Sinilnikova, O. M., Antoniou, A. C., Simard, J., Healey, S., Leone, M., Sinnett, D., Spurdle, A. B., Beesley, J., Chen, X., Greene, M. H., Loud, J. T., Lejbkowicz, F., Rennert, G., Dishon, S., Andrulis, I. L., Domchek, S. M., Nathanson, K. L., Manoukian, S., Radice, P., Konstantopoulou, I., Blanco, I., Laborde, A. L., Duran, M., Osorio, A., Benitez, J., Hamann, U., Hogervorst, F. B. L., van Os, T. A. M., Gille, H. J. P., Peock, S., Cook, M., Luccarini, C., Evans, D. G., Lalloo, F., Eeles, R., Pichert, G., Davidson, R., Cole, T., Cook, J., Paterson, J., Brewer, C., Hughes, D. J., Coupier, I., Giraud, S., Coulet, F., Colas, C., Soubrier, F., Rouleau, E., Bieche, I., Lidereau, R., Demange, L., Nogues, C., Lynch, H. T., Schmutzler, R. K., Versmold, B., Engel, C., Meindl, A., Arnold, N., Sutter, C., Deissler, H., Schaefer, D., Froster, U. G., Aittomaki, K., Nevanlinna, H., McGuffog, L., Easton, D. F., Chenevix-Trench, G., Stoppa-Lyonnet, D., kConFab, [Group Author], OCGN, [Group Author], HEBON, [Group Author], EMBRACE, [Group Author], GEMO, [Group Author], GC-HBOC, [Group Author], Consortium Investigators Modifiers, [Group Author] (2009) The TP53 Arg72Pro and MDM2 309G > T polymorphisms are not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. BRITISH JOURNAL OF CANCER, 101 (8). pp. 1456-1460. ISSN 0007-0920

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Abstract

BACKGROUND: The TP53 pathway, in which TP53 and its negative regulator MDM2 are the central elements, has an important role in carcinogenesis, particularly in BRCA1- and BRCA2-mediated carcinogenesis. A single nucleotide polymorphism (SNP) in the promoter region of MDM2 (309T > G, rs2279744) and a coding SNP of TP53 (Arg72Pro, rs1042522) have been shown to be of functional significance. METHODS: To investigate whether these SNPs modify breast cancer risk for BRCA1 and BRCA2 mutation carriers, we pooled genotype data on the TP53 Arg72Pro SNP in 7011 mutation carriers and on the MDM2 309T > G SNP in 2222 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analysed using a Cox proportional hazards model within a retrospective likelihood framework. RESULTS: No association was found between these SNPs and breast cancer risk for BRCA1 (TP53: per-allele hazard ratio (HR) = 1.01, 95% confidence interval (CI): 0.93-1.10, P-trend = 0.77; MDM2: HR = 0.96, 95% CI: 0.84-1.09, P-trend = 0.54) or for BRCA2 mutation carriers (TP53: HR = 0.99, 95% CI: 0.87-1.12, P-trend = 0.83; MDM2: HR = 0.98, 95% CI: 0.80-1.21, P-trend = 0.88). We also evaluated the potential combined effects of both SNPs on breast cancer risk, however, none of their combined genotypes showed any evidence of association. CONCLUSION: There was no evidence that TP53 Arg72Pro or MDM2 309T > G, either singly or in combination, influence breast cancer risk in BRCA1 or BRCA2 mutation carriers. British Journal of Cancer (2009) 101, 1456-1460. doi: 10.1038/sj.bjc.6605279 www.bjcancer.com Published online 25 August 2009 (C) 2009 Cancer Research UK

Item Type:	Article
Authors (ICR Faculty only):	Eeles, Rosalind
All Authors:	Sinilnikova, O. M., Antoniou, A. C., Simard, J., Healey, S., Leone, M., Sinnett, D., Spurdle, A. B., Beesley, J., Chen, X., Greene, M. H., Loud, J. T., Lejbkowicz, F., Rennert, G., Dishon, S., Andrulis, I. L., Domchek, S. M., Nathanson, K. L., Manoukian, S., Radice, P., Konstantopoulou, I., Blanco, I., Laborde, A. L., Duran, M., Osorio, A., Benitez, J., Hamann, U., Hogervorst, F. B. L., van Os, T. A. M., Gille, H. J. P., Peock, S., Cook, M., Luccarini, C., Evans, D. G., Lalloo, F., Eeles, R., Pichert, G., Davidson, R., Cole, T., Cook, J., Paterson, J., Brewer, C., Hughes, D. J., Coupier, I., Giraud, S., Coulet, F., Colas, C., Soubrier, F., Rouleau, E., Bieche, I., Lidereau, R., Demange, L., Nogues, C., Lynch, H. T., Schmutzler, R. K., Versmold, B., Engel, C., Meindl, A., Arnold, N., Sutter, C., Deissler, H., Schaefer, D., Froster, U. G., Aittomaki, K., Nevanlinna, H., McGuffog, L., Easton, D. F., Chenevix-Trench, G., Stoppa-Lyonnet, D., kConFab, [Group Author], OCGN, [Group Author], HEBON, [Group Author], EMBRACE, [Group Author], GEMO, [Group Author], GC-HBOC, [Group Author], Consortium Investigators Modifiers, [Group Author]
Uncontrolled Keywords:	TP53; MDM2; BRCA1/2; breast cancer; polymorphism; risk;SINGLE NUCLEOTIDE POLYMORPHISM; LI-FRAUMENI-SYNDROME; P53; SNP309; CARCINOGENESIS; CONSORTIUM; MODIFIERS; INS16BP; PATHWAY
Funding Acknowledgement:	German Cancer Aid [107054]; Center for Molecular Medicine Cologne [TV93]; Helsinki University Central Hospital Research Fund ; Academy of Finland [110663]; Finnish Cancer Society ; Sigrid Juselius Foundation
Funding Text:	We thank Juliane Koehler for her excellent technical assistance and the 12 centers of the GC-HBOC (German Consortium of Hereditary Breast and Ovarian Cancer) for providing samples and clinical data. GC-HBOC is supported by a grant of the German Cancer Aid (grant 107054) and the Center for Molecular Medicine Cologne (grant TV93) to Rita K Schmutzler. We thank Drs Kirsimari Aaltonen, Carl Blomqvist and RN Hanna Jantti for their help with the patient data and Dr Johanna Tommiska for her kind help with the genetic analyses. The Finnish Cancer registry is gratefully acknowledged for the cancer data. The HEBCS study has been financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (110663), Finnish Cancer Society and the Sigrid Juselius Foundation.
Research teams:	ICR divisions > Genetics and Epidemiology > Oncogenetics ICR divisions > Radiotherapy and Imaging > Oncogenetics
Depositing User:	Users 10 not found.
Date Deposited:	02 Nov 2009 09:34
Last Modified:	10 Feb 2010 11:52
URI:	http://publications.icr.ac.uk/id/eprint/8952

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