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Allelic modification of breast cancer risk in women with an NBN mutation

  • Bogna Rusak
  • Wojciech Kluźniak
  • Dominika Wokołorczyk
  • Klaudia Stempa
  • Aniruddh Kashyap
  • Helena Rudnicka
  • Jacek Gronwald
  • Tomasz Huzarski
  • Tadeusz Dębniak
  • Anna Jakubowska
  • Marek Szwiec
  • Mohammad R. Akbari
  • Steven A. NarodEmail author
  • Jan Lubiński
  • Cezary CybulskiEmail author
  • the Polish Hereditary Breast Cancer Consortium
Epidemiology
  • 14 Downloads

Abstract

Background

NBN 657del5 founder mutation predisposes to breast and prostate cancer. Recently, it has been reported that the pathogenicity of this mutation with regard to prostate cancer risk is modified by a missense variant of the same gene (E185Q).

Methods

To evaluate the interaction of the 657del5 and E185Q founder alleles of NBN on breast cancer risk in Poland, 4964 women with breast cancer and 6152 controls were genotyped for these two recurrent variants of NBN (657del5 truncating variant and E185Q missense variant).

Results

The NBN 657del5 mutation was detected in 57 of 4964 unselected cases and in 35 of 6152 controls (OR = 2.0, p = 0.001). The E185Q GG genotype was detected in 2167 of 4964 unselected cases and in 2617 of 6152 controls (OR = 1.04, p = 0.3). In carriers of the 657del5 deletion, the elevated cancer risk was restricted to women with the GG genotype of the E185Q variant (OR = 3.6, 95% CI 1.9–6.6; p < 0.0001). Among women with other E185Q genotypes, the OR associated with 657del5 was 1.0 (95% CI 0.5–1.8; p = 0.9). The interaction between the two alleles was statistically significant (homogeneity p = 0.003).

Conclusion

In Poland, the pathogenicity of the NBN 657del5 mutation is restricted to women with a homozygous GG genotype of missense variant of the same gene (E185Q). This is the first clear example whereby a moderate penetrance breast cancer gene is impacted by a genetic modifier.

Keywords

NBN NBS1 Mutation Breast cancer 

Notes

Acknowledgements

This study was funded by National Science Centre, Poland; Project Number: 2015/17/B/NZ5/02543. The study was approved by the Ethics Committee of the Pomeranian Medical University in Szczecin. Patient clinical data have been obtained in a manner conforming with the IRB ethical guidelines. We thank Daria Zanoza and Ewa Putresza for their help with managing databases.

Funding

This study was funded by National Science Centre (Narodowe Centrum Nauki), Poland; Project Number: 2015/17/B/NZ5/02543.

Compliance with ethical standards

Conflict of interest

All authors declare no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments. The study was approved by the Ethics Committee of the Pomeranian Medical University in Szczecin.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Bogna Rusak
    • 1
  • Wojciech Kluźniak
    • 1
  • Dominika Wokołorczyk
    • 1
  • Klaudia Stempa
    • 1
  • Aniruddh Kashyap
    • 1
  • Helena Rudnicka
    • 1
  • Jacek Gronwald
    • 1
  • Tomasz Huzarski
    • 1
    • 2
  • Tadeusz Dębniak
    • 1
  • Anna Jakubowska
    • 1
    • 3
  • Marek Szwiec
    • 4
    • 5
  • Mohammad R. Akbari
    • 6
    • 7
  • Steven A. Narod
    • 6
    • 7
    Email author
  • Jan Lubiński
    • 1
  • Cezary Cybulski
    • 1
    Email author
  • the Polish Hereditary Breast Cancer Consortium
  1. 1.Department of Genetics and Pathology, International Hereditary Cancer CenterPomeranian Medical UniversitySzczecinPoland
  2. 2.Department of Clinical Genetics and PathologyUniversity of Zielona GóraZielona GóraPoland
  3. 3.Independent Laboratory of Molecular Biology and Genetic DiagnosticsPomeranian Medical UniversitySzczecinPoland
  4. 4.Department of Surgery and OncologyUniversity of Zielona GóraZielona GóraPoland
  5. 5.Department of Clinical OncologyUniversity of Zielona GóraZielona GóraPoland
  6. 6.Women’s College Research InstituteWomen’s College HospitalTorontoCanada
  7. 7.Dalla Lana School of Public HealthUniversity of TorontoTorontoCanada

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