Rare germline mutations in PALB2 and breast cancer risk: A population-based study

Authors

  • Marc Tischkowitz,

    Corresponding author
    1. Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada
    2. Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec, Canada
    3. Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom
    • Department of Medical Genetics, University of Cambridge, Level 6, Addenbrooke's Treatment Centre, Box 134, Addenbrooke's Hospital, Cambridge CB2 0QQ
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  • Marinela Capanu,

    1. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York
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  • Nelly Sabbaghian,

    1. Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada
    2. Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec, Canada
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  • Lili Li,

    1. Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada
    2. Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec, Canada
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  • Xiaolin Liang,

    1. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York
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  • Maxime P. Vallée,

    1. International Agency for Research on Cancer, Lyon, France
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  • Sean V. Tavtigian,

    1. Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah
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  • Patrick Concannon,

    1. Department of Biochemistry and Molecular Genetics and Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia
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  • William D. Foulkes,

    1. Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada
    2. Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec, Canada
    3. The Research Institute, McGill University Health Centre, Montreal, Quebec, Canada
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  • Leslie Bernstein,

    1. Beckman Research Institute, City of Hope, Duarte, California
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  • The WECARE Study Collaborative Group,

    1. Members listed in Acknowledgments section
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  • Jonine L. Bernstein,

    1. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York
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  • Colin B. Begg

    1. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York
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  • Communicated by Michael Dean

Abstract

Germline mutations in the PALB2 gene are associated with an increased risk of developing breast cancer but little is known about the frequencies of rare variants in PALB2 and the nature of the variants that influence risk. We selected participants recruited to the Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study and screened lymphocyte DNA from cases with contralateral breast cancer (n = 559) and matched controls with unilateral breast cancer (n = 565) for PALB2 mutations. Five pathogenic PALB2 mutations were identified among the cases (0.9%) versus none among the controls (P = 0.04). The first-degree female relatives of these five carriers demonstrated significantly higher incidence of breast cancer than relatives of noncarrier cases, indicating that pathogenic PALB2 mutations confer an estimated 5.3-fold increase in risk (95% CI: 1.8–13.2). The frequency of rare (<1% MAF) missense mutations was similar in both groups (23 vs. 21). Our findings confirm in a population-based study setting of women with breast cancer the strong risk associated with truncating mutations in PALB2 that has been reported in family studies. Conversely, there is no evidence from this study that rare PALB2 missense mutations strongly influence breast cancer risk. Hum Mutat 33:674–680, 2012. © 2012 Wiley Periodicals, Inc.

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