Mutations in p53, p53 protein overexpression and breast cancer survival
Corresponding Author
Pavel Rossner Jr
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA
Laboratory of Genetic Ecotoxicology, Institute of Experimental Medicine AS CR, Prague, Czech Republic
Correspondence to: Pavel ROSSNER Jr., PhD, Institute of Experimental Medicine AS CR, v.v.i., Vìdeňská 1083, 142 20 Prague, Czech Republic.Tel.: +420–24106-2675Fax: +420–24106-2785E-mail: [email protected]Search for more papers by this authorMarilie D. Gammon
Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC, USA
Search for more papers by this authorYu-Jing Zhang
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA
Search for more papers by this authorMary Beth Terry
Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
Search for more papers by this authorHanina Hibshoosh
Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
Search for more papers by this authorLorenzo Memeo
Pathology Unit Mediterranean Institute of Oncology, Catania, Italy
Search for more papers by this authorMahesh Mansukhani
Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
Search for more papers by this authorChang-Min Long
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA
Search for more papers by this authorGail Garbowski
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA
Search for more papers by this authorMeenakshi Agrawal
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA
Search for more papers by this authorTara S. Kalra
Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
Search for more papers by this authorMia M. Gaudet
Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC, USA
Search for more papers by this authorSusan L. Teitelbaum
Department of Community and Preventive Medicine, Mt. Sinai School of Medicine, New York, NY, USA
Search for more papers by this authorAlfred I. Neugut
Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
Search for more papers by this authorRegina M. Santella
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA
Search for more papers by this authorCorresponding Author
Pavel Rossner Jr
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA
Laboratory of Genetic Ecotoxicology, Institute of Experimental Medicine AS CR, Prague, Czech Republic
Correspondence to: Pavel ROSSNER Jr., PhD, Institute of Experimental Medicine AS CR, v.v.i., Vìdeňská 1083, 142 20 Prague, Czech Republic.Tel.: +420–24106-2675Fax: +420–24106-2785E-mail: [email protected]Search for more papers by this authorMarilie D. Gammon
Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC, USA
Search for more papers by this authorYu-Jing Zhang
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA
Search for more papers by this authorMary Beth Terry
Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
Search for more papers by this authorHanina Hibshoosh
Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
Search for more papers by this authorLorenzo Memeo
Pathology Unit Mediterranean Institute of Oncology, Catania, Italy
Search for more papers by this authorMahesh Mansukhani
Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
Search for more papers by this authorChang-Min Long
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA
Search for more papers by this authorGail Garbowski
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA
Search for more papers by this authorMeenakshi Agrawal
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA
Search for more papers by this authorTara S. Kalra
Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
Search for more papers by this authorMia M. Gaudet
Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC, USA
Search for more papers by this authorSusan L. Teitelbaum
Department of Community and Preventive Medicine, Mt. Sinai School of Medicine, New York, NY, USA
Search for more papers by this authorAlfred I. Neugut
Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
Search for more papers by this authorRegina M. Santella
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA
Search for more papers by this authorAbstract
p53 is an important tumour suppressor gene that encodes p53 protein, a molecule involved in cell cycle regulation and has been inconsistently linked to breast cancer survival. Using archived tumour tissue from a population-based sample of 859 women diagnosed with breast cancer between 1996 and 1997, we determined p53 mutations in exons 5–8 and p53 protein overexpression. We examined the association of p53 mutations with overexpression and selected tumour clinical parameters. We assessed whether either p53 marker was associated with survival through 2002, adjusting for other tumour markers and prognostic factors. The prevalence of protein overexpression in the tumour was 36% (307/859) and of any p53 mutation was 15% (128/859). p53 overexpression was positively associated with the presence of any p53 mutation (odds ratio [OR]= 2.2, 95% confidence interval [CI]= 1.5–3.2), particularly missense mutations (ER = 7.0, 95% CI = 3.6–13.7). Negative oestrogen and progesterone receptor (ER/PR) status was positively associated with both p53 protein overexpression (= 2.6, 95% CI = 1.7–4.0) and p53 mutation (OR = 3.9, 95% CI = 2.4–6.5). Any p53 mutation and missense mutations, but not p53 protein overexpression, were associated with breast cancer-specific mortality (hazard ratio [HR]= 1.7, 95% CI = 1.0–2.8; HR = 2.0, 95% CI = 1.1–3.6, respectively) and all-cause mortality (HR = 1.5, 95% CI = 1.0–2.4; HR = 2.0, 95% CI = 1.2–3.4, respectively); nonsense mutations were associated only with breast cancer-specific mortality (HR = 3.0, 95% CI = 1.1–8.1). These associations however did not remain after adjusting for ER/PR status. Thus, in this population-based cohort of women with breast cancer, although p53 protein overexpression and p53 mutations were associated with each other, neither independently impacted breast cancer-specific or all-causing mortality, after considering ER/PR status.
