Journal of Cancer Research and Clinical Oncology

, Volume 136, Issue 11, pp 1657–1669 | Cite as

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

  • Stefan S. Bozhanov
  • Svetla G. Angelova
  • Maria E. Krasteva
  • Tsanko L. Markov
  • Svetlana L. Christova
  • Ivan G. Gavrilov
  • Elena I. GeorgievaEmail author
Original Paper



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.


Breast cancer Tumor suppressor genes Proto-oncogenes Mutations Clinicopathological characteristics Overall survival 



Breast cancer


Immunohistochemical analysis


Chromogenic in situ Hybridization


Overall survival


Tumor size


Nodal status


Grade of malignancy


Estrogen receptor


Progesterone receptor


Hazard ratio


Confidence interval



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.


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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Stefan S. Bozhanov
    • 1
  • Svetla G. Angelova
    • 1
  • Maria E. Krasteva
    • 1
  • Tsanko L. Markov
    • 1
  • Svetlana L. Christova
    • 2
  • Ivan G. Gavrilov
    • 3
  • Elena I. Georgieva
    • 1
    Email author
  1. 1.Institute of Genetics “Akad. Doncho Kostoff”, Department of Molecular GeneticsBulgarian Academy of SciencesSofiaBulgaria
  2. 2.Department of General and Clinical PathologyMedical UniversitySofiaBulgaria
  3. 3.National Oncological Centre HospitalSofiaBulgaria

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