Abstract
Context. p53 mutation is associated with poor prognosis in breast cancer patients. Mutations in different structural and functional domains of p53 have different effects on its biological activities. Nevertheless, few studies have examined the full spectrum of p53 gene mutations in relation to breast cancer survival.
Objective. To evaluate the prognostic significance of the types, localizations, and multiplicity of p53 gene mutations in breast cancer patients.
Design, setting, and participants. Prospective cohort study of a consecutive series of 271 women with histologically confirmed primary breast cancer who underwent breast resection at the Jackson Memorial Hospital, Miami, FL, between 1984 and 1986.
Main outcome measures. Ten year overall and breast-cancer-specific deaths.
Results. After adjustment for tumor stage, treatment regimen, and the number of mutations, patients with p53 mutations had significantly greater breast-cancer-specific mortality than did patients without p53 mutations (hazard ratio = 2.86; 95% confidence interval: 1.15–7.11). Further analysis of mutation characteristics showed that patients with the following mutations had significantly poorer breast cancer disease-free survival: silent/missense mixed mutations (7.95; 1.28–49.62), nonsense mutations (9.43; 1.29–69.12), transitions (3.79; 1.46–9.88), mutations in which guanine changed (3.32; 1.01–10.35), and mutations on exon 7 (6.46; 1.78–23.45).
Conclusions. Breast-cancer-specific and all-cause mortality are increased in female breast cancer patients with the following p53 mutation characteristics: silent and missense mixed mutations, transitional mutations, mutations in which guanine changed, mutations on exon 7, or multiple mutations occurring within 60 codons. These findings indicate that not just p53 mutation per se but the full spectrum (i.e., different types, locations, and numbers) of p53 mutation needs to be examined when it is used as a prognostic marker of survival in breast cancer patients.
Similar content being viewed by others
References
Harris CC: p53: at the crossroads of molecular carcinogenesis and molecular epidemiology. J Invest Dermatol Symp Proc 1(2): 115–118, 1996
Lane DP: p53 and human cancers. Br Med Bull 50(3): 582–599, 1994
Hollstein M, Sidransky D, Vogelstein B, Harris CC: p53 mutations in human cancers. Science 253(5015): 49–53, 1991
Stenmark-Askmalm M, Stal O, Sullivan S, Ferraud L, Sun XF, Carstensen J, Nordenskjold B: Cellular accumulation of p53 protein: an independent prognostic factor in stage II breast cancer. Eur J Cancer 30A(2): 175–180, 1994
Thor AD, Koerner FC, Edgerton SM, Wood WC, Stracher MA, Schwartz LH: pS2 expression in primary breast carcinomas: relationship to clinical and histological features and survival. Breast Cancer Res Treat 21(2): 111–119, 1992
Allred DC, Clark GM, Elledge R, Fuqua SA, Brown RW, Chamness GC, Osborne CK, McGuire WL: Association of p53 protein expression with tumor cell proliferation rate and clinical outcome in node-negative breast cancer. J Natl Cancer Inst 85(3): 200–206, 1993
Barnes DM, Dublin EA, Fisher CJ, Levison DA, Millis RR: Immunohistochemical detection of p53 protein in mammary carcinoma: an important new independent indicator of prognosis? Hum Pathol 24(5): 469–476, 1993
Elledge RM, Clark GM, Chamness GC, Osborne CK: Tumor biologic factors and breast cancer prognosis among white, Hispanic, and black women in the United States. J Natl Cancer Inst 86(9): 705–712, 1994
Beck T, Weller EE, Weikel W, Brumm C, Wilkens C, Knapstein PG: Usefulness of immunohistochemical staining for p53 in the prognosis of breast carcinomas: correlations with established prognosis parameters and with the proliferation marker, MIB-1. Gynecol Oncol 57(1): 96–104, 1995
Levesque MA, Yu H, Clark GM, Diamandis EP: Enzyme-linked immunoabsorbent assay-detected p53 protein accumulation: a prognostic factor in a large breast cancer cohort. J Clin Oncol 16(8): 2641–2650, 1998
Isola J, Visakorpi T, Holli K, Kallioniemi OP: Association of overexpression of tumor suppressor protein p53 with rapid cell proliferation and poor prognosis in node-negative breast cancer patients. J Natl Cancer Inst 84(14): 1109–1114, 1992
Bianchi S, Calzolari A, Vezzosi V, Zampi G, Cardona G, Cataliotti L, Bonardi R, Ciatto S: Lack of prognostic value of p53 protein expression in node-negative breast cancer. Tumori 83(3): 669–672, 1997
Gohring UJ, Scharl A, Heckel C, Ahr A, Crombach G: p53 protein in 204 patients with primary breast carcinoma-immunohistochemical detection and clinical value as a prognostic factor. Arch Gynecol Obstet 256(3): 139–146, 1995
Hartmann A, Blaszyk H, Kovach JS, Sommer SS: The molecular epidemiology of p53 gene mutations in human breast cancer. Trends Genet 13(1): 27–33, 1997
Pharoah PD, Day NE, Caldas C: Somatic mutations in the p53 gene and prognosis in breast cancer: a meta-analysis. Br J Cancer 80(12): 1968–1973, 1999