References
- 1 Braithwaite AW, Royds JA, Jackson P. The p53 story: layers of complexity. Carcinogenesis. 2005; 26: 1161–9.
- 2 Olivier M, Hainaut P. TP53 mutation patterns in breast cancers: searching for clues of environmental carcinogenesis. Semin Cancer Biol. 2001; 11: 353–60.
- 3 Borresen-Dale AL. TP53 and breast cancer. Hum Mutat. 2003; 21: 292–300.
- 4 Hill KA, Sommer SS. p53 as a mutagen test in breast cancer. Environ Mol Mutagen. 2002; 39: 216–27.
- 5 Lacroix M, Toillon RA, Leclercq G. p53 and breast cancer, an update. Endocr Relat Cancer. 2006; 13: 293–325.
- 6 Hall PA, McCluggage WG. Assessing p53 in clinical contexts: unlearned lessons and new perspectives. J Pathol. 2006; 208: 1–6.
- 7 Elledge RM, Allred DC. Prognostic and predictive value of p53 and p21 in breast cancer. Breast Cancer Res Treat. 1998; 52: 79–98.
- 8 Pakos EE, Kyzas PA, Ioannidis JP. Prognostic significance of TP53 tumor suppressor gene expression and mutations in human osteosarcoma: a meta-analysis. Clin Cancer Res. 2004; 10: 6208–14.
- 9 Malats N, Bustos A, Nascimento CM, et al . P53 as a prognostic marker for bladder cancer: a meta-analysis and review. Lancet Oncol. 2005; 6: 678–86.
- 10 Pharoah PD, Day NE, Caldas C. Somatic mutations in the p53 gene and prognosis in breast cancer: a meta-analysis. Br J Cancer. 1999; 80: 1968–73.
- 11 Olivier M, Langerod A, Carrieri P, et al . The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer. Clin Cancer Res. 2006; 12: 1157–67.
- 12 Cianfrocca M, Goldstein LJ. Prognostic and predictive factors in early-stage breast cancer. Oncologist. 2004; 9: 606–16.
- 13 Gammon MD, Neugut AI, Santella RM, et al . The Long Island Breast Cancer Study Project: description of a multi-institutional collaboration to identify environmental risk factors for breast cancer. Breast Cancer Res Treat. 2002; 74: 235–54.
- 14 Cleveland RJ, Eng SM, Abrahamson PE, et al . Weight gain prior to breast cancer diagnosis and survival. Cancer Epidemiol Biomarkers Prev. 2007; 16: 1803–11.
- 15 Fink BN, Gaudet MM, Britton JA, et al . Fruits, vegetables, and micronutrient intake in relation to breast cancer survival. Breast Cancer Res Treat. 2006; 98: 199–208.
- 16 Gaudet MM, Britton JA, Kabat GC, et al . Fruits, vegetables, and micronutrients in relation to breast cancer modified by menopause and hormone receptor status. Cancer Epidemiol Biomarkers Prev. 2004; 13: 1485–94.
- 17 Qiu P, Shandilya H, D’Alessio JM, et al . Mutation detection using Surveyor nuclease. Biotechniques. 2004; 36: 702–7.
- 18 Hosmer DW, Lemeshow S. Applied logistic regression. New York : John Wiley & Sons; 1989.
- 19 Hosmer DW, Lemeshow S. Applied survival analysis: regression modeling of time to event data. New York : John Wiley & Sons, Inc.; 1999.
- 20 Olivier M, Eeles R, Hollstein M, et al . The IARC TP53 database: new online mutation analysis and recommendations to users. Hum Mutat. 2002; 19: 607–14.
