scholarly journals Identifying and testing for hereditary susceptibility to breast/ovarian cancer in Serbia: Where are we now?

2006 ◽  
Vol 14 (3-4) ◽  
pp. 131-135
Author(s):  
Mirjana Brankovic-Magic ◽  
Jelena Dobricic ◽  
Radmila Jankovic ◽  
Irene Konstantopoulou ◽  
Drakoulis Yannoukakos ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Brca Mutation ◽  
Brca1 Gene ◽  
Ovarian Cancer Risk ◽  
Breast Cancers ◽  
Brca Testing ◽  
Coding Region ◽  
Brca1 And Brca2 ◽  
Brca Mutations ◽  
Polymorphic Variants

About 90% of all breast cancers can be considered as sporadic, without inherited gene alteration. The rest of breast cancers (about 5 to 10%) are considered hereditary, most commonly caused by alterations of BRCA1/2 tumor suppressor genes. Lifetime risks for breast and ovarian cancers are increased among BRCA1/2 mutation carriers - 4 to 8 and 10 to 20 fold higher respectively. Due to the small proportion of hereditary form of disease, as well as to the high cost, BRCA testing is not screening test for general population. It is addressed to selected part of population that fit to recommended criteria. Full coding region sequencing of both genes is "gold standard" for detection of BRCA mutation. Concerning BRCA testing in Serbia, complete or partial sequencing of BRCA1/2 coding region was performed in 60 samples. The presence of 4 BRCA1 known mutations, previously detected elsewhere, has been shown: 185delAG, C61G, 3447del4 and 5382insC (detected twice). In BRCA1 gene, exon 16, an unclassified variant M1652I was found. Polymorphic variants in BRCA1 (8 polymorphisms) and BRCA2 (5 polymorphisms) genes were also detected. The majority of found BRCA1 and BRCA2 polymorphic variants are the missense ones and their influence on breast/ovarian cancer risk in our population has to be proved. Identification of BRCA mutations carriers and establishment of spectra and frequency of BRCA mutations should enable introduction of BRCA1/2 testing into the clinical practice of Serbia. .

scholarly journals Factors influencing women’s decisions to getting tested for BRCA mutation

2018 ◽  
Vol 9 (3) ◽  
pp. 33 ◽  
Author(s):  
Suha Al-Oballi Kridli ◽  
Holly Austin
Keyword(s):  
Ovarian Cancer ◽  
Brca Mutation ◽  
Genetic Mutations ◽  
Inclusion Criteria ◽  
Breast And Ovarian Cancer ◽  
Brca1 And Brca2 ◽  
Brca Mutations ◽  
Factors Influencing ◽  
Brca1 And Brca2 Mutations ◽  
Internal And External Factors

Ovarian cancer is the leading cause of death among gynecological cancers. There are many risk factors that can increase a woman’s susceptibility to breast and ovarian cancers, some of which are modifiable.  However, non-modifiable risks for breast and ovarian cancer include the presence of genetic mutations (BRCA) increase the risk of these diseases. The purpose of this review was to identify factors, reported in the literature, known to affect women’s decision to get genetic testing for BRCA1 and BRCA2 mutations for hereditary breast and ovarian cancer. A total of 31 studies that met the inclusion criteria were included in this review. Several internal and external factors, influencing women’s decision to getting tested for BRCA mutations, were identified and explained. Implications for clinical practice were provided.

scholarly journals Tailoring Ovarian Cancer Treatment: Implications of BRCA1/2 Mutations

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 416 ◽  
Author(s):  
Ainhoa Madariaga ◽  
Stephanie Lheureux ◽  
Amit Oza
Keyword(s):  
Ovarian Cancer ◽  
Brca Mutation ◽  
Repair Process ◽  
Resistance Mechanisms ◽  
Tumour Suppressor Genes ◽  
Brca1 And Brca2 ◽  
Brca Mutations ◽  
Damage Repair ◽  
Brca Mutation Carriers ◽  
Drug Efflux Pumps

High grade serous ovarian cancer (HGSOC) is the most common epithelial ovarian cancer, harbouring more than 20% germline or somatic mutations in the tumour suppressor genes BRCA1 and BRCA2. These genes are involved in both DNA damage repair process via homologous recombination (HR) and transcriptional regulation. BRCA mutation confers distinct characteristics, including an increased response to DNA-damaging agents, such us platinum chemotherapy and poly-ADP ribose polymerase inhibitors (PARPi). However, several mechanisms of resistance to these agents have been described, including increased HR capacity through reverse BRCA mutations, non-homologous end-joint (NHEJ) repair alterations and drug efflux pumps. Current treatments of ovarian cancer including surgery, chemotherapy, targeted treatment and maintenance strategies, as well as resistance mechanisms will be reviewed, focusing on future trends with respect to BRCA mutation carriers.

