Top

Published in:

01-11-2011 | Epidemiology

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

Authors: Alexandra J. van den Broek, Annegien Broeks, Hugo M. Horlings, Sander V. M. Canisius, Linde M. Braaf, Anita Langerød, Laura J. Van’t Veer, Marjanka K. Schmidt

Published in: Breast Cancer Research and Treatment | Issue 2/2011

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.

Available only for authorised users

Jin S, Levine AJ (2001) The p53 functional circuit. J Cell Sci 114:4139–4140PubMed

Zhou BB, Elledge SJ (2000) The DNA damage response: putting checkpoints in perspective. Nature 408:433–439PubMedCrossRef

Levine AJ (1997) p53, the cellular gatekeeper for growth and division. Cell 88:323–331PubMedCrossRef

Bond GL, Hu W, Levine AJ (2005) MDM2 is a central node in the p53 pathway: 12 years and counting. Curr Cancer Drug Targets 5:3–8PubMedCrossRef

Michael D, Oren M (2003) The p53-Mdm2 module and the ubiquitin system. Semin Cancer Biol 13:49–58PubMedCrossRef

Whibley C, Pharoah PD, Hollstein M (2009) p53 polymorphisms: cancer implications. Nat Rev Cancer 9:95–107PubMedCrossRef

Petitjean A, Achatz MI, Borresen-Dale AL, Hainaut P, Olivier M (2007) TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes. Oncogene 26:2157–2165PubMedCrossRef

Pharoah PD, Day NE, Caldas C (1999) Somatic mutations in the p53 gene and prognosis in breast cancer: a meta-analysis. Br J Cancer 80:1968–1973PubMedCrossRef

Chompret A (2002) The Li-Fraumeni syndrome. Biochimie 84:75–82PubMedCrossRef

10.

Matlashewski GJ, Tuck S, Pim D, Lamb P, Schneider J, Crawford LV (1987) Primary structure polymorphism at amino acid residue 72 of human p53. Mol Cell Biol 7:961–963PubMed

11.

Sakamuro D, Sabbatini P, White E, Prendergast GC (1997) The polyproline region of p53 is required to activate apoptosis but not growth arrest. Oncogene 15:887–898PubMedCrossRef

12.

Walker KK, Levine AJ (1996) Identification of a novel p53 functional domain that is necessary for efficient growth suppression. Proc Natl Acad Sci USA 93:15335–15340PubMedCrossRef

13.

Dumont P, Leu JI, Della Pietra AC III, George DL, Murphy M (2003) The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat Genet 33:357–365PubMedCrossRef

14.

Pim D, Banks L (2004) p53 polymorphic variants at codon 72 exert different effects on cell cycle progression. Int J Cancer 108:196–199PubMedCrossRef

15.

Thomas M, Kalita A, Labrecque S, Pim D, Banks L, Matlashewski G (1999) Two polymorphic variants of wild-type p53 differ biochemically and biologically. Mol Cell Biol 19:1092–1100PubMed

16.

Tommiska J, Eerola H, Heinonen M, Salonen L, Kaare M, Tallila J, Ristimaki A, von Smitten K, Aittomaki K, Heikkila P et al (2005) Breast cancer patients with p53 Pro72 homozygous genotype have a poorer survival. Clin Cancer Res 11:5098–5103PubMedCrossRef

17.

Schmidt MK, Tommiska J, Broeks A, van Leeuwen FE, van’t Veer LJ, Pharoah PD, Easton DF, Shah M, Humphreys M, Dork T et al (2009) Combined effects of single nucleotide polymorphisms TP53 R72P and MDM2 SNP309, and p53 expression on survival of breast cancer patients. Breast Cancer Res 11:R89PubMedCrossRef

18.

Goode EL, Dunning AM, Kuschel B, Healey CS, Day NE, Ponder BA, Easton DF, Pharoah PP (2002) Effect of germ-line genetic variation on breast cancer survival in a population-based study. Cancer Res 62:3052–3057PubMed

19.

Vannini I, Zoli W, Tesei A, Rosetti M, Sansone P, Storci G, Passardi A, Massa I, Ricci M, Gusolfino D et al (2008) Role of p53 codon 72 arginine allele in cell survival in vitro and in the clinical outcome of patients with advanced breast cancer. Tumour Biol 29:145–151PubMedCrossRef

20.

