N10: Breast Cancer Risk In Neurofibromatosis Type 1 Is A Function Of The Type Of NF1 Gene Mutation: A New Genotype-Phenotype Correlation.

I. Frayling1, V. F. Mautner2, R. van Minkelen3, R. A. Kallionpää4, S. Aktaş5, D. Baralle6, S. Ben-Shachar7, A. Callaway8, H. Cox1, D. M. Eccles6, S. Ferkal9, H. LaDuca10, C. Lázaro11, M. T. Rogers1, A. J. Stuenkel10, P. Summerour10, A. Varan12, Y. S. Yap13, J. Peltonen4, D. G. Evans14, 15, P. Wolkenstein16, M. Upadhyaya1

1 – Institute of Cancer & Genetics, Cardiff University, Cardiff, UK. 2 – Neurofibromatose–Ambulanz–Hamburg, Gebäude O 54 im UKE, Martinistraße 52, 20246 Hamburg, DE. 3 – Klinische Genetica, Erasmus MC, Rotterdam, NL. 4 – Department of Cell Biology and Anatomy, University of Turku, Turku, FI. 5 – Dokuz Eylül Üniversitesi, Izmir, TR. 6 – Faculty of Medicine, Southampton University, Southampton, UK. 7 – The Genetic Institute, Tel-Aviv Sourasky Medical Center, Tel-Aviv, IL. 8 – Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury, UK. 9 – Service de Santé Publique, Hôpital Henri Mondor, Créteil, FR. 10 – Ambry Genetics, Aliso Viejo, CA, USA. 11 – Institut Català d’Oncologia, L’Hospitalet, ES. 12 – Hacettepe Üniversitesi Kanser Enstitüsü, TR. 13 – Department of Medical Oncology, National Cancer Centre, Singapore, SG. 14 – Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK. 15 – Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK. 16 – Immunity Transplantation Infections, Hôpital Henri Mondor, APHP University Paris Est Créteil, Créteil, FR.


Aim: NF1 predisposes to breast cancer (BC), but no genotype-phenotype correlations have been described.

Method: Constitutional NF1 mutations in 78 NF1 patients with BC (NF1-BC) were compared to the NF1 LOVD (N=3432).

Results: There are no gross relationships with mutation position.  No cases were observed with large deletions (HR=0.10; 95%CI: 0.006–1.63; p=0.014, Fisher’s exact (FE)) 64.3% of the 70 different mutations have p<0.05 (FE), while 74.3% are significant when adjusted for multiple comparisons (Benjamini-Hochberg p≤0.125).  Two pairs of patients shared the same predicted effects on neurofibromin, but had different mutations at the DNA level.  6/14 (43%) of the missenses (MS) were located in the CSRD (p=0.093; FE). 10/11 (91%) of MS cases with known age of BC occurred <50y (p=0.041; FE).  18 had BRCA1/2 testing, revealing one BRCA2 mutation.

Conclusion: This demonstrates that certain heritable mutation types, and indeed certain specific mutations in NF1 confer different risks of BC. The observation that NF1 amplification does not always occur with, and can occur independently of ERBB2 amplification, supports the concept that BC risk in NF1 may be due to gain of function mutations. A prospective NF1-BC study needs to be established. Regardless of NF1 mutation status NF1-BC patients warrant testing of other BC-predisposing genes.