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

Bozhanov, Stefan; Angelova, Svetla; Krasteva, Maria; Markov, Tsanko; Christova, S.; Gavrilov, I.; Georgieva, Elena

doi:10.1007/s00432-010-0824-9

Cited by 32 publications

(25 citation statements)

References 55 publications

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“…Tumors with abnormal BRCA1 methylation tended to be smaller in size, predominantly at T1 (P = 0.066). BRCA1 methylation status was further correlated with several tumor molecular characteristics found previously (17), including mutations in breast cancer related genes such as p53, ATM and PIK3CA genes, and overexpression of HER2 protein (Table 1). Interestingly, we found that all hypermethylated tumors were p53 negative (P = 0.073).…”

Section: Brca1mentioning

confidence: 68%

“…Patients were followed for a five-year period. All patients were BRCA1 mutation negative as confirmed by previous PCR-SSCP analysis (17). Written consent was taken from all participants in the study.…”

Section: Methodsmentioning

confidence: 93%

“…Another favorable characteristic of the hypermethylated tumors was the observation that none of them had a p53 mutation. Mutated p53 was found to significantly correlate with a greater carcinogenic aggressiveness and worse OS of breast cancer patients (17,(36)(37)(38). Since p53 and BRCA1 are involved in a same cancer pathway, it could be speculated that the inactivation of the pathway does not require inactivation of both genes (inactivation of one gene may be sufficient).…”

Section: Discussionmentioning

confidence: 99%

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Breast cancer patients with hypermethylation in the promoter of BRCA1 gene exhibit favorable clinical status

Krasteva¹,

Bozhanov²,

G³

et al. 2012

neo

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Promoter hypermethylation was shown to be involved in human cancerogenesis through silencing gene expression. Several studies were dedicated to explore the frequency and clinical significance of BRCA1 hypermethylation in sporadic breast cancer to identify a specific molecular and clinico-pathological phenotype. However the available data are limited and rather too heterogeneous. In this study we investigated the level of methylation in the promoter region of BRCA1 and its correlation with clinico-pathological and molecular characteristics in a group of 135 Bulgarian patients. Methylation specific PCR was applied to determine methylation status of tumor samples. Clinical impact of BRCA1 hypermethylation was estimated using standard statistical methods including Fisher's exact and the Chi-squared tests, the Kaplan-Meier method, the univariate and multivariate Cox proportional hazards regression model. We found that hypermethylation was present in 17.04% of the cases (23/135). Patients with hypermethylation in BRCA1 displayed favorable clinical status as their tumors were smaller in size (P = 0.066), lacked p53 gene mutations (P = 0.073) and were of lobular type (P = 0.046). The presence of hypermethylation was weakly associated with better overall survival (P = 0.2) with a hazard ratio of 0.47 (95% CI 0.14-1.54, P = 0.213). Our study provides the first data on the BRCA1 hypermethylation of Bulgarian patients and contributes to elucidation of its clinical significance in sporadic breast cancer. Key words: Breast cancer, BRCA1, Hypermethylation, Clinicopathological characteristics, Overall survivalBreast cancer (BC) represents a major challenge to modern human oncology because of its high and constantly increasing frequency, and growing mortality and morbidity rate in women below the age of 45. Every year in Bulgaria, approximately 3600 women are diagnosed and about 1300 die of BC (1). The major risk factors are sex, age, family predisposition, as well as some reproductive and hormonal factors like early menarche and late menopause, late first childbirth, shorter breastfeeding period, use of oral contraceptives and hormone replacement therapy. Clinically BC is very heterogeneous, which is due to heterogeneity in disease mechanisms.BC results from accumulation of genetic and epigenetic changes in tumor suppressor genes and proto-oncogenes. Some of these genes -р53, PIK3CA, CHEK2, АТМ, HER2, are involved in the pathogenesis of different type of tumors. Others are specific only to breast/ovarian cancer -BRCA1 and BRCA2. A large number of studies demonstrate a correlation between the genetic/epigenetic status of BC related genes and clinicopathological characteristics of the patients. Such investigations could contribute to a more effective BC prevention and therapy, which will increase the survival rate and will significantly improve the quality of life of the patients. However, the results so far are contradictory and need further elucidation.BRCA1 (BReast CAncer susceptibility gene 1) tumor suppressor gene maps to 17...

