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Double heterozygotes among breast cancer patients analyzed for BRCA1, CHEK2, ATM, NBN/NBS1, and BLM germ-line mutations

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Abstract

17 double heterozygous (DH) breast cancer (BC) patients were identified upon the analysis of 5,391 affected women for recurrent Slavic mutations in BRCA1, CHEK2, NBN/NBS1, ATM, and BLM genes. Double heterozygosity was found for BRCA1 and BLM (4 patients), BRCA1 and CHEK2 (4 patients), CHEK2 and NBS1 (3 patients), BRCA1 and ATM (2 patients), CHEK2 and BLM (2 patients), CHEK2 and ATM (1 patient), and NBS1 and BLM (1 patient). DH BC patients were on average not younger than single mutation carriers and did not have an excess of bilateral BC; an additional non-breast tumor was documented in two BRCA1/BLM DH patients (ovarian cancer and lymphoplasmacytic lymphoma). Loss-of-heterozygosity (LOH) analysis of involved genes was performed in 5 tumors, and revealed a single instance of somatic loss of the wild-type allele (LOH at CHEK2 locus in BRCA1/CHEK2 double heterozygote). Distribution of mutations in patients and controls favors the hypothesis on multiplicative interaction between at least some of the analyzed genes. Other studies on double heterozygosity for BC-predisposing germ-line mutations are reviewed.

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Fig. 1

Abbreviations

BC:

Breast cancer

DH:

Double heterozygote

FH:

Family history

LOH:

Loss of heterozygosity

OC:

Ovarian cancer

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Acknowledgments

This work has been supported by the Russian Foundation for Basic Research (grants 12-04-31567, 13-04-92613, 14-04-00411), the German Research Foundation (Do 761/7-1), the State Committee for Scientific Research, Poland (grant PBZ_KBN_122/P05/2004), the Dynasty Foundation (contract 18/13), and the President’s Research Council for Support of Young Russian Scientists (fellowships 768.2012.4 and 790.2012.4).

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None.

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Authors and Affiliations

  1. Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, Pesochny-2, 197758, St.-Petersburg, Russia

    Anna P. Sokolenko, Elena V. Preobrazhenskaya, Ekatherina S. Kuligina, Aglaya G. Iyevleva, Svetlana N. Aleksakhina, Natalia V. Mitiushkina, Tatiana V. Gorodnova, Alexandr V. Togo & Evgeny N. Imyanitov

  2. St.-Petersburg Pediatric Medical University, 194100, St.-Petersburg, Russia

    Anna P. Sokolenko, Aglaya G. Iyevleva, Alexandr V. Togo & Evgeny N. Imyanitov

  3. Hannover Medical School, 30625, Hannover, Germany

    Natalia Bogdanova & Thilo Dörk

  4. International Hereditary Cancer Center, Pomeranian Medical University, 70-204, Szczecin, Poland

    Wojciech Kluzniak, Jan Lubiński, Cezary Cybulski & Anna Jakubowska

  5. City Cancer Center, 197758, St.-Petersburg, Russia

    Alexandr A. Bessonov

  6. I.I. Mechnikov North-Western Medical University, 191015, St-Petersburg, Russia

    Evgeny N. Imyanitov

Authors
  1. Anna P. Sokolenko
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  2. Natalia Bogdanova
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  3. Wojciech Kluzniak
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  4. Elena V. Preobrazhenskaya
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  5. Ekatherina S. Kuligina
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  6. Aglaya G. Iyevleva
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  7. Svetlana N. Aleksakhina
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  8. Natalia V. Mitiushkina
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  9. Tatiana V. Gorodnova
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  10. Alexandr A. Bessonov
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  11. Alexandr V. Togo
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  13. Cezary Cybulski
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  16. Evgeny N. Imyanitov
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Correspondence to Evgeny N. Imyanitov.

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Sokolenko, A.P., Bogdanova, N., Kluzniak, W. et al. Double heterozygotes among breast cancer patients analyzed for BRCA1, CHEK2, ATM, NBN/NBS1, and BLM germ-line mutations. Breast Cancer Res Treat 145, 553–562 (2014). https://doi.org/10.1007/s10549-014-2971-1

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