Genetic and epigenetic profiling of the BRCA1 / 2 genes in solitary ovarian cancer and multiple primary ovarian tumors

2021 ◽  
Vol 11 (2) ◽  
pp. 11-18
Author(s):  
M. E. Esenova ◽  
Yu. G. Payanidi ◽  
S. V. Vinokurova ◽  
A. S. Shevchuk ◽  
M. N. Tikhonovskaya ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Venous Blood ◽  
Gene Mutations ◽  
Gene Promoter ◽  
Brca1 Gene ◽  
Ovarian Tumors ◽  
Serous Ovarian Cancer ◽  
Promoter Regions ◽  
Brca1 And Brca2 ◽  
Multiple Primary

Background. Ovarian cancer is a complex and poorly studied disease that kills nearly 70–80 % of patients. Therefore, practitioners are interested in any opportunity of improving survival of these patients. From this point of view, investigation of genetic and epigenetic functions associated with this pathology is quite promising.Objective: to assess clinical and morphological characteristics of tumors in ovarian cancer patients, considering the presence of mutations and methylation in the BRCA1/2 gene.Materials and methods. This study included 180 ovarian cancer patients (FIGO stage I–IV) treated in the N. N. Blokhin Russian Cancer Research Center between 2008 and 2019. Study participants were divided into 3 groups according to their BRCA status and the number of primary tumors. We collected and analyzed venous blood, biopsy samples of ovarian cancer, archived histological sections, and paraffin-embedded tissue blocks. DNA isolated from venous blood was used to identify the following germline mutation by pyrosequencing: BRCA1 5382insC, BRCA1 4153delA, BRCA1 185delAG, and BRCA26174delT. DNA isolated from biopsy specimens and paraffin-embedded tissue specimens was used to analyze methylation in the promoter regions of the BRCA1 and BRCA2 genes by bisulfite sequencing (PyroMark Q24 DNA Sequencer; Qiagen, USA) with specific primers targeting promoter regions of the BRCA1 and BRCA2 genes.Results. Molecular testing demonstrated that the frequency of BRCA1 gene mutations was 21.1 % (38/148) in patients with solitary ovarian cancer and 40.6 % (13/32) in patients with multiple primary ovarian cancers. The frequency of methylation of the BRCA1 gene promoter was 2.2 % (18/148) in patients with solitary ovarian cancer and 3.1 % (1 case) in patients with multiple primary ovarian cancers. All BRCA1 methylated ovarian tumors were serous adenocarcinomas, including high grade tumors in 15 patients (78.9 %) and low-grade tumors in 4 patients (21.1 %).Conclusion. Hypermethylation of the BRCA1 gene promoter was observed only in individuals with sporadic serous ovarian cancer. No methylation was detected in patients with non-serous ovarian cancer, as well as in patients carrying BRCA1 gene mutations (both with solitary ovarian cancer and with primary multiple ovarian tumors).

scholarly journals A MOLECULAR-BASED APPROACH TO INVESTIGATE BREAST CANCER 1 AND BREAST CANCER 2 STATUS IN OVARIAN CANCER AMONG IRAQI WOMEN

2018 ◽  
Vol 11 (7) ◽  
pp. 199
Author(s):  
Muhannad Shweash ◽  
Saddam Jumaa Naseer ◽  
Maisam Khider Al-anii ◽  
Thulfiqar Fawwaz Mutar
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Cancer Patients ◽  
Gene Mutations ◽  
Healthy Controls ◽  
Brca1 And Brca2 ◽  
First Degree Relatives ◽  
Brca Gene ◽  
Brca2 Mutations ◽  
Brca1 And Brca2 Mutations

