 missense cases with known age of BC occurred at <50 years (p=0.041). Eighteen cases had BRCA1/2 testing, revealing one BRCA2 mutation.

Discussion These data strongly support the hypothesis that certain constitutional mutation types, and indeed certain specific variants in NF1 confer different risks of BC. The lack of large deletions and excess of nonsenses and missenses is consistent with gain of function mutations conferring risk of BC, and also that neurofibromin may function as a dimer. The observation that somatic NF1 amplification can occur independently of ERBB2 amplification in sporadic BC supports this concept. A prospective clinical-molecular study of NF1-BC needs to be established to confirm and build on these findings, but regardless of NF1 mutation status patients with NF1-BC warrant testing of other BC-predisposing genes.

  • breast cancer
  • genotype-phenotype correlation
  • neurofibromatosis Type 1
  • Nf1 microdeletion
  • Brca1/2
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  • Contributors V-FM and MU had the original idea for the study, IMF and MU designed it. IMF sought institutional approval, compiled, checked and analysed the data, managed the study database, computed the results and wrote the initial draft of the manuscript including text, tables and figures. RAK, JP and IMF worked on the statistical analyses. RvM compiles, checks and curates the online NF1 database (LOVD); RvM and IMF shared appropriate data. DGE, JP and MU reviewed the initial draft of the manuscript. IMF, V-FM, RvM, RAK, SA, DB, SB-S, AC, HC, DME, SF, HLD, CL, MTR, AJS, PS, AV, YSY, OZ, JP, DGE, PW and MU all contributed data, critically reviewed study design, interpretation of mutations and results and commented on and approved the final manuscript. IMF submitted the study and is responsible as guarantor for overall content.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests Dr IMF reports support from St Vincent’s University Hospital, Dublin, Impact Genetics, Bowmanville, Ontario, Canada and Ambry Genetics, Aliso Viejo, California, USA, and Professor GDE reports support from AstraZeneca, both for travel, both outside the submitted work. Professor MU thanks the Ian Owen Fund for support.

  • Ethics approval Cardiff and Vale University Health Board (13/DHD/5637).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement NF1 gene variant data not already listed on the public LOVD at will be deposited on the LOVD. We welcome submission of further NF1 breast cancer cases to the LOVD to extend the study, and request that submitters contact the corresponding author. Within the limitations of the original retrospective study, as stated in the paper, there are some extra clinical data which can be made available to those contributing more cases.

  • Correction notice The article has been corrected since it was published online first. The name of author D Gareth Evans has been corrected.

  • Patient consent for publication Cardiff and Vale University Health Board approved the study as not requiring specific ethical approval, because it only used anonymous data collected during routine patient care, and hence individual patient consent was not necessary (13/DHD/5637).

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