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Association of the germline TP53 R72P and MDM2 SNP309 variants with breast cancer survival in specific breast tumor subgroups

  • Epidemiology
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Abstract

The tumor suppressor gene TP53 and its regulator MDM2 are both important players in the DNA-damage repair “TP53 response pathway”. Common germline polymorphisms in these genes may affect outcome in patients with tumors characterized by additional somatic changes in the same or a related pathway. To evaluate this hypothesis, we determined the effect of the common germline TP53 R72P and MDM2 SNP309 polymorphisms on breast cancer survival in a consecutive cohort of breast cancer patients (age at diagnosis <53 years, n = 295) with gene expression data available. Patients were classified in subgroups according to their tumor TP53 mutation status and three gene expression profiles; a TP53 mutation status expression signature, a PTEN/PI3K pathway signature and the 70-gene prognosis profile. Survival analyses were performed using Cox regression models adjusting for clinico-pathological characteristics and treatment. An increase in breast cancer-specific mortality was observed for carriers of the germline MDM2 SNP309 rare GG-genotype (range hazard ratios: 2–3) or TP53 R72P heterozygous GC-genotype (range hazard ratios: 1–2) compared to those having the common genotypes within subgroups of tumors displaying a “more aggressive phenotype” gene expression profile. There was no evidence of such an effect on survival within the TP53-mutated tumor group for TP53 R72P carriers but a suggestion of an effect for MDM2 SNP309 carriers (GG vs. TT-genotype HR 2.99, P = 0.06). These results indicate that common polymorphisms in specific pathways may add to the worse prognosis of patients with tumors in which these pathways are affected by somatic alterations.

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Acknowledgments

We thank our colleagues at the Netherlands Cancer Institute Flora E. van Leeuwen for discussion of the results in this paper and Petra Kristel for germline DNA isolations. Grant support: Dutch Cancer Society (DCS-NKI 2007-3839; 2009-4363), Dutch Genomics Initiative 2008 ‘Cancer Genomics Centre’, and EU 7th framework Collaborative Oncology Gene-environment study (HEALTH-2007-2.4.1-11).

Conflict of interest

Laura J. van’t Veer is named inventor on a MammaPrint™ patent and reports holding equity in Agendia BV.

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Authors and Affiliations

  1. Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Alexandra J. van den Broek & Marjanka K. Schmidt

  2. Division of Experimental Therapy, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Annegien Broeks, Hugo M. Horlings, Linde M. Braaf, Laura J. Van’t Veer & Marjanka K. Schmidt

  3. Division of Bioinformatics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Sander V. M. Canisius

  4. Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, 0310, Norway

    Anita Langerød

  5. Department of Pathology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands

    Hugo M. Horlings

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  1. Alexandra J. van den Broek
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Correspondence to Marjanka K. Schmidt.

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van den Broek, A.J., Broeks, A., Horlings, H.M. et al. Association of the germline TP53 R72P and MDM2 SNP309 variants with breast cancer survival in specific breast tumor subgroups. Breast Cancer Res Treat 130, 599–608 (2011). https://doi.org/10.1007/s10549-011-1615-y

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  • DOI: https://doi.org/10.1007/s10549-011-1615-y

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