Objective: Cancer ovary is one of the fatal gynecologic malignancies worldwide. Since breast cancer (BRCA) genes are considered tumor suppressor genes and play important roles in cancer by repairing of chromosomal damage with the error repair of DNA breaks. Therefore, breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) gene mutations strongly enhance the development of ovarian cancer risk among women. Here, we report that both genes are an essential mediator of progress ovarian cancer, to determine the influence of BRCA1 and BRCA2 mutations in the improvement of ovarian cancer.Methods: A total of 25 subjects were chosen for the genetic studies, and three groups were recruited: fifteen ovarian cancer patients group, five healthy controls, and five first-degree relatives to a known case of ovarian cancer patients.Results: A genetic analysis revealed that a strong correlation exists between both gene mutations’ status in ovarian cancer, and BRCA gene mutations (185delAG, 5382insC, and 4153delA in BRCA1 and 6174delT in BRCA2) remained to establish to have a relatively high frequency among people in this study among ovarian cancer patients. Furthermore, seven patients with ovarian cancer carried all of the four investigated mutations, and five had three mutations.Conclusion: Otherwise, BRCA gene frequency showed low prevalence among first-degree relatives, and to a lesser extent among healthy controls, with only a few had all of the mutations combined. These data demonstrate for the first time a molecular link between BRCA1 and BRCA2 mutations in ovarian cancer progression in Iraq.

Whence High-Grade Serous Ovarian Cancer

2017 ◽  
pp. 443-448 ◽  
Author(s):  
Elise C. Kohn ◽  
S. Percy Ivy
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Rational Design ◽  
Driver Mutations ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Loss Of Function ◽  
Brca1 And Brca2 ◽  
Unique Type ◽  
Cellular Environment

Our understanding of epithelial ovarian cancer has blossomed, and we now recognize that it is a collection of varied histologic and molecularly different malignancies, many of which may not derive from a true ovarian anatomic precursor. High-grade serous ovarian cancer (HGSOC) is a unique type of epithelial cancer. It is characterized by nearly universal mutation in and dysfunction of p53, genomic instability rather than driver mutations, advanced stage at onset, and probable fallopian tube epithelium origin, with a serous tubal in situ carcinoma precursor. Germline deleterious mutations in BRCA1 and BRCA2, as well as other less prevalent genes involved in DNA repair, such as PALB2 and RAD51c, are associated with its carcinogenesis and may predict susceptibility to classes of treatment agents, including DNA-damaging agents and DNA repair inhibitors. Loss of function of these genes is associated with homologous recombination dysfunction (HRD). It is now recognized that there may be HGSOC with wild-type BRCA1 and BRCA2 with an identifiable HRD phenotype. Such HRD tumors also may be more susceptible to certain classes of treatments and may be phenotypically detectable with a composite molecular biomarker that has been shown to be predictive for response to PARP inhibitors. Use of this new knowledge of the anatomic and molecular background of HGSOC has led to the rational design of novel combinations of treatment classes to create an HRD-like cellular environment and thus drive treatment benefits.

Effect on response to neoadjuvant chemotherapy in high-grade serous ovarian cancer by inhibiting the GAS6/AXL pathway and inducing homologous recombination deficiency.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6080-6080
Author(s):  
Mary M Mullen ◽  
Elena Lomonosova ◽  
Michael Driscoll Toboni ◽  
Hollie M Noia ◽  
Danny Wilke ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Neoadjuvant Chemotherapy ◽  
Mouse Models ◽  
Poor Response ◽  
Tumor Burden ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Brca1 And Brca2 ◽  
Response To Neoadjuvant Chemotherapy