The Effects of Parity, Breastfeeding, and Infertility Treatment on the Risk of Hereditary Breast and Ovarian Cancer: A Review

2010 ◽  
Vol 20 (Suppl 2) ◽  
pp. S31-S33 ◽  
Author(s):  
Ami Fishman
Keyword(s):  
Ovarian Cancer ◽  
Brca Mutation ◽  
Brca2 Mutation ◽  
Infertility Treatment ◽  
Accurate Information ◽  
Ovarian Cancer Risk ◽  
Breast And Ovarian Cancer ◽  
Brca1 And Brca2 ◽  
Mutation Carriers ◽  
Risk Of Cancer

Knowledge of the potential association of parity, breastfeeding, and infertility treatment on breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers is important and should be a crucial part of genetic counseling. The discussion of parity and clinical management of infertility in these women is complex, and patient preferences should be considered. Ideally, these preferences should be informed by accurate information on the risks and benefits of the interventions considered. However, this important subject has been investigated in a relatively small number of studies, thus, the existing data remain somewhat limited, and the estimated risk of cancer in BRCA mutation carriers is imprecise.

scholarly journals PARP Trapping Beyond Homologous Recombination and Platinum Sensitivity in Cancers

2019 ◽  
Vol 3 (1) ◽  
pp. 131-150 ◽  
Author(s):  
Junko Murai ◽  
Yves Pommier
Keyword(s):  
Homologous Recombination ◽  
Synthetic Lethality ◽  
Brca Mutation ◽  
Dna Lesions ◽  
Breast Cancers ◽  
Brca1 And Brca2 ◽  
Brca Mutations ◽  
Topoisomerase 1 ◽  
Platinum Based Chemotherapy ◽  
Determining Factors

Poly(ADP-ribose) polymerase inhibitors (PARPis) have recently been approved for the treatment of ovarian and breast cancers with BRCA mutations, as well as for maintenance therapies regardless of BRCA mutation for ovarian and primary peritoneal cancers that previously responded to platinum-based chemotherapy. The rationale of these indications is derived from the facts that cancer cells with BRCA mutations are defective in homologous recombination (HR), which confers synthetic lethality with PARPis, and that some of the sensitivity-determining factors for PARPis are shared with platinums. Although BRCA1 and BRCA2 are central for HR, more players within and beyond HR are emerging as response determinants to PARPis. Furthermore, there are similarities as well as differences in the DNA lesions and repair pathways induced by PARPis, platinums, and camptothecin topoisomerase 1 (TOP1) inhibitors. Here we review the sensitivity-determining factors for PARPis and the rationale for using PARPis as single agents and in combination therapy for cancers.

The importance of variants of unknown significance (VUS) in BRCA mutation.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e22507-e22507
Author(s):  
N Mullai
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Brca Mutation ◽  
Brca1 And Brca2 ◽  
Management Options ◽  
Brca Mutations ◽  
Variants Of Unknown Significance ◽  
Family Histories ◽  
Unknown Significance ◽  
Brca2 Mutations

e22507 Background: Genetic testing of patients for BRCA mutation may report variants of unknown significance (VUS). The use of multi-gene panels in clinical care has been increasing. Consequently, the reporting of variants of unknown significance has also increased. More than two decades of research and testing have elevated the status of BRCA1 and BRCA2 genes as the most well characterized genes. However, VUS are found even in BRCA1/2 testing. This raises many ethical and policy issues including communicating the significance of the results and possible clinical management options to patients. The practicing physicians would face the ethical and potential legal burden of contacting and explaining to patients, when any role of VUS changes and gets reclassified as potentially harmful. Methods: Data were collected retrospectively from medical records of patients tested for BRCA mutations. The results of fifty-two patients were analyzed. Eight patients had BRCA1 and BRCA2 mutations and twelve patients had variants of unknown significance. Results: When the results of thirteen patients with BRCA mutations with VUS were analyzed further, the variants included POLE, CHEK2, PALB2, MUTHYH, BR1P1, MSH3, ATM, RAD51C, GALNT12, etc. The age of these patients ranged from 39 years to 69 years. Four patients had ovarian cancer and eight patients had breast cancer, and one patient had both breast and ovarian cancers. The number of patients with stage IV, III, II, and I diseases were six, one, two, and two respectively. One patient had bilateral breast cancer and one patient had carcinoma in-situ. Eight patients had family histories of various cancers, including cancers of the breast, uterine, and prostate cancer. All patients were treated appropriately and three patients died due to their disease. Conclusions: Based on patients’ age, family histories, and disease characteristics BRCA mutation analyses were done. All patients tested positive for BRCA mutations and VUS were informed about their results. Variants of BRCA1 and BRCA2 occur in 2%-4% of tests depending on the laboratories, where the tests were performed. There is no concordance as to how VUS results were reported. There is conflicting evidence regarding the pathogenicity of VUS. These make clinical recommendations very complex. Based on existing guidelines, physicians can explain the details of the significance of BRCA! And BRCA2 mutations to patients with clarity. However, it is difficult and unclear to give recommendations regarding prophylactic measures, specific treatment options for BRCA mutation positive breast and ovarian cancer, follow-ups, and family testing in patients with VUS. Therefore, during BRCA testing, when VUS are reported routinely along with mutations of known significance, the treating physicians would need a better guidance to advise their patients without unduly increasing their anxiety, fear, and potential for misunderstanding.

