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Do MDM2 SNP309 and TP53 R72P Interact in Breast Cancer Susceptibility? A Large Pooled Series from the Breast Cancer Association Consortium

¹ Netherlands Cancer Institute, Amsterdam, the Netherlands; ² Departments of Gynaecology and Radiation Oncology, Hannover Medical School, Hannover, Germany; ³ Leiden University Medical Center, Leiden, the Netherlands; ⁴ Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research; ⁵ Cancer Research UK Genetics and Epidemiology Group, London School of Hygiene and Tropical Medicine, London, United Kingdom; ⁶ The Institute of Cancer Research, Sutton, Surrey, United Kingdom; Departments of ⁷ Obstetrics and Gynecology and ⁸ Oncology, Helsinki University Central Hospital, Helsinki, Finland; and ⁹ Strangeway's Research Laboratory, Cambridge, United Kingdom

Requests for reprints: Laura J. Van't Veer, Department of Pathology, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands. Phone: 31-20-512-2754; E-mail: l.vt.veer{at}nki.nl.

Association studies in large series of breast cancer patients can be used to identify single-nucleotide polymorphisms (SNP) contributing to breast cancer susceptibility. Previous studies have suggested associations between variants in TP53 (R72P) and MDM2 (SNP309) and cancer risk. Data from molecular studies suggest a functional interaction between these genes. We therefore investigated the effect of TP53 R72P and MDM2 SNP309 on breast cancer risk and age at onset of breast cancer in a pooled series of 5,191 cases and 3,834 controls from the Breast Cancer Association Consortium (BCAC). Breast cancer risk was not found to be associated with the combined variant alleles [odds ratio (OR), 1.00; 95% confidence interval (95% CI), 0.81–1.23]. Estimated ORs were 1.01 (95% CI, 0.93–1.09) per MDM2 SNP309 allele and 0.98 (95% CI, 0.91–1.04) for TP53 R72P. Although we did find evidence for a 4-year earlier age at onset for carriers of both variant alleles in one of the breast cancer patient series of the BCAC (the German series), we were not able to confirm this effect in the pooled analysis. Even so, carriers of both variant alleles did not have different risk estimates for bilateral or estrogen receptor–positive breast cancer. In conclusion, in this large collaborative study, we did not find an association of MDM2 SNP309 and TP53 R72P, separately or in interaction, with breast cancer. This suggests that any effect of these two variants would be very small and possibly confined to subgroups that were not assessed in our present study. [Cancer Res 2007;67(19):9584–90]

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