Toyama T, Zhang Z, Nishio M, Hamaguchi M, Kondo N, Iwase H, Iwata H, Takahashi S, Yamashita H, Fujii Y (2007) Association of TP53 codon 72 polymorphism and the outcome of adjuvant therapy in breast cancer patients. Breast Cancer Res 9:R34PubMedCrossRef

21.

Xu Y, Yao L, Zhao A, Ouyang T, Li J, Wang T, Fan Z, Fan T, Lin B, Lu Y et al (2008) Effect of p53 codon 72 genotype on breast cancer survival depends on p53 gene status. Int J Cancer 122:2761–2766PubMedCrossRef

22.

Martin AM, Kanetsky PA, Amirimani B, Colligon TA, Athanasiadis G, Shih HA, Gerrero MR, Calzone K, Rebbeck TR, Weber BL (2003) Germline TP53 mutations in breast cancer families with multiple primary cancers: is TP53 a modifier of BRCA1? J Med Genet 40:e34PubMedCrossRef

23.

Bougeard G, Baert-Desurmont S, Tournier I, Vasseur S, Martin C, Brugieres L, Chompret A, Bressac-de Paillerets B, Stoppa-Lyonnet D, Bonaiti-Pellie C et al (2006) Impact of the MDM2 SNP309 and p53 Arg72Pro polymorphism on age of tumour onset in Li-Fraumeni syndrome. J Med Genet 43:531–533PubMedCrossRef

24.

Schmidt MK, Reincke S, Broeks A, Braaf LM, Hogervorst FB, Tollenaar RA, Johnson N, Fletcher O, Peto J, Tommiska J et al (2007) Do MDM2 SNP309 and TP53 R72P interact in breast cancer susceptibility? A large pooled series from the breast cancer association consortium. Cancer Res 67:9584–9590PubMedCrossRef

25.

Bond GL, Hu W, Bond EE, Robins H, Lutzker SG, Arva NC, Bargonetti J, Bartel F, Taubert H, Wuerl P et al (2004) A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119:591–602PubMedCrossRef

26.

Bond GL, Hu W, Levine A (2005) A single nucleotide polymorphism in the MDM2 gene: from a molecular and cellular explanation to clinical effect. Cancer Res 65:5481–5484PubMedCrossRef

27.

Boersma BJ, Howe TM, Goodman JE, Yfantis HG, Lee DH, Chanock SJ, Ambs S (2006) Association of breast cancer outcome with status of p53 and MDM2 SNP309. J Natl Cancer Inst 98:911–919PubMedCrossRef

28.

Nechushtan H, Hamburger T, Mendelson S, Kadouri L, Sharon N, Pikarsky E, Peretz T (2009) Effects of the single nucleotide polymorphism at MDM2 309 on breast cancer patients with/without BRCA1/2 mutations. BMC Cancer 9:60PubMedCrossRef

29.

Ruijs MW, Schmidt MK, Nevanlinna H, Tommiska J, Aittomaki K, Pruntel R, Verhoef S, van’t Veer LJ (2007) The single-nucleotide polymorphism 309 in the MDM2 gene contributes to the Li-Fraumeni syndrome and related phenotypes. Eur J Hum Genet 15:110–114PubMedCrossRef

30.

Faur N, Araud L, Laroche-Clary A, Kanno J, Toutain J, Yamori T, Robert J, Le Morvan V (2009) The association between the T309G polymorphism of the MDM2 gene and sensitivity to anticancer drug is dependent on the p53 mutational status in cellular models. Br J Cancer 101:350–356PubMedCrossRef

31.

Takahashi S, Moriya T, Ishida T, Shibata H, Sasano H, Ohuchi N, Ishioka C (2008) Prediction of breast cancer prognosis by gene expression profile of TP53 status. Cancer Sci 99:324–332PubMedCrossRef

32.

Saal LH, Johansson P, Holm K, Gruvberger-Saal SK, She QB, Maurer M, Koujak S, Ferrando AA, Malmstrom P, Memeo L et al (2007) Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proc Natl Acad Sci USA 104:7564–7569PubMedCrossRef

33.

‘t Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT et al (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530–536PubMedCrossRef

34.

van de Vijver MJ, He YD, van’t Veer LJ, Dai H, Hart AA, Voskuil DW, Schreiber GJ, Peterse JL, Roberts C, Marton MJ et al (2002) A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347:1999–2009PubMedCrossRef

35.