- 21 Bannwarth S, Procaccio V, Paquis-Flucklinger V. Surveyor nuclease: a new strategy for a rapid identification of heteroplasmic mitochondrial DNA mutations in patients with respiratory chain defects. Hum Mutat. 2005; 25: 575–82.
- 22 Nowak D, Mossner M, Baldus CD, et al . Mutation analysis of hCDC4 in AML cells identifies a new intronic polymorphism. Int J Med Sci. 2006; 3: 148–51.
- 23 Mitani N, Niwa Y, Okamoto Y. Surveyor nuclease-based detection of p53 gene mutations in haematological malignancy. Ann Clin Biochem. 2007; 44: 557–9.
- 24 Lukas J, Niu N, Press MF. p53 mutations and expression in breast carcinoma in situ. Am J Pathol. 2000; 156: 183–91.
- 25 Iwase H, Ando Y, Ichihara S, et al . Immunohistochemical analysis on biological markers in ductal carcinoma in situ of the breast. Breast Cancer. 2001; 8: 98–104.
- 26 Thorlacius S, Thorgilsson B, Bjornsson J, et al . TP53 mutations and abnormal p53 protein staining in breast carcinomas related to prognosis. Eur J Cancer. 1995; 31A: 1856–61.
- 27 Naidu R, Yadav M, Nair S, et al . Immunohistochemical analysis of p53 expression in primary breast carcinomas. Anticancer Res. 1998; 18: 65–70.
- 28 Tan PH, Chuah KL, Chiang G, et al . Correlation of p53 and cerbB2 expression and hormonal receptor status with clinicopathologic parameters in ductal carcinoma in situ of the breast. Oncol Rep. 2002; 9: 1081–6.
- 29 Erdem O, Dursun A, Coskun U, et al . The prognostic value of p53 and c-erbB-2 expression, proliferative activity and angiogenesis in node-negative breast carcinoma. Tumori. 2005; 91: 46–52.
- 30 McCabe A, Dolled-Filhart M, Camp RL, et al . Automated quantitative analysis (AQUA) of in situ protein expression, antibody concentration, and prognosis. J Natl Cancer Inst. 2005; 97: 1808–15.
- 31 Schmitt FC, Soares R, Cirnes L, et al . P53 in breast carcinomas: association between presence of mutation and immunohistochemical expression using a semiquantitative approach. Pathol Res Pract. 1998; 194: 815–9.
- 32 Umekita Y, Kobayashi K, Saheki T, et al . Nuclear accumulation of p53 protein correlates with mutations in the p53 gene on archival paraffin-embedded tissues of human breast cancer. Jpn J Cancer Res. 1994; 85: 825–30.
- 33 Lisboa BW, Vogtlander S, Gilster T, et al . Molecular and immunohistochemical analysis of p53 mutations in scrapings and tissue from preinvasive and invasive breast cancer. Virchows Arch. 1997; 431: 375–81.
- 34 Lohmann D, Ruhri C, Schmitt M, et al . Accumulation of p53 protein as an indicator for p53 gene mutation in breast cancer. Occurrence of false-positives and false-negatives. Diagn Mol Pathol. 1993; 2: 36–41.
- 35 Nicolini A, Carpi A, Tarro G. Biomolecular markers of breast cancer. Front Biosci. 2006; 11: 1818–43.
- 36 Putti TC, El-Rehim DM, Rakha EA, et al . Estrogen receptor-negative breast carcinomas: a review of morphology and immunophenotypical analysis. Mod Pathol. 2005; 18: 26–35.
- 37 Gammon MD, Hibshoosh H, Terry MB, et al . Cigarette smoking and other risk factors in relation to p53 expression in breast cancer among young women. Cancer Epidemiology Biomarkers Prev. 1999; 8: 255–63.
- 38
Reed W,
Hannisdal E,
Boehler PJ,
et al
.
The prognostic value of p53 and c-erb B-2 immunostaining is overrated for patients with lymph node negative breast carcinoma: a multivariate analysis of prognostic factors in 613 patients with a follow-up of 14–30 years.
Cancer.
2000; 88: 804–13.
