STATUS METILASI GEN BRCA1 GEN BRCA2 EKSPRESI PROTEIN BRCA1 PROTEIN BRCA2 HUBUNGANNYA DENGAN TERJADINYA TUMOR EPITELIAL OVARIUM DERAJAD DIFERENSIASI JENIS HISTOPATOLOGI STADIUM DAN SURVIVAL PENDERITA KANKER EPITELIAL OVARIUM
| Main Authors: | , Heru Pradjatmo, dr.,Sp.OG(K).,M.Kes., , Prof. dr. H. Djaswadi Dasuki SpOG(K), |
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| Format: | Thesis NonPeerReviewed |
| Terbitan: |
[Yogyakarta] : Universitas Gadjah Mada
, 2013
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| Subjects: | |
| Online Access: |
https://repository.ugm.ac.id/118593/ http://etd.ugm.ac.id/index.php?mod=penelitian_detail&sub=PenelitianDetail&act=view&typ=html&buku_id=58568 |
Daftar Isi:
- Cancer initiation and progression are controlled by genetic and epigenetic events. Cancer develops through multistep process in which the genomes of cancer cells mutate in several groups of genes such as proto-oncogen, tumor suppresor genes and other genes which directly or indirectly control the cell proliferation. Cancer cells also retain genetic instability that allows the cells to change all the time. The epigenetic process which is widely known is DNA methylation. Methylation is adding four atoms in cytosine one of four DNA nucleotides. This additional atom blocks proteins which transcribe the genes. Several study reported that BRCA1 methylation was beetwen 10 % to 65 % and the study of the BRCA2 methylation in ovarian cancer was rare and it was said that methylation was very low up to 4 %. The study design was a prospective-cohort study. The study was conducted at Sardjito Hospital. Methylation status of BRCA1 and BRCA2 genes was examined using MS-PCR methode, and expression of BRCA1 and BRCA2 protein was examined using immunohistochemistry staining to the tumor tissue. The aim of study are: 1) Identifying the methylation status of BRCA1 and BRCA2 genes in patients with epithelial ovarian cancer. 2) Identifying the methylation status of BRCA1 and tumor suppresor genes in the epithelial ovarian cancer tissue cells is compared with the methylation status of BRCA1 and BRCA2 genes fragment of the DNA in the patient�s blood serum. 3) Identifying whether the proportion of BRCA1 and BRCA2 methylation status would affect the stage, the degree of differentiation and the histopathology type of epithelial ovarian cancer. 4) Identifying whether the BRCA1 and BRCA2 gene methylation and protein expression of BRCA1 and BRCA2 were associated with the survival of epithelial ovarian cancer patients. The study result gathering 99 cases which consisted of 30 cases of benign ovarian epithelial tumors and 69 cases of malignant epithelial ovarian tumors was analyzed in this study. The result showed that the methylation status of BRCA1 were 62/68 cases (89.9%) in the benign tumor were 26/30 cases (86,7%). The methylation status of BRCA2 68/69 cases (98,6 %), in the benign ovarian tumor methylation status of BRCA2 were 29/30 cases (96,7 %). Statisticaly no significance different p = 0,643 and p = 0,540 respectively. Seem that these result were very hight, then internal and external validation was done, the result is same. BRCA1 and BRCA2 of the serum that were isoloted was examined the methylation status. The proportion of methylation is not significantly different p =0,528 and 0,626 respectively. However, the Kappa statistic between methylation status in the tissue and serum of BRCA1 and BRCA2 were � 0,035 and � 0,062 respectively. Its mean that methylation status in serum cannot be used to predict methylation status of BRCA1 and BRCA2 in the tissue. It was probably due to the primer that was used to detect DNA fragment in serum was to long same as that was used in the tissue. Multinomial logistic regression analysis found that BRCA1 methylation status, BRCA1 protein expression and BRCA2 protein expression clinically significant influenced to histopathology type espescially endometrioid adenocarcinoma and clear cell adenocarcinoma OR= 3,90 (CI: 0,27 � 54,67), OR = 0,27 (CI: 0,03 � 2,18), OR = 6,95 (CI: 0,83 � 57,99) respectively. BRCA1 methylation status and BRCA2 protein expression clinically significant influenced to the grading of the tumor especially to moderate and poorly differentiated OR = 3,57 (CI: 0,50 � 25,37), OR = 2,16 (CI: 0,47 � 9,90). BRCA1 methylathion status, BRCA1 protein expression and BRCA2 protein expression clinically significant influenced to the stage of diseases especially to late stage OR = 2,59 (CI: 0,33 � 20,15), OR = 2,92 (CI: 0,47 � 18, 08), OR = 2,71(0,48 � 15,08). Factors that clinically influeced to patients survival were BRCA2 protein expression HR = 2,04 (CI: 0,61 � 0,677), stage of diseases HR 0,42 (CI: 0,11 � 1,62). Factors that statistically significant influenced patient survival were the age of menarche and CA 125 conccentration. Conclusions: (1) Methylation status of BRCA1 and BRCA2 genes in the epithelial ovarian cancer were 89,9 % and q 98,6 % respectively, (2) Methylation status of DNA fragmen in the serum patients was not able to use for predicting methylation status of BRCA1 and BRCA2 genes in the ovarian tumor tissue, (3) BRCA1 methylation status, BRCA1 protein expression and BRCA2 protein expression clinically significant influenced to histopathology. BRCA1 methylation status and BRCA2 protein expression clinically significant influenced to the grading of the tumor, (4) BRCA1, BRCA2 genes methylation and BRCA1 protein expression were not as the prognostic factors of the survival of epithelial ovarian cancer patients. However, BRCA2 protein expression clinically influenced to survival of the patients.