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Section: Brca1mentioning

confidence: 68%

Section: Methodsmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Breast cancer patients with hypermethylation in the promoter of BRCA1 gene exhibit favorable clinical status

Krasteva¹,

Bozhanov²,

G³

et al. 2012

neo

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“…After screenings, 68 articles were chosen for further full-text review. Ultimately, 32 eligible studies were included in our meta-analysis59101112131415161718192021222324252627282930313233343536373839 (Figure 1). …”

Section: Resultsmentioning

confidence: 99%

Prognostic role of PIK3CA mutations and their association with hormone receptor expression in breast cancer: a meta-analysis

Pang

Cheng

Sun

et al. 2014

Sci Rep

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The phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) gene is frequently mutated in breast cancer (BCa). Sex hormone receptors (HRs), including estrogen receptor (ER) and progesterone receptor (PR) play pivotal roles in BCa. In this study, we evaluated the association between PIK3CA mutations and ER/PR expression and the prognostic role of PIK3CA mutations in BCa patients, and in particular, HR-positive BCa. Thirty-two studies involving 5719 cases of BCa obtained from database searches were examined. PIK3CA gene mutations correlated significantly with ER/PR expression (p < 0.00001) and relapse-free survival (RFS) (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.59–0.98, p = 0.03) but not overall survival (OS) (HR 1.14, 95%CI 0.72–1.82, p = 0.57) in unsorted BCa patients. PIK3CA mutations were not associated with OS (HR 1.06, 95%CI 0.67–1.67, p = 0.81) or RFS (HR 0.86, 95%CI 0.53–1.40, p = 0.55) in HR-positive BCa patients. In conclusion, PIK3CA mutations were significantly related to ER/PR expression and RFS in unsorted BCa patients. However, the clinical implications of PIK3CA mutations may vary according to different mutant exons. And PIK3CA mutations alone may have limited prognostic value for HR-positive BCa patients.

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“…[12][13][14][15][30][31][32][33][34][35][36][37][38][39][40][41][42][43] However, the mutation prevalence in breast columnar cell lesions, as well as the evolution of activating point mutations across different breast lesions in a single patient, has not been well studied to date. In a cohort of 24 columnar cell lesions, encompassing columnar cell change, columnar cell hyperplasia, and flat epithelial atypia, we found PIK3CA mutations in 13 samples.…”

Section: Discussionmentioning

confidence: 99%

Phosphatidylinositol-3-kinase pathway mutations are common in breast columnar cell lesions

et al. 2012

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The phosphatidylinositol-3-kinase pathway is one of the most commonly mutated pathways in invasive breast carcinoma, with PIK3CA mutations in B25% of invasive carcinomas, and AKT1 mutations in up to 5%. Ductal carcinoma in situ, and benign papillomas harbor similar mutations. However, activating point mutations in breast columnar cell lesions have been infrequently studied. Twenty-three breast resection specimens containing columnar cell lesions were identified; 14 with associated invasive carcinoma or carcinoma in situ. DNA extracts were prepared from formalin-fixed paraffin-embedded tissue and screened for a panel of point mutations (321 mutations in 30 genes) using a multiplex PCR panel with mass-spectroscopy readout. PIK3CA mutations were identified in 13/24 columnar cell lesions (54%) and 3/8 invasive carcinomas (37%). The mutation status of columnar cell lesions and associated carcinoma was frequently discordant. Of the 14 cases, only 5 demonstrated the same genotype in matched samples of columnar cell lesions and carcinoma (4 wild type, 1 PIK3CA H1047R). Interestingly, five patients had mutations in columnar cell lesions with wild-type carcinoma; two patients had different point mutations in columnar cell lesions and carcinoma. Only three cases had wildtype columnar cell lesion and mutated carcinoma. The 50% PIK3CA mutation prevalence in columnar cell lesions is greater than reported in most studies of invasive breast cancer. Further, columnar cell lesions and carcinoma were frequently discordant for PIK3CA/AKT1 mutation status. These findings raise interesting questions about the role of PIK3CA/AKT pathway in breast carcinogenesis, and the biologic/precursor potential of columnar cell lesions. The phosphatidylinositol-3-kinase pathway is activated in numerous cancer types and is one of the most commonly mutated pathways in invasive breast carcinoma. Activating mutations in the phosphatidylinositol-3-kinase catalytic subunit (PIK3CA) are present in B25% of invasive carcinomas, with mutations clustering in 'hotspots' in exon 9 (helical domain) and exon 20 (kinase domain). 1-10In addition, this pathway is activated by mutations in the plekstrin-homology domain of AKT1 in up to 5% of breast carcinomas, or by the loss of the phosphatase PTEN (phosphatase and tensin homolog) in nearly half of breast cancers.2,11 Several groups have demonstrated a similar frequency of mutations in breast carcinoma in situ, with paired invasive and in situ carcinoma from the same patient concordant for PIK3CA mutation status in 66-100% of tested cases.12-15 However, other breast proliferative or putative precursor lesions have been little studied. Li et al 13 found PIK3CA hotspot mutations in only 6% of 52 tested cases of Ductal Intraepithelial Neoplasia 1A-B lesions (DIN1A-B, atypical ductal hyperplasia and flat epithelial atypia, also known as columnar cell change with atypia). Our group previously identified PIK3CA/

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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: 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.

Cited by 32 publications

References 55 publications

Breast cancer patients with hypermethylation in the promoter of BRCA1 gene exhibit favorable clinical status

Breast cancer patients with hypermethylation in the promoter of BRCA1 gene exhibit favorable clinical status

Prognostic role of PIK3CA mutations and their association with hormone receptor expression in breast cancer: a meta-analysis

Phosphatidylinositol-3-kinase pathway mutations are common in breast columnar cell lesions

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