Alterations in p53, BRCA1, ATM, PIK3CA, and HER2 genes and their effect in modifying clinicopathological characteristics and overall survival of Bulgarian patients with breast cancer
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Though p53, BRCA1, ATM, PIK3CA, and HER2 genes are shown to be involved in various aspects of breast carcinogenesis, their functional relationship and clinical value are still disputable. We investigated the genetic status or expression profile of these genes to further elucidate their clinical significance.
PCR-SSCP-Sequencing of p53, BRCA1, ATM, and PIK3CA was performed in 145 Bulgarian patients with sporadic breast cancer. Expression profiles of HER2 were determined by ICH and CISH. Relationship between mutations and clinicopathological characteristics was evaluated by Chi-squared and Fisher’s exact tests. Multivariate Cox proportional hazard test and Kaplan–Meier analysis were used to evaluate differences in overall survival between groups.
The frequency of p53 (22.07%), BRCA1 (0.69%), ATM (7.59%), and PIK3CA (31.25%) alterations and HER2 (21.21%) overexpression was estimated. Mutated p53 was associated with tumor size (P = 0.033) and grade of malignancy (P = 0.001), ATM—with grade of malignancy (P = 0.032), and PIK3CA—with PR-positive tumors (P = 0.047). HER2 overexpression correlated with age of diagnosis (P = 0.009), tumor size (P = 0.0004), and ER expression (P = 0.011). Univariate survival analysis showed that mutated p53 is an indicator for worse outcome (P = 0.041). Combination of two genetic abnormalities did not correlate with more aggressive carcinogenesis and worse overall survival.
Our data indicated that p53, BRCA1, ATM, PIK3CA, and HER2 alterations specifically correlate with clinicopathological characteristics of Bulgarian patients with breast cancer. Of these genes, only mutated p53 showed significant, though not independent, negative effect on overall survival.
KeywordsBreast cancer Tumor suppressor genes Proto-oncogenes Mutations Clinicopathological characteristics Overall survival
Chromogenic in situ Hybridization
Grade of malignancy
Authors express their gratitude to Dr. Maria Nacheva who provided assistance in collecting of samples. We are grateful to Dr. Milka Georgieva for the critical reading of manuscript. This work was funded by the Bulgarian Ministry of Education and Science, projects No G-1-04/04 and DO 02.310/08.
Conflict of interest statement
We declare that we have no competing interests.
- Barbareschi M, Buttitta F, Felicioni L, Cotrupi S, Barassi F, Del Grammastro M, Ferro A, Dalla Palma P, Galligioni E, Marchetti A (2007) Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas. Clin Cancer Res 13:6064–6069. doi: 10.1158/1078-0432.CCR-07-0266 CrossRefPubMedGoogle Scholar
- Bull SB, Ozcelik H, Pinnaduwage D, Blackstein ME, Sutherland DA, Pritchard KI, Tzontcheva AT, Sidlofsky S, Hanna WM, Qizilbash AH, Tweeddale ME, Fine S, McCready DR, Andrulis IL (2004) The combination of p53 mutation and neu/erbB-2 amplification is associated with poor survival in node-negative breast cancer. J Clin Oncol 22:86–96. doi: 10.1200/JCO.2004.09.128 CrossRefPubMedGoogle Scholar
- Danon Sh, Valerianova Zdr, Ivanova Tzv (2006) Bulgarian National Cancer Registry. Cancer incidence in Bulgaria 2003. Bulgarian Publishing House, SofiaGoogle Scholar
- Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, Bussaglia E, Prat J, Harkes IC, Repasky EA, Gabrielson E, Schutte M, Baylin SB, Herman JG (2000) Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst 92(Suppl 7):564–569CrossRefPubMedGoogle Scholar
- Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop DT, Weber B, Lenoir G, Chang-Claude J, Sobol H, Teare MD, Struewing J, Arason A, Scherneck S, Peto J, Rebbeck TR, Tonin P, Neuhausen S, Barkardottir R, Eyfjord J, Lynch H, Ponder BAJ, Gayther SA, Birch JM, Lindblom A, Stoppa-Lyonnet D, Bignon Y, Borg A, Hamann U et al (1998) Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet 62:676–689CrossRefPubMedGoogle Scholar
- Liedtke C, Cardone L, Tordai A, Yan K, Gomez HL, Figureoa LB, Hubbard RE, Valero V, Souchon EA, Symmans WF, Hortobagyi GN, Bardelli A, Pusztai L (2008) PIK3CA-activating mutations and chemotherapy sensitivity in stage II–III breast cancer. Breast Cancer Res 10(Suppl 2):27. doi: 10.1186/bcr1984 CrossRefGoogle Scholar
- Maillet P, Chappuis PO, Vaudan G, Dobbie Z, Muller H, Hutter P, Sappino AP (2000) A polymorphism in the ATM gene modulates the penetrance of hereditary non-polyposis colorectal cancer. Int J Cancer 88:928–931. doi: 10.1002/1097-0215(20001215)88:6<928:AID-IJC14>3.0.CO;2-P CrossRefPubMedGoogle Scholar
- Markoff A, Sormbroen H, Bogdanova N, Preisler-Adams S, Ganev V, Dworniczak B, Horst J (1998) Comparison of conformation-sensitive gel electrophoresis and single-strand conformation polymorphism analysis for detection of mutations in the BRCA1 gene using optimized conformation analysis protocols. Eur J Hum Genet 6:145–150CrossRefPubMedGoogle Scholar
- Olivier M, Langerod A, Carrieri P, Bergh J, Klaar S, Eyfjord J, Theillet C, Rodriguez C, Lidereau R, Bieche I, Varley J, Bignon Y, Uhrhammer N, Winqvist R, Jukkola-Vuorinen A, Niederacher D, Kato S, Ishioka C, Hainaut P, Borresen-Dale AL (2006) The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer. Clin Cancer Res 12:1157–1167. doi: 10.1158/1078-0432.CCR-05-1029 CrossRefPubMedGoogle Scholar
- Rudolph P, Olsson H, Bonatz G, Ratjen V, Bolte H, Baldetorp B, Fernö M, Parwaresch R, Alm P (1999) Correlation between p53, c-erbB-2, and topoisomerase II alpha expression, DNA ploidy, hormonal receptor status and proliferation in 356 node-negative breast carcinomas: prognostic implications. J Pathol 187:207–216. doi: 10.1002/(SICI)1096-9896(199901)187:2<207:AID-PATH223>3.0.CO;2-U CrossRefPubMedGoogle Scholar
- Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, Yu JS, Malmstrom PO, Mansukhani M, Enoksson J, Hibshoosh H, Borg A, Parsons R (2005) PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res 65:2554–2559CrossRefPubMedGoogle Scholar
- Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304:554. doi: 10.1126/science.1096502 CrossRefPubMedGoogle Scholar
- Sawaki M, Ito Y, Akiyama F, Tokudome N, Horii R, Mizunuma N, Takahashi S, Horikoshi N, Imai T, Nakao A, Kasumi F, Sakamoto G, Hatake K (2006) High prevalence of HER-2/neu and p53 overexpression in inflammatory breast cancer. Breast Cancer 13:172–178. doi: 10.2325/jbcs.13.172 CrossRefPubMedGoogle Scholar
- Yamashita H, Nishio M, Kobayashi S, Ando A, Sugiura H, Zhang Z, Hamaguchi M, Mita K, Fujii Y, Iwase H (2005) Phosphorylation of estrogen receptor a serine167 is predictive of response to endocrine therapy and increases post relapse survival in metastatic breast cancer. Breast Cancer Res 7:753–764. doi: 10.1186/bcr1536 CrossRefGoogle Scholar