الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Breast cancer has become the leading cause of cancer death for females in Egypt. Genetic change in cell populations plays an important role in carcinogenesis leading to development of breast cancer and there is expanding body of literature suggesting that host factors, including genetic polymorphism may explain individual differences in cancer risk.
In this study, our aim was to investigate the association of CCND1 G870A and p73 G4C14-to-A4T14 (GC/AT) polymorphisms with breast cancer risk and survival.
80 newly diagnosed females representing Egyptian population confirmed breast cancer patients and 40 healthy controls, recruited from departments of Experimental and Clinical Surgery and Cancer Management and Research, Medical Research Institute, Alexandria University. The two important single nucleotides polymorphisms (SNPs) in CCND1 (G870A) and p73 (G4C14-to-A4T14) genes were determined in these samples by PCR-RFLP, using the corresponding restriction enzyme, and PCR-CTPP techniques respectively.
The present study revealed that CCND1 AA, AG and combined variant genotypes AA/AG frequencies were more frequently observed in breast cancer patients whereas CCND1 GG genotype frequency was significantly higher in control group. Furthermore we found a significant difference in the genotypes distribution between patients and control group suggesting that CCND1 G870A polymorphism is associated with susceptibility to breast cancer.
It is well established that CCND1 is an essential regulator of cell cycle progression; therefore any genetic variation that disturb the normal function of this gene product is ultimately a target for association with cancer risk and survival. The present study revealed that individuals carrying CCND1 AA, AG and combined variant (AA/AG genotypes) had a 2.9, 3.3 and 3.1 fold increased risk for the development of breast cancer compared with those carrying GG genotype, respectively.
In addition we noticed that, breast cancer females less than 45 years of age carrying (AA / AG genotypes) were at decreased risk for breast cancer than those with GG genotype .This lead us to hypothesize that variant 870A allele may play a role in increasing estrogen metabolism and inhibiting cell proliferation. On the other hand postmenopausal females with AA and combined variant AA/AG genotypes were at increased risk for breast cancer when compared with those carrying GG genotype; these results lead us to suggest that A allele might play more important role in the development of breast cancer among postmenopausal females.
Furthermore, we evaluated the association between CCND1 G870A polymorphism with clinicopathological parameters of breast cancer patients. We found insignificant association between these parameters in patients carrying A allele (AA/AG genotypes) when compared with those carrying GG genotype.
With respect to prognostic study, we found that breast cancer patients carrying A allele (AA/AG) genotypes had a longer DFS than did patients with GG genotype. The favorable disease free survival (DFS) for breast cancer patients carrying the A allele of CCND1 G870A despite its positive association with risk of breast cancer may be attributed to the induction of cyclin D1 degradation by chemotherapy causing cell death and apoptosis.
Also, we noticed that the two genotypes P73 (GC/AT) and (AT/AT) as well as the combined variants (GC/AT)/ (AT/AT) were more frequently observed in breast cancer patients, whereas P73 GC/GC frequency was significantly higher in controls. However, insignificance difference in the genotypes distribution between patients and controls was observed.
Moreover, breast cancer females carrying the variant (GC/AT) / (AT/AT) were associated with increased risk of breast cancer than those with GC/GC genotype. Although how this P73 polymorphism influences development of breast cancer is unknown, one possible explanation is that GC to AT change may lead to formation of a stem loop structure and so may influence the translation efficiency of P73. Another possibility is that the P73 polymorphism is in linkage disequilibrium with other functional polymorphisms that affect either the expression or activity levels of enzymes involved in tumorigenesis.
Also we evaluated the association of P73 genotypes with pathological parameters of breast cancer patients. Compared with GC/GC genotype, the combined variant p73 (GC/AT) / (AT/AT) genotypes were found to be associated with increased risk for breast cancer among women with pathological grade III, clinical stage III, tumor size ≥ 5 cm, axillary lymph node involvement and the +ve Her2/neu expression . These results suggest that AT variant allele has an important role in breast cancer progression, and may provide the clinician with additional information regarding patients carrying AT variant with risk of recurrence.
With respect to prognostic study, we found that patients with combined variants (AT/AT) / (GC/AT) had more favorable survival than those with GC/GC genotype.
In this study we noticed that, mean values of CA15.3 in breast cancer patients were significantly higher than normal healthy women, and insignificantly correlated with clinicopathological parameters of breast cancer patients. The high level of CA15.3 observed in this study may be attributed to the presence of malignant disease.
Our study observed that, CA15.3 failed to predict survival or relapse in breast cancer patients. Therefore, we can suggest that serum CA15.3 levels cannot be used for monitoring the response to chemotherapy and surveillance. Moreover, ROC curve showed that this parameter was not a suitable diagnostic marker since it lacks sensitivity for detecting metastasis.
CONCULSIONS
In conclusion, this study provides the first indication that CCND1 870A allele (AA/AG genotypes) and p73 A4T14 variants (AT/AT)/ (GC/AT) are risk factors for breast cancer susceptibility in Egyptian women. Thus analysis of CCND1 G870A and p73 G4C14- to- A4T14 polymorphism may be useful for identifying females with higher risk to develop cancer.
As compared with CCND1 870A allele and p73 A4T14 variant genotypes, CCND1 GG and P73 GC/GC genotypes were significantly associated with shorter disease free survival in breast cancer patients. Therefore analysis of these genes may also be useful in identifying the breast cancer patients that have a high risk of relapse and most likely to be benefit from the adjuvant chemotherapy.
CA15.3 failed to predict survival or relapse in breast cancer patients. Therefore, we can suggest that serum CA15.3 levels cannot be used for monitoring the response to chemotherapy and surveillance. Moreover, ROC curve showed that this parameter was not a suitable diagnostic marker since it lacks sensitivity for detecting metastasis.
Nevertheless, the fact that the number of subjects involved in the present study was relatively small, invites future research efforts to validate the association of CCND1 G870A and p73 G4C14-to-A4T14 polymorphic variants with human malignancies in Egyptian population.