6080 Background: Less than 10% of patients with high grade serous ovarian cancer (HGSC) have a complete pathologic response to neoadjuvant chemotherapy. We aimed to identify a biomarker predictive of response to neoadjuvant chemotherapy and to determine if GAS6/AXL inhibition with AVB500 (AVB) could increase platinum response. Methods: AVB was supplied by Aravive Biologics. HGSC tumor samples were obtained pre- and post-neoadjuvant chemotherapy. GAS6 expression was measured by tissue immunohistochemistry (IHC) and serum ELISA. Four HGSC cell lines were used for all experiments. Immunofluorescent (IF) assays targeting ɣH2AX for DNA damage, RAD51, BRCA1, and BRCA2 for homologous recombination (HR) and 53BP1 for non-homologous end joining (NHEJ) were performed. Flow cytometry was used to evaluate RPA binding. DNA fiber assays were performed. In vitro clonogenic assays were done on chemoresistant ovarian tumor cells treated with carboplatin (carbo) +/- AVB and olaparib +/- AVB. Synergy assays were analyzed using Combenefit software. Mouse models were used to evaluate the combination of carboplatin + AVB and olaparib + AVB on tumor burden. Results: Patients with high pretreatment tumor GAS6 IHC expression ( > 85%) or serum GAS6 concentrations ( > 25ng/mL) were more likely to have a poor response to neoadjuvant chemotherapy than those with low GAS6 (P = 0.002). Additionally, high GAS6 concentration was associated with decreased overall survival (24.4 months versus undefined, P = 0.009). Carbo + AVB resulted in decreased clonogenic colonies compared to carbo alone (p < 0.05). In vivo tumor mouse models treated with chemotherapy + AVB had significantly less tumor burden than those treated with chemotherapy alone (50mg vs 357mg, P = 0.003). We identified an induction in HR deficiency by a decrease in RAD51, BRCA1, and BRCA2 foci and RPA binding in cells treated with carbo + AVB compared to carbo (P < 0.05). There was increase in ɣH2AX and 53BP1 foci as well as replication fork slowing in tumor cells treated with carboplatin + AVB (P < 0.01). We also AVB and carboplatin were synergistic. Olaparib + AVB resulted in decreased clonogenic colonies (P < 0.05) and decreased tumor burden in mouse models (76mg vs 171mg, P = 0.03) compared to olaparib alone. Conclusions: GAS6 is a potential biomarker predictive of poor response to neoadjuvant chemotherapy in HGSC. Inhibition of this GAS6/AXL pathway with AVB improves sensitivity to traditional neoadjuvant chemotherapy by inducing a homologous recombination deficiency.

scholarly journals Analysis of BRCA1 and BRCA2 genes mutations in breast cancer patients in an experiment

2020 ◽  
Vol 101 (3) ◽  
pp. 342-346
Author(s):  
L M Saрtarova ◽  
E N Cogina ◽  
L M Khasanshina ◽  
Sh N Galimov
Keyword(s):  
Breast Cancer ◽  
Cancer Risk ◽  
Brca2 Mutation ◽  
Venous Blood ◽  
Brca1 Gene ◽  
Control Group ◽  
Breast Cancer Patients ◽  
Brca1 And Brca2 ◽  
Screening Programs ◽  
Brca1 And Brca2 Genes

Aim. To assess the presence of mutations based on the analysis of the prevalence of polymorphisms in the BRCA1 and BRCA2 genes in patients admitted to the Republican clinical Oncology dispensary of the Ministry of Health of the Republic of Bashkortostan with breast cancer. Methods. 137 patients with breast cancer aged 25 to 80 years underwent molecular genetic testing to detect BRCA1 and BRCA2 mutations by using allele-specific real-time polymerase chain reaction. Venous blood from 105 healthy donors was used as a control group. Results. The study of genetic modifiers of cancer risk for BRCA1 and BRCA2 mutation carriers revealed mutations in the genes BRCA1 185delAG, 4153delA, 5382insC, T300G and BRCA2-6174 del T, which help identify genetic susceptibility to breast cancer (NSCLC). The most common form of genetic variation in patients with breast cancer was 5382insC mutation in BRCA1 gene, which was 14.59% of the total number of examined patients and 90% of the total number of positive results. BRCA1 and BRCA2 genes mutations lead to producing truncated protein, which cannot properly perform its functions and ensure DNA cell stability. Conclusion. Considering high breast cancer risk in BRCA1 and BRCA2 genes mutations carriers, our results show the advisability of including screening for 5382insC, 4153delA and T300G mutations in the BRCA1 gene to the screening programs for determining the risk of breast cancer.

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