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تقييم تغيرات جين Topoisomerase II alpha بواسطة التهجين الموضعي الصبغي وعلاقته بمستقبل الاستروجين ER ومستقبل البروجستيرون PR ومعلم ki - وher2/neu67 في سرطان الثدي عند الانسان == Evaluation of Topoisomerase II alpha Gene Alterations by Chromogenic in situ Hybridization in Correlation with ER, PR, HER2/neu, and Ki?67 in Human Breast Cancer

Author name: رشا عبد الرؤوف نعمة الصافي
Supervisor name: منال عدنان حبيب | ساهرة عبود علي
General topic: Medicine
Specific topic: Tissue Diseases
Degree: Higher Diploma
University: University of Baghdad - Faculty Of Medicine
Language: English
University location: Baghdad
First pages:
Abstract: Breast cancer is a clinically and biologically heterogeneous disease,Characterized by dys - regulation of multiple cellular pathways anddifferent sensitivities and responses to treatment. There is high tendencythat all diagnosed breast cancers should be tested for her2/neu oncogeneamplification with an in situ hybridization tests for further evaluation ofan equivocal cases (2+) detected by immunostaining.Topoisomerase II alpha gene is located on chromosome 17 adjacent toher2/neu gene, and Topoisomerase II alpha gene is responsible for codingtopoisomerases enzymes that modulate the topology of DNA duringcellular proliferative process. Topoisomerase II alpha is a moleculartarget for some important anticancer drugs, including anthracyclines,which are the key chemotherapeutic agents in the treatment of breastcancer.Fluorescent In situ hybridization is widely used technique in clinicaldiagnoses to identify oncogene amplification and chromosomaltranslocation in the cellular genome. Recently it was stated thatchromogenic in situ hybridization is regarded as a good alternative forfluorescent in Situ hybridization. Dual color - chromogenic in situhybridization combines the advantages of both FISH and CISH andallows the assessment of ratio of gene copy number to the chromosomalcentromere along with proper histopathological examination and the easeof bright - field microscopy.VIThe aim of the study is to evaluate Topoisomerase II alpha geneamplification and deletion by dual color chromogenic in situ hybridization in females with invasive breast cancer and to correlate Topoisomerase II alpha gene status with her2/neu, estrogen receptor, progesterone receptor and ki - 67 index and to detect the elation of Topoisomerase II alpha gene with clinico - pathological parameters like age, histological types, stage, grade and lymph node involvement in females with breast cancer.This study was done from July 2014 to February 2015. Females diagnosed to have invasive breast carcinoma reaching Oncology hospital in Baghdad Medical City were enrolled in the study. All females have been experienced modified radical mastectomy with axillary clearance. Immunohistochemical study for Estrogen receptor; Progesterone receptor; Her2/neu and Ki67 were done for their tissue blocks. Patients with Her2/neu equivocal (score 2+) and strong positive her2/neu (score 3+) were selected forming seventy five cases. Dual color chromogenic in situ hybridization was done in central public health laboratory/Baghdad for all cases for evaluation of topoisomerase 2 alpha gene and for further evaluation of her/neu in equivocal cases. Just 53 cases were successfully hybridized and enrolled in the study by applying Her2/neu and Topoisomerase II alpha genes probes. There was no topoisomerase II alpha gene deletion. No significant statistical relationship between topoisomerase alpha gene amplification and age, histological types of breast cancer, stage and lymph nodes while the relation was significant with the grades of breast cancer in that the highest level of gene amplification was in grade III detected in 9 (64.3%) of cases.There was a significant negative relationship between topoisomerase II alpha gene and hormone receptors (estrogen receptor and progesterone receptor) as the highest gene amplification was detected in hormone negative cases. The relation of topoisomerase II alpha gene with ki - 67 was not significant. After Chromogenic in Situ Hybridization study 12 (44.4%) out of 27 equivocal cases show her2/neu gene amplification as 4 (14.8%) cases and 8(29.6%) for high and low her2/neu gene amplification respectively.Accordingly the amplified cases of her2/neu gene were gathered with the strongly positive her2/neu cases from immunohistochemistry to form 38 (71.7%) out of 53 cases which representing the first group of total positive her2/neu cases out of total 53 cases. The second negative her2/neu group of 15 / 53 cases representing cases which were resulted from Chromogenic In Situ Hybridization study.The relation between topoisomerase II alpha gene and her2/neu gene was statistically significant in that 50% of her2/neu amplified cases show topoisomerase II alpha gene amplification (co - amplification). Thirty nine percent 39% of total positive 38 cases show Topoisomerase 2 alpha gene co - amplification, from these 11/ 28.9% cases show high level of amplification. .So a significant positive correlation of topoisomerase 2 alpha gene with her2/neu and its negative correlation with estrogen and progesterone receptors may indicate that it could be considered as a bad prognostic factor.