الفهرس 
Review of LiteratureOnly 14 pages are availabe for public view
Abstract
Breast cancer is a global public health issue characterized by its heterogeneity. In the clinical management, early detection of breast cancer is essential for the success of patients’ favourable evaluation and the efficacy of subsequent therapies. Many tumours escape these detection methods until they reach a relatively advanced stage. Therefore, it is important that new methods be developed to provide more sensitive approaches for the detection of early-developed breast cancers, especially in women under age of 50 years who usually develop aggressive cancers.
There is a growing body of evidence indicating that CpG islands involve both genetic and epigenetic changes that cause aberrant gene function. Epigenetic refers to changes in phenotype or gene expression that are caused by mechanisms other than changes in the DNA sequence. This study demonstrated the methylation status of the promoters of the two genes APC and RASSF1A among breast diseases’ patients using relative Q-MSP method, thus providing a promising new diagnostic tool using the blood serum for the early diagnosis of breast cancer patients. This approach has the benefit of avoiding the probable of metastasis that may follow getting a biopsy from the suspected breast.
The study groups were classified into:
group 1; consisted of 93 women insulted with breast cancer. They were divided into 41 patients with non-invasive duct carcinoma [NIDC] and 52 patients with invasive duct carcinoma [IDC]. Based on their clinical and radiological evaluations, all the patients had no evidence of other cancers; also none of them received any chemotherapy or radiotherapy prior to blood collection.
group 2; consisted of 55 female patients; they displayed benign breast tumours. The benign breast diseases were categorized as follows: breast cyst “n=23”, breast duct ectasia “n=19” and fibroadenoma “n=13”.
group 3; consisted of 30 normal healthy female volunteers recruited as controls. They have no reports of any specific breast diseases.
A significant difference was reported between malignant, benign and normal individuals.
The carcinoembryonic antigen (CEA) level was detected and reported significant difference among the three enrolled groups (Frequency “F” =37.097, p < 0.0001). There was no statistical difference between the CEA level and the different clinicopathological characteristics. The best cutoff point for CEA was 5 ng\ml. It was determined using the “receiver operating characteristic” (ROC) curve that discriminates between malignant and non-malignant individuals. The present study found that the percentage of CEA in the breast cancer patients were significantly higher (X2= 16.80, p < 0.0001) compared to the benign and control. There was no significant relation between the frequency rate of CEA and clinicopathological factors apart from that reported between CEA and lymph-node and ER.
Cancer Antigen 15-3 (CA15-3) was detected and showed significant difference among the three investigated groups (F=17.957, p < 0.0001) as CA15-3 was highly-detected in breast cancer patients followed by the benign, then the control individuals. There was no statistical difference between the CA15-3 level and the different clinicopathological characteristics. There was only a significant difference among the pathological types of the patients. The best cutoff point for CA15-3 was 15 ng/ml which was determined using ROC curve. The percentage of CA15-3 in the breast cancer patients was significantly higher (X2= 51.006, p < 0.0001) regarding the CA15-3 percentage compared to the benign and control individuals. There was no significant relation between the frequency of CA15-3 and the clinicopathological factors apart from the significance reported between CA15-3 and pathological types.
The levels of methylated RASSF1A were found to be high in the breast cancer patients (F= 137.945, p < 0.0001), followed by the benign-tumour patients, while the control individuals displayed the lowest levels. There were no statistical differences between the methylated RASSF1A level neither with age nor with the different clinicopathological characteristics. The best cutoff point for RASSF1A was 1.06 ng\ml which was determined using ROC curve. A significant level of the percentage of the methylated RASSF1A was evident when its cutoff value among the different investigated groups was considered, (X2= 103.0, p < 0.0001). There was no significant relation between the frequency rate of RASSF1A and the studied clinicopathological factors.
The levels of APC were reported to be high in malignant breast cancer patients, followed by the benign patients, while the control individuals showed the lowest levels (F= 108.2, p < 0.0001). In the malignant group, APC level was reported to be significant when correlated with the age of patient, ER, PgR and Her2/neu levels. On comparing the mean ranks, the present study showed that there was no significant relation between the frequency rate of APC and the studied clinicopathological factors apart from that reported between APC and age of the patient ER, PgR and Her2/neu levels. The best cutoff point for APC was 5.637 ng\ml which was determined using ROC curve. There is a significant relation between the percentage of APC and clinicopathological factors in the different groups of the study (X2= 141.1, p < 0.0001). Significant relations were reported between the frequency rate of APC and some clinicopathological factors, such as age of patients, Her2/neu and PgR levels.
The overall sensitivity and specificity of the investigated markers were found to have an absolute sensitivity when combined with both APC and RASSF1A (98.9%) followed by RASSF1A (96.8%), and APC (95.7%); while both the traditionally-used markers (CEA and CA15-3) reported the lowest sensitivities (73.1%) for the early detection of breast cancer. The sensitivity of RASSF1A (95.6%) and APC (94.1%) for detection of early-stage in the breast cancer patients were higher than that reported in CEA or CA15-3 (76.5%). Moreover, the highest sensitivity was reached when RASSF1A was combined with CEA and CA15-3. Similarly, the sensitivities of RASSF1A (95.9%) and APC (94.6%) for detection of low-grade breast cancer patients were higher than that reported for CEA or CA15-3 (74.3%). Moreover, the highest sensitivity was reached when RASSF1A is combined with CEA and CA15-3 (97.3%) and in case of combined APC and RASSF1A (98.6%).
Further multifaceted studies are required to define the impact of these molecular markers for early diagnosis and disease monitoring. Also, further follow-up of the different breast cancer subtypes is needed to understand the association of methylation of candidate genes in cancer development and personalized treatments