Preventing Future Cancers by Testing Women With Ovarian Cancer for BRCA Mutations

2010 ◽  
Vol 28 (4) ◽  
pp. 675-682 ◽  
Author(s):  
Janice S. Kwon ◽  
Molly S. Daniels ◽  
Charlotte C. Sun ◽  
Karen H. Lu
Keyword(s):  
Ovarian Cancer ◽  
Cost Effectiveness ◽  
Family History ◽  
Brca Mutation ◽  
Health Benefit ◽  
Ashkenazi Jewish ◽  
Brca Testing ◽  
Brca Mutations ◽  
Jewish Ancestry ◽  
History Of

Purpose Women with ovarian cancer have a 10% probability of carrying a BRCA mutation. If a mutation is identified, unaffected family members can undergo genetic testing and cancer risk-reducing strategies. We estimated the net health benefits and cost-effectiveness of different criteria for BRCA mutation testing in women with ovarian cancer, and the downstream benefits for their first-degree relatives (FDRs). Methods We developed a Markov Monte Carlo simulation model to compare four criteria for BRCA testing in women with ovarian cancer: no testing (reference); only if personal history of breast cancer, family history of breast/ovarian cancer, or Ashkenazi Jewish ancestry; only if invasive serous cancer; any invasive nonmucinous epithelial cancer. Net health benefit was life expectancy for FDRs and primary outcome was the incremental cost-effectiveness ratio (ICER). The model estimated the number of future breast and ovarian cancer cases in FDRs. Results BRCA testing based on personal/family history and ancestry could prevent future cases in FDRs with an ICER of $32,018 per year of life (LY) gained compared with the reference strategy. BRCA testing based on serous or any nonmucinous epithelial ovarian cancer could prevent more cancer cases, but at ICERs of $128,465 and $148,363 per LY gained, respectively. Conclusion BRCA testing of women with ovarian cancer based on personal/family history of cancer or Ashkenazi Jewish ancestry is a cost-effective strategy to prevent future breast and ovarian cancers among FDRs. More inclusive testing strategies prevent additional cancer cases but at significant cost.

Primary Fallopian Tube Malignancies in BRCA-Positive Women Undergoing Surgery for Ovarian Cancer Risk Reduction

2007 ◽  
Vol 25 (25) ◽  
pp. 3985-3990 ◽  
Author(s):  
Michael J. Callahan ◽  
Christopher P. Crum ◽  
Fabiola Medeiros ◽  
David W. Kindelberger ◽  
Julia A. Elvin ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Risk ◽  
Risk Reduction ◽  
Fallopian Tube ◽  
Brca Mutation ◽  
Gynecologic Oncology ◽  
Prophylactic Surgery ◽  
Ovarian Cancer Risk ◽  
Brca Mutations ◽  
Cancer Risk Reduction

Purpose To review the frequency and location of malignancies detected after prophylactic salpingo-oophorectomy in women with BRCA mutations. Methods Medical records and pathology findings were reviewed from BRCA-positive women undergoing prophylactic surgery for ovarian cancer risk reduction who underwent complete examination of the adnexa. Patients undergoing this procedure between January 1999 and January 2007 were identified. Results From January 1999 to January 2007, 122 BRCA-positive patients underwent prophylactic surgery in the Division of Gynecologic Oncology at Brigham and Women's Hospital. The median age was 46.5 years (range, 33 to 76 years). Seven (5.7%) were found to have an early malignancy in the upper genital tract and all patients were age ≥ 44 years at diagnosis. Of seven consecutive cancers culled between January 1999 and January 2007, all (100%) originated in the fimbrial or ampullary region of the tube; six had an early (intraepithelial) component. Two were associated with surface implants on the ovary and two required repeated sectioning to detect microscopic carcinomas in the fimbria. Conclusion The distal fallopian tube seems to be the dominant site of origin for early malignancies detected in approximately 6% of women undergoing ovarian cancer risk-reduction surgery. The greatest proportion of serous cancer risk in BRCA mutation–positive women should be assigned to the fimbria rather than the ovary, and future clinical and research protocols should employ thorough examination of the fimbria, including multiple sections from each tissue block, to maximize detection of early malignancies in this population.

Expanding the Criteria forBRCAMutation Testing in Breast Cancer Survivors

2010 ◽