Distinct tumor protein p53 mutants in breast cancer subgroups

Authors

  • Anne Dumay,

    1. Département de Biochimie, AP-HP, Hôpital Saint-Louis, Institut Universitaire d'Hématologie, CNRS UMR7212/INSERM U944/University Paris Diderot, Sorbonne Paris Cité, Paris, France
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    • A.D. and J.-P.F. contributed equally to this work

  • Jean-Paul Feugeas,

    1. Département de Biochimie, AP-HP, Hôpital Saint-Louis, Institut Universitaire d'Hématologie, CNRS UMR7212/INSERM U944/University Paris Diderot, Sorbonne Paris Cité, Paris, France
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    • A.D. and J.-P.F. contributed equally to this work

  • Evelyne Wittmer,

    1. Département de Biochimie, AP-HP, Hôpital Saint-Louis, Institut Universitaire d'Hématologie, CNRS UMR7212/INSERM U944/University Paris Diderot, Sorbonne Paris Cité, Paris, France
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  • Jacqueline Lehmann-Che,

    1. Département de Biochimie, AP-HP, Hôpital Saint-Louis, Institut Universitaire d'Hématologie, CNRS UMR7212/INSERM U944/University Paris Diderot, Sorbonne Paris Cité, Paris, France
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  • Philippe Bertheau,

    1. Département de Biochimie, AP-HP, Hôpital Saint-Louis, Institut Universitaire d'Hématologie, CNRS UMR7212/INSERM U944/University Paris Diderot, Sorbonne Paris Cité, Paris, France
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  • Marc Espié,

    1. Département de Biochimie, AP-HP, Hôpital Saint-Louis, Institut Universitaire d'Hématologie, CNRS UMR7212/INSERM U944/University Paris Diderot, Sorbonne Paris Cité, Paris, France
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  • Louis-François Plassa,

    1. Département de Biochimie, AP-HP, Hôpital Saint-Louis, Institut Universitaire d'Hématologie, CNRS UMR7212/INSERM U944/University Paris Diderot, Sorbonne Paris Cité, Paris, France
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  • Paul Cottu,

    1. Department of Medical Oncology, Institut Curie, Paris, France
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  • Michel Marty,

    1. Department of Medical Oncology, AP-HP, Hôpital Saint-Louis, Centre des Innovations Thérapeutiques en Oncologie et Hématologie, University Paris Diderot, Sorbonne Paris Cité, Paris, France
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  • Fabrice André,

    1. Department of Medical Oncology, INSERM U981 and University Paris XI, Institut Gustave Roussy, Villejuif, France
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  • Christos Sotiriou,

    1. Department of Medical Oncology and Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Bruxelles, Belgium
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  • Lajos Pusztai,

    1. Department of Breast Medical Oncology, MD Anderson Cancer Center, Houston, TX
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  • Hugues de Thé

    Corresponding author
    1. Département de Biochimie, AP-HP, Hôpital Saint-Louis, Institut Universitaire d'Hématologie, CNRS UMR7212/INSERM U944/University Paris Diderot, Sorbonne Paris Cité, Paris, France
    • AP-HP, Hôpital Saint-Louis, Département de Biochimie, and Institut Universitaire d'Hématologie, CNRS UMR7212/INSERM U944/, University Paris Diderot, Sorbonne Paris Cité, Paris, France
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Abstract

Tumor protein p53 (TP53) is mutated in approximately 30% of breast cancers, but this frequency fluctuates widely between subclasses. We investigated the p53 mutation status in 572 breast tumors, classified into luminal, basal and molecular apocrine subgroups. As expected, the lowest mutation frequency was observed in luminal (26%), and the highest in basal (88%) tumors. Luminal tumors showed significantly higher frequency of substitutions (82 vs. 65%), notably A/T to G/C transitions (31 vs. 15%), whereas molecular apocrine and basal tumors presented much higher frequencies of complex mutations (deletions/insertions) (36 and 33%, respectively, vs. 18%). Accordingly, missense mutations were significantly more frequent in luminal tumors (75 vs. 54%), whereas basal tumors displayed significantly increased rates of TP53 truncations (43 vs. 25%), resulting in loss of function and/or expression. Interestingly, as basal tumors, molecular apocrine tumors presented with a high rate of complex mutations, but paradoxically, these were not associated with increased frequency of p53 truncation. As in luminal tumors, this could reflect a selective pressure for p53 gain of function, possibly through P63/P73 inactivation. Collectively, these observations point not only to different mechanisms of TP53 alterations, but also to different functional consequences in the different breast cancer subtypes.

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