title: 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.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Genetics Akad. Doncho Kostoff, Department of Molecular Genetics, Bulgarian Academy of Sciences, Plovdivsko shosse 13 km., 1113 Sofia, Bulgaria.
authors.forename: Stefan S
authors.initials: SS
authors.lastname: Bozhanov
authors.forename: Svetla G
authors.initials: SG
authors.lastname: Angelova
authors.forename: Maria E
authors.initials: ME
authors.lastname: Krasteva
authors.forename: Tsanko L
authors.initials: TL
authors.lastname: Markov
authors.forename: Svetlana L
authors.initials: SL
authors.lastname: Christova
authors.forename: Ivan G
authors.initials: IG
authors.lastname: Gavrilov
authors.forename: Elena I
authors.initials: EI
authors.lastname: Georgieva
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002031:Bulgaria; D018797:Cell Cycle Proteins / Q000235:genetics*; D058534:Class I Phosphatidylinositol 3-Kinases; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D018734:Genes, erbB-2; D016158:Genes, p53; D006801:Humans; D007438:Introns / Q000235:genetics; D008207:Lymphatic Metastasis / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D016016:Proportional Hazards Models; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D011960:Receptors, Estrogen / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics; D017741:Survivors; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D058534:Class I Phosphatidylinositol 3-Kinases; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D025521:Tumor Suppressor Proteins; C484760:PIK3CA protein, human; C508053:ERBB2 protein, human; C576324:ATM protein, human