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Prediction of BRCA1-association in hereditary non-BRCA1/2 breast carcinomas with array-CGH

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Abstract

Background While new defects in BRCA1 are still being found, it is unclear whether current breast cancer diagnostics misses many BRCA1-associated cases. A reliable test that is able to indicate the involvement of BRCA1 deficiency in cancer genesis could support decision making in genetic counselling and clinical management. To find BRCA1-specific markers and explore the effectiveness of the current diagnostic strategy, we designed a classification method, validated it and examined whether we could find BRCA1-like breast tumours in a group of patients initially diagnosed as non-BRCA1/2 mutation carriers. Methods A classifier was built based on array-CGH profiles of 18 BRCA1-related and 32 control breast tumours, and validated on independent sets of 16 BRCA1-related and 16 control breast carcinomas. Subsequently, we applied the classifier to 48 breast tumours of patients from Hereditary Breast and Ovarian Cancer (HBOC) families in whom no germ line BRCA1/BRCA2 mutations were identified. Results The classifier showed an accuracy of 91% when applied to the validation sets. In 48 non-BRCA1/2 patients, only two breast tumours presented a BRCA1-like CGH profile. Additional evidence for BRCA1 dysfunction was found in one of these tumours. Conclusion We here describe the specific chromosomal aberrations in BRCA1-related breast carcinomas. We developed a predictive genetic test for BRCA1-association and show that BRCA1-related tumours can still be identified in HBOC families after routine DNA diagnostics.

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Abbreviations

CGH:

Comparative genomic hybridisation

FE:

Fisher’s exact

FFPE:

Formalin-fixed, paraffin-embedded

HBOC:

Hereditary breast and ovarian cancer

LOH:

Loss of heterozygosity

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Acknowledgements

We like to acknowledge the Central Microarray Facility (NKI) for the production of the microarrays, Aafke Ariaens and Roelof Pruntel for technical support, Sonja Springer for management of material and Juliane Hannemann for critically reading the manuscript. Grant support Dutch Cancer Society/Koningin Wilhelmina Fonds grant NKB_NKI2005-3436.

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Author notes

  1. Erik H. van Beers

    Present address: Skyline-Diagnostics B.V, Rotterdam, The Netherlands

Authors and Affiliations

  1. Division of Experimental Therapy, The Netherlands Cancer Institute NKI/AvL, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands

    Simon A. Joosse, Erik H. van Beers & Hugo Horlings

  2. Department of Pathology, The Netherlands Cancer Institute NKI/AvL, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands

    Ivon H. G. Tielen, Johannes L. Peterse, Frans B. L. Hogervorst & Petra M. Nederlof

  3. Department of Human Genetics, Radboud University Nijmegen Medical Centre, P. O. Box 9101, 6500HB, Nijmegen, The Netherlands

    Nicoline Hoogerbrugge & Marjolijn J. Ligtenberg

  4. Department of Pathology, Radboud University Nijmegen Medical Centre, P. O. Box 9101, 6500HB, Nijmegen, The Netherlands

    Marjolijn J. Ligtenberg

  5. Department of Molecular Biology, The Netherlands Cancer Institute NKI/AvL, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands

    Lodewyk F. A. Wessels

  6. Family Cancer Clinic, The Netherlands Cancer Institute NKI/AvL, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands

    Priscilla Axwijk & Senno Verhoef

  7. Postbus 90203, 1006BE, Amsterdam, The Netherlands

    Petra M. Nederlof

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  1. Simon A. Joosse
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Correspondence to Petra M. Nederlof.

Additional information

S. A. Joosse and E. H. van Beers are shared first authors.

Johannes L. Peterse—deceased.

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Joosse, S.A., van Beers, E.H., Tielen, I.H.G. et al. Prediction of BRCA1-association in hereditary non-BRCA1/2 breast carcinomas with array-CGH. Breast Cancer Res Treat 116, 479–489 (2009). https://doi.org/10.1007/s10549-008-0117-z

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