Mook S, Schmidt MK, Rutgers EJ, van de Velde AO, Visser O, Rutgers SM, Armstrong N, van’t Veer LJ, Ravdin PM (2009) Calibration and discriminatory accuracy of prognosis calculation for breast cancer with the online Adjuvant! program: a hospital-based retrospective cohort study. Lancet Oncol 10:1070–1076PubMedCrossRef

36.

Zhou W, Muggerud AA, Vu P, Due EU, Sorlie T, Borresen-Dale AL, Warnberg F, Langerod A (2009) Full sequencing of TP53 identifies identical mutations within in situ and invasive components in breast cancer suggesting clonal evolution. Mol Oncol 3:214–219

37.

Allred DC, Harvey JM, Berardo M, Clark GM (1998) Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol 11:155–168PubMed

38.

Harvey JM, Clark GM, Osborne CK, Allred DC (1999) Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17:1474–1481PubMed

39.

Olivier M, Langerod A, Carrieri P, Bergh J, Klaar S, Eyfjord J, Theillet C, Rodriguez C, Lidereau R, Bieche I et al (2006) The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer. Clin Cancer Res 12:1157–1167PubMedCrossRef

40.

Miller LD, Smeds J, George J, Vega VB, Vergara L, Ploner A, Pawitan Y, Hall P, Klaar S, Liu ET et al (2005) An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. Proc Natl Acad Sci USA 102:13550–13555PubMedCrossRef

41.

Li L, Ross AH (2007) Why is PTEN an important tumor suppressor? J Cell Biochem 102:1368–1374PubMedCrossRef

42.

Cully M, You H, Levine AJ, Mak TW (2006) Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer 6:184–192PubMedCrossRef

43.

Sjogren S, Inganas M, Norberg T, Lindgren A, Nordgren H, Holmberg L, Bergh J (1996) The p53 gene in breast cancer: prognostic value of complementary DNA sequencing versus immunohistochemistry. J Natl Cancer Inst 88:173–182PubMedCrossRef

44.

Norberg T, Lennerstrand J, Inganas M, Bergh J (1998) Comparison between p53 protein measurements using the luminometric immunoassay and immunohistochemistry with detection of p53 gene mutations using cDNA sequencing in human breast tumors. Int J Cancer 79:376–383PubMedCrossRef

45.

Kyndi M, Alsner J, Hansen LL, Sorensen FB, Overgaard J (2006) LOH rather than genotypes of TP53 codon 72 is associated with disease-free survival in primary breast cancer. Acta Oncol 45:602–609PubMedCrossRef

46.

Borresen-Dale AL (2003) TP53 and breast cancer. Hum Mutat 21:292–300PubMedCrossRef

47.

Langerod A, Bukholm IR, Bregard A, Lonning PE, Andersen TI, Rognum TO, Meling GI, Lothe RA, Borresen-Dale AL (2002) The TP53 codon 72 polymorphism may affect the function of TP53 mutations in breast carcinomas but not in colorectal carcinomas. Cancer Epidemiol Biomarkers Prev 11:1684–1688PubMed

48.

Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365:1687–1717CrossRef

49.

Cheok CF, Verma CS, Baselga J, Lane DP (2011) Translating p53 into the clinic. Nat Rev Clin Oncol 8:25–37PubMedCrossRef

Title: Association of the germline TP53 R72P and MDM2 SNP309 variants with breast cancer survival in specific breast tumor subgroups
Authors: Alexandra J. van den Broek
Annegien Broeks
Hugo M. Horlings
Sander V. M. Canisius
Linde M. Braaf
Anita Langerød
Laura J. Van’t Veer
Marjanka K. Schmidt
Publication date: 01-11-2011
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 2/2011
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-011-1615-y

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2011

Association between the p53 polymorphisms and breast cancer risk: meta-analysis based on case–control study

CD8+ cytotoxic T cell and FOXP3+ regulatory T cell infiltration in relation to breast cancer survival and molecular subtypes

Young age is associated with ipsilateral breast tumor recurrence after breast conserving surgery and radiation therapy in patients with HER2-positive/ER-negative subtype

Epithelial-mesenchymal transition and stemness features in circulating tumor cells from breast cancer patients

Unmet supportive care needs: a cross-cultural comparison between Hong Kong Chinese and German Caucasian women with breast cancer

Addition of a histone deacetylase inhibitor redirects tamoxifen-treated breast cancer cells into apoptosis, which is opposed by the induction of autophagy

Keynote webinar | Spotlight on antibody–drug conjugates in cancer