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The Clinical Value of Somatic TP53 Gene Mutations in 1,794 Patients with Breast Cancer

Authors' Affiliations: ¹ IARC, Lyon, France; ² Department of Genetics, The Norwegian Radium Hospital, and Faculty Division, University of Oslo, Oslo, Norway; ³ INSERM U379, ORS PACA, Epidémiologie Sociale Appliquée à l'Innovation, Marseille, France; ⁴ Department of Oncology (Radiumhemmet), Karolinska Hospital and Institute, Stockholm, Sweden; ⁵ The Icelandic Cancer Society, Molecular and Cell Biology Research Laboratory, and Faculty of Medicine, University of Iceland, Reykjavik, Iceland; ⁶ INSERM E 229, CRLC Val d'Aurelle/Paul Lamarque, Montpellier Cedex, France; ⁷ INSERM U735/Oncogénétique, Centre René Huguenin, St. Cloud, France; ⁸ Paterson Institute for Cancer Research, Manchester, United Kingdom; ⁹ Department of Oncogenetics, Centre Jean Perrin, Clermont-Ferrand Cedex, France; Departments of ¹⁰ Clinical Genetics and ¹¹ Oncology, Oulu University Hospital, University of Oulu, Oulu, Finland; ¹² Molekulargenetisches Labor, Frauenklinik des Universitätsklinikums Düsseldorf, Gebäude, Düsseldorf, Germany; and ¹³ Department of Clinical Oncology, Institute of Development Aging and Cancer, Aoba-ku, Sendai, Japan

Requests for reprints: Pierre Hainaut, IARC, 150 Cours Albert Thomas, F-69372 Lyon, France. Phone: 33-472-738-532; Fax: 33-472-738-322; E-mail: hainaut{at}iarc.fr.

To investigate the clinical value of somatic TP53 mutations in breast cancer, we assembled clinical and molecular data on 1,794 women with primary breast cancer with long-term follow-up and whose tumor has been screened for mutation in exons 5 to 8 of TP53 by gene sequencing. TP53 mutations were more frequent in tumors of ductal and medullar types, aggressive phenotype (high grade, large size, node positive cases, and low hormone receptor content) and in women <60 years old. TP53 mutations within exons 5 to 8 conferred an elevated risk of breast cancer–specific death of 2.27 (relative risk >10 years; P < 0.0001) compared with patients with no such mutation. The prognostic value of TP53 mutation was independent of tumor size, node status, and hormone receptor content, confirming and reconciling previous findings in smaller series. Moreover, an interaction between TP53 mutation and progesterone receptor (PR) status was revealed, TP53 mutation combined with the absence of progesterone receptor being associated with the worst prognosis. Whereas previous studies have emphasized the fact that missense mutations in the DNA-binding motifs have a worse prognosis than missense mutations outside these motifs, we show that non–missense mutations have prognostic value similar to missense mutations in DNA-binding motifs. Nonetheless, specific missense mutants (codon 179 and R248W) seem to be associated with an even worse prognosis. These results, obtained on the largest series analyzed thus far, show that TP53 mutations identified by gene sequencing have an independent prognostic value in breast cancer and could have potential uses in clinical practice.

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