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Mutation analysis of five candidate genes in familial breast cancer

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Abstract

Most of the known breast cancer susceptibility genes (BRCA1, BRCA2, CHEK2 and ATM) are involved in the damage response pathway. Other members of this pathway are therefore good candidates for additional breast cancer susceptibility genes. ATR, along with ATM, plays a central role in DNA damage recognition and Chk1 relays checkpoint signals from both ATR and ATM. PPP2R1B and PPP2R5B code for subunits of protein phosphatase 2A (PP2A), which regulates autophosphorylation of ATM. In addition, EIF2S6/Int-6, which was originally identified as a common integration site for the mouse mammary tumour virus in virally induced mouse mammary tumours, is a candidate breast cancer susceptibility gene because of its putative role in maintaining chromosome stability. To investigate the role of ATR, CHK1, PPP2R1B, PPP2R5B and EIF2S6/Int-6, we carried out mutation analysis of these genes in the index cases from non-BRCA1/BRCA2 breast cancer families. We also screened sporadic breast tumours for somatic mutations in PPP2R1B and PPP2R5B. Although we identified many novel variants, we found no evidence that highly penetrant germline mutations in these five genes contribute to familial breast cancer susceptibility.

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Acknowledgements

We wish to thank David Goldgar for performing the Bayes analysis, Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, and the Clinical Follow Up Study (funded by NHMRC Grants 145684 and 288704) for their contributions to this resource, and the many families who contribute to kConFab. kConFab is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC) and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia and the Cancer Foundation of Western Australia. We would like to thank all the Australian Red Cross Blood Services (ARCBS) donors who participated as healthy controls in this study, Rachelle Morris and the staff at the ARCBS for their assistance with the collection of risk factor information and blood samples, Helene Holland for data management, and Joanne Young, Melanie Higgins, Kimberly Hinze, Robert Smith, Judith Clements, Melissa Barker, Rebecca Magson, Genevieve Birney and all the other members of the Molecular Cancer Epidemiology Laboratory, for their assistance with collection and processing of blood samples. Sporadic tumour specimens were provided by the Peter MacCallum Cancer Centre Tissue Bank, a member of the ABN-Oncology group, which is supported by National Health and Medical Research Council funding. This work is supported by a program grant from the NHMRC. ABS is funded by an NHMRC Career Development Award and KKK and GCT are NHMRC Principal Research Fellows.

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Authors and Affiliations

  1. Cancer and Cell Biology, Queensland Institute of Medical Research, c/o RBH Post Office, Herston, Brisbane, QLD , 4029 , Australia

    Anna Marsh, Sue Healey, Aaron Lewis, Amanda B. Spurdle, Kum Kum Khanna, Sunil R. Lakhani & Georgia Chenevix-Trench

  2. Queensland University of Technology, Brisbane, Australia

    Mary Anne Kedda

  3. Westmead Institute for Cancer Research, Sydney, Australia

    Graham J. Mann & Gulietta M. Pupo

  4. Molecular and Cellular Pathology, School of Medicine, University of Queensland, Brisbane, Australia

    Sunil R. Lakhani

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  1. Anna Marsh
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Correspondence to Georgia Chenevix-Trench.

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Marsh, A., Healey, S., Lewis, A. et al. Mutation analysis of five candidate genes in familial breast cancer. Breast Cancer Res Treat 105, 377–389 (2007). https://doi.org/10.1007/s10549-006-9461-z

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  • DOI: https://doi.org/10.1007/s10549-006-9461-z

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