Breast Cancer Research and Treatment

, Volume 171, Issue 3, pp 719–735 | Cite as

Breast cancer in women with neurofibromatosis type 1 (NF1): a comprehensive case series with molecular insights into its aggressive phenotype

  • Yoon-Sim YapEmail author
  • Prabhakaran Munusamy
  • Cindy Lim
  • Claire H. T. Chan
  • Aldo Prawira
  • Sau-Yeen Loke
  • Swee-Ho Lim
  • Kong-Wee Ong
  • Wei-Sean Yong
  • Sarah B. H. Ng
  • Iain B. H. Tan
  • David F. Callen
  • Jeffrey C. T. Lim
  • Aye-Aye Thike
  • Puay-Hoon Tan
  • Ann S. G. LeeEmail author



The purpose of the study was to improve the understanding of NF1-associated breast cancer, given the increased risk of breast cancer in this tumour predisposition syndrome and the limited data.


We identified 18 women with NF1 and breast cancer at our institution. Clinical and pathologic characteristics of NF1-associated breast cancers were compared with 7132 breast cancers in patients without NF1 from our institutional database. Next generation sequencing was performed on DNA from blood and breast cancer specimens available. Blood specimens negative for NF1 mutation were subjected to multiplex ligation-dependent probe amplification (MLPA) to identify complete/partial deletions or duplications. Expression of neurofibromin in the NF1-associated breast cancers was evaluated using immunohistochemistry.


There was a higher frequency of grade 3 (83.3% vs 45.4%, p = 0.005), oestrogen receptor (ER) negative (66.7% vs 26.3%, p < 0.001) and human epidermal growth factor receptor 2 (HER2)-positive (66.7% vs 23.4%, p < 0.001) tumours among NF1 patients compared to non-NF1 breast cancers. Overall survival was inferior in NF1 patients in multivariable analysis (hazard ratio 2.25, 95% CI 1.11–4.60; p = 0.025). Apart from germline NF1 mutations (11/16; 69%), somatic mutations in TP53 (8/10; 80%), second-hit NF1 (2/10; 20%), KMT2C (4/10; 40%), KMT2D (2/10; 20%), and PIK3CA (2/10; 20%) were observed. Immunohistochemical expression of neurofibromin was seen in the nuclei and/or cytoplasm of all specimens, but without any consistent pattern in the intensity or extent.


This comprehensive series of NF1-associated breast cancers suggests that their aggressive features are related to germline NF1 mutations in cooperation with somatic mutations in TP53, KMT2C and other genes.


Neurofibromatosis type 1 NF1 Tumour suppressor Breast cancer 



We are grateful to all the patients who participated in this study. We also wish to thank the investigators and staff at National Cancer Centre Singapore, SingHealth campus, as well as the SingHealth Tissue Repository and Joint Breast Cancer Registry for their support.

Author contributions

Conception and design: YSY and ASGL. Development of methodology: YSY, CL, DAT, PHT, IBT and ASGL. Acquisition of material (including recruitment of patients): YSY, KWO, WSY and SHL. Acquisition of data (conducted experiments and tests): YSY, CL, CHC, AP, SYL, JCL, DAT and SBN. Analysis and interpretation of data (e.g. statistical analysis, biostatistics, computational analysis): YSY, PM, CL, DAT, DFC, SBN and ASGL. Writing, review, and/or revision of the manuscript: all co-authors. Study support and supervision: YSY and ASGL. All authors read and approved the final manuscript.


This study was supported by the SingHealth Foundation Research Grant (SHF/FG426S/2009).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

All patients for this study provided written informed consent, except for deceased patients (waiver of consent for deceased patients granted by institutional review board).

Supplementary material

10549_2018_4851_MOESM1_ESM.xlsx (16 kb)
Supplementary table S1: Gene panels (XLSX 16 KB)
10549_2018_4851_MOESM2_ESM.docx (17 kb)
Supplementary material 2 (DOCX 17 KB)
10549_2018_4851_MOESM3_ESM.xlsx (23 kb)
Supplementary table S4: List of mutations detected from blood and tumour in NF1 patients (XLSX 23 KB)
10549_2018_4851_MOESM4_ESM.xlsx (10 kb)
Supplementary table S5: Immunohistochemical expression of neurofibromin (XLSX 9 KB)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Yoon-Sim Yap
    • 1
    • 2
    Email author
  • Prabhakaran Munusamy
    • 3
  • Cindy Lim
    • 4
  • Claire H. T. Chan
    • 3
  • Aldo Prawira
    • 3
  • Sau-Yeen Loke
    • 3
  • Swee-Ho Lim
    • 5
  • Kong-Wee Ong
    • 6
  • Wei-Sean Yong
    • 6
  • Sarah B. H. Ng
    • 7
  • Iain B. H. Tan
    • 1
    • 7
  • David F. Callen
    • 2
  • Jeffrey C. T. Lim
    • 8
  • Aye-Aye Thike
    • 8
  • Puay-Hoon Tan
    • 8
  • Ann S. G. Lee
    • 3
    • 9
    • 10
    Email author
  1. 1.Division of Medical OncologyNational Cancer Centre SingaporeSingaporeSingapore
  2. 2.Faculty of Health Sciences, School of MedicineUniversity of AdelaideAdelaideAustralia
  3. 3.Division of Cellular and Molecular ResearchNational Cancer Centre SingaporeSingaporeSingapore
  4. 4.Division of Clinical Trials and Epidemiological SciencesNational Cancer Centre SingaporeSingaporeSingapore
  5. 5.Breast DepartmentKK Women’s and Children’s HospitalSingaporeSingapore
  6. 6.Division of Surgical OncologyNational Cancer Centre SingaporeSingaporeSingapore
  7. 7.Genome Institute of Singapore, A*STARSingaporeSingapore
  8. 8.Division of PathologySingapore General HospitalSingaporeSingapore
  9. 9.Department of PhysiologyYong Loo Lin School of Medicine, National University of SingaporeSingaporeSingapore
  10. 10.Office of Clinical & Academic Faculty AffairsDuke-NUS Graduate Medical SchoolSingaporeSingapore

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