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BRIP1, PALB2, and RAD51C mutation analysis reveals their relative importance as genetic susceptibility factors for breast cancer

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Abstract

Mutations in the recognized breast cancer susceptibility genes BRCA1, BRCA2, TP53, ATM, and CHEK2 account for approximately 20% of hereditary breast cancer. This raises the possibility that mutations in other biologically relevant genes may be involved in genetic predisposition to breast cancer. In this study, BRIP1, PALB2, and RAD51C were sequenced for mutations as a result of previously being associated with breast cancer risk due to their role in the double-strand break repair pathway and their close association with BRCA1 and BRCA2. Two truncating mutations in PALB2 (Q66X and W1038X), one of which is has not been reported before, were detected in an independent Australian cohort of 70 individuals with breast or ovarian cancer, and have strong family histories of breast or breast/ovarian cancer. In addition, six missense variants predicted to be causative were detected, one in BRIP1 and five in PALB2. No causative variants were identified in RAD51C. This study supports recent observations that although rare, PALB2 mutations are present in a small but substantial proportion of inherited breast cancer cases, and indicates that RAD51C at a population level does not account for a substantial number of familial breast cancer cases.

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Fig. 1
Fig. 2

Abbreviations

AML:

Acute myeloid leukemia

FA:

Fanconi anemia

MLPA:

Multiplex ligation-dependent probe amplification

PCR:

Polymerase chain reaction

SNP:

Single nucleotide polymorphism

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Acknowledgments

We would like to thank all the patients for their consent to the use of their samples in this study. We would also like to acknowledge Dr. Allan Spigelman, Claire Groombridge, and Margaret Gleeson for providing patient samples and family information. This study was supported by Grant from National Breast Cancer Foundation (NBCF), Australia.

Conflict of interest

The authors of this article declare no competing interests related to the study and no commercial associations that may pose a conflict of interest.

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Authors and Affiliations

  1. Discipline of Medical Genetics and Centre for Information-Based Medicine (CIBM), The University of Newcastle, Hunter Medical Research Institute (HMRI), John Hunter Hospital, Newcastle, NSW, 2305, Australia

    Michelle W. Wong, David Mossman, Kelly A. Avery-Kiejda, Bente Talseth-Palmer, Nikola A. Bowden & Rodney J. Scott

  2. Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Solna (L1:00), 171 76, Stockholm, Sweden

    Cecilia Nordfors

  3. Division of Genetics, Hunter Area Pathology Service (HAPS), John Hunter Hospital, Lookout Road, New Lambton Heights, Newcastle, NSW, 2305, Australia

    Gordana Pecenpetelovska & Rodney J. Scott

Authors
  1. Michelle W. Wong
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  2. Cecilia Nordfors
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  3. David Mossman
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  5. Kelly A. Avery-Kiejda
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Corresponding author

Correspondence to Rodney J. Scott.

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Wong, M.W., Nordfors, C., Mossman, D. et al. BRIP1, PALB2, and RAD51C mutation analysis reveals their relative importance as genetic susceptibility factors for breast cancer. Breast Cancer Res Treat 127, 853–859 (2011). https://doi.org/10.1007/s10549-011-1443-0

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  • DOI: https://doi.org/10.1007/s10549-011-1443-0

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