Borresen AL, Andersen TI, Eyfjord JE, Cornelis RS, Thorlacius S, Borg A, Johansson U, Theillet C, Scherneck S, Hartman S: TP53 mutations and breast cancer prognosis: particularly poor survival rates for cases with mutations in the zinc-binding domains. Genes Chromosomes Cancer 14(1): 71–75, 1995
Gentile M, Olsen K, Dufmats M, Wingren S: Frequent allelic losses at 11q24.1-q25 in young women with breast cancer: association with poor survival. Br J Cancer 80(5-6): 843–849, 1999
Kucera E, Speiser P, Gnant M, Szabo L, Samonigg H, Hausmaninger H, Mittlbock M, Fridrik M, Seifert M, Kubista E, Reiner A, Zeillinger R, Jakesz R: Prognostic significance of mutations in the p53 gene, particularly in the zinc-binding domains, in lymph node and steroid receptor positive breast cancer patients. Austrian Breast Cancer Study Group. Eur J Cancer 35(3): 398–405, 1999
Bergh J, Norberg T, Sjogren S, Lindgren A, Holmberg L: Complete sequencing of the p53 gene provides prognostic information in breast cancer patients, particularly in relation to adjuvant systemic therapy and radiotherapy. Nat Med 1(10): 1029–1034, 1995
Berns EM, van Staveren IL, Look MP, Smid M, Klijn JG, Foekens JA: Mutations in residues of TP53 that directly contact DNA predict poor outcome in human primary breast cancer. Br J Cancer 77(7): 1130–1136, 1998
Powell B, Soong R, Iacopetta B, Seshadri R, Smith DR: Prognostic significance of mutations to different structural and functional regions of the p53 gene in breast cancer. Clin Cancer Res 6(2): 443–451, 2000
Nadji M, Meng L, Lin L, Nassiri M, Morales AR: Detection of p53 gene abnormality by sequence analysis of archival paraffin tissue. A comparison with fresh-frozen specimens. Diagn Mol Pathol 5(4): 279–283, 1996
SAS User's Guide: Statistics V6. SAS Institute, Inc., Cary, NC, 1996
Levine AJ, Chang A, Dittmer D, Notterman DA, Silver A, Thorn K, Welsh D, Wu M: The p53 tumor suppressor gene. J Lab Clin Med 123(6): 817–823, 1994
Harris CC, Hollstein M: Clinical implications of the p53 tumor-suppressor gene. N Engl J Med 329(18): 1318–1327, 1993
Greenblatt MS, Bennett WP, Hollstein M, Harris CC: Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 54(18): 4855–4878, 1994
Tsuda H, Hirohashi S: Association among p53 gene mutation, nuclear accumulation of the p53 protein and aggressive phenotypes in breast cancer. Int J Cancer 57(4): 498–503, 1994
Sjogren S, Inganas M, Norberg T, Lindgren A, Nordgren H, Holmberg L, Bergh J: The p53 gene in breast cancer: prognostic value of complementary DNA sequencing versus immunohistochemistry. J Natl Cancer Inst 88(3-4): 173–182, 1996
Elledge RM: Assessing p53 status in breast cancer prognosis: where should you put the thermometer if you think your p53 is sick? J Natl Cancer Inst 88(3-4): 141–143, 1996
Kanjilal S, Strom SS, Clayman GL, Weber RS, el-Naggar AK, Kapur V et al.: p53 mutations in nonmelanoma skin cancer of the head and neck: molecular evidence for field cancerization. Cancer Res 55: 3604–3609, 1995
Hollstein M, Shomer B, Greenblatt M, Soussi T, Hovig E, Montesano R et al.: Somatic point mutations in the p53 gene of human tumors and cell lines: updated compilation. Nucl Acids Res 24: 141–146, 1996
Carbore D, Chiba I, Mitsudomi T: Polymorphism at codon 213 within p53 gene. Oncogene 6: 1691–1692, 1991
Meng L, Lin L, Zhang H, Nassiri M, Morales AR, Nadji M: Multiple mutations of the p53 gene in human mammary carcinoma. Mutat Res 435: 263–269, 1999
Mirza AN, Mirza NQ, Vlastos G, Singletary SE: Prognostic factors in node-negative breast cancer: a review of studies with sample size more than 200 and follow-up more than 5 years. Ann Surg 235(1): 10–26, 2002
Cho Y, Gorina S, Jeffrey PD, Pavletich NP: Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science 265(5170): 346–355, 1994
Chene P, Mittl P, Grutter M: In vitro structure-function analysis of the beta-strand 326-333 of human p53. J Mol Biol 273(4): 873–881, 1997
Venot C, Maratrat M, Dureuil C, Conseiller E, Bracco L, Debussche L: The requirement for the p53 proline-rich functional domain for mediation of apoptosis is correlated with specific PIG3 gene transactivation and with transcriptional repression. EMBO J 17(16): 4668–4679, 1998
Zhu J, Zhou W, Jiang J, Chen X: Identification of a novel p53 functional domain that is necessary for mediating apoptosis. J Biol Chem 273(21): 13030–13036, 1998
May P, May E: Twenty years of p53 research: structural and functional aspects of the p53 protein. Oncogene 18(53): 7621–7636, 1999
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Lai, H., Ma, F., Trapido, E. et al. Spectrum of p53 Tumor Suppressor Gene Mutations and Breast Cancer Survival. Breast Cancer Res Treat 83, 57–66 (2004). https://doi.org/10.1023/B:BREA.0000010699.53742.60
Issue Date:
DOI: https://doi.org/10.1023/B:BREA.0000010699.53742.60