10.1002/(SICI)1097-0142(20000215)88:4<804::AID-CNCR11>3.0.CO;2-Y CAS PubMed Web of Science® Google Scholar
- 39 Warnberg F, Nordgren H, Bergkvist L, et al . Tumour markers in breast carcinoma correlate with grade rather than with invasiveness. Br J Cancer. 2001; 85: 869–74.
- 40 Conway K, Edmiston SN, Cui L, et al . Prevalence and spectrum of p53 mutations associated with smoking in breast cancer. Cancer Res. 2002; 62: 1987–95.
- 41
Chappuis PO,
Estreicher A,
Dieterich B,
et al
.
Prognostic significance of p53 mutation in breast cancer: frequent detection of non-missense mutations by yeast functional assay.
Int J Cancer.
1999; 84: 587–93.
10.1002/(SICI)1097-0215(19991222)84:6<587::AID-IJC8>3.0.CO;2-8 CAS PubMed Web of Science® Google Scholar
- 42 Powell B, Soong R, Iacopetta B, et al . Prognostic significance of mutations to different structural and functional regions of the p53 gene in breast cancer. Clin Cancer Res. 2000; 6: 443–51.
- 43 Overgaard J, Yilmaz M, Guldberg P, et al . TP53 mutation is an independent prognostic marker for poor outcome in both node-negative and node-positive breast cancer. Acta Oncol. 2000; 39: 327–33.
- 44 Lai H, Ma F, Trapido E, Meng L, et al . Spectrum of p53 tumor suppressor gene mutations and breast cancer survival. Breast Cancer Res Treat. 2004; 83: 57–66.
- 45
Ho GH,
Calvano JE,
Bisogna M,
et al
.
In microdissected ductal carcinoma in situ, HER-2/neu amplification, but not p53 mutation, is associated with high nuclear grade and comedo histology.
Cancer.
2000; 89: 2153–60.
10.1002/1097-0142(20001201)89:11<2153::AID-CNCR2>3.0.CO;2-O CAS PubMed Web of Science® Google Scholar
- 46 Done SJ, Eskandarian S, Bull S, et al . p53 missense mutations in microdissected high-grade ductal carcinoma in situ of the breast. J Natl Cancer Inst. 2001; 93: 700–4.
- 47 Kang JH, Kim SJ, Noh DY, et al . The timing and characterization of p53 mutations in progression from atypical ductal hyperplasia to invasive lesions in the breast cancer. J Mol Med. 2001; 79: 648–55.
- 48 Terry MB, Neugut AI, Schwartz S, et al . Risk factors for a causal intermediate and an endpoint: reconciling differences. Am J Epidemiol. 2000; 151: 339–45.
- 49 Thorlacius S, Borresen AL, Eyfjord JE. Somatic p53 mutations in human breast carcinomas in an Icelandic population: a prognostic factor. Cancer Res. 1993; 53: 1637–41.
- 50 Boersma BJ, Howe TM, Goodman JE, et al . Association of breast cancer outcome with status of p53 and MDM2 SNP309. J Natl Cancer Inst. 2006; 98: 911–9.
- 51 Barbareschi M. Prognostic value of the immunohistochemical expression of p53 in breast carcinomas-A review of the literature involving over 9,000 patients. Appl Immunohistochem. 1996; 4: 106–16.
- 52 Dimitrakakis C, Konstadoulakis M, Messaris E, et al . Molecular markers in breast cancer: can we use c-erbB-2, p53, bcl-2 and Bax gene expression as prognostic factors Breast. 2002; 11: 279–85.
- 53 Hlupic L, Jakic-Razumovic J, Bozikov J, et al . Prognostic value of different factors in breast carcinoma. Tumori. 2004; 90: 112–9.
- 54 Caffo O, Doglioni C, Veronese S, et al . Prognostic value of p21(WAF1) and p53 expression in breast carcinoma: an immunohistochemical study in 261 patients with long-term follow-up. Clin Cancer Res. 1996; 2: 1591–99.
- 55 Montero S, Guzman C, Vargas C, et al . Prognostic value of cytosolic p53 protein in breast cancer. Tumour Biol. 2001; 22: 337–44.
- 56 Linjawi A, Kontogiannea M, Halwani F, et al . Prognostic significance of p53, bcl-2, and Bax expression in early breast cancer. J Am Coll Surg. 2004; 198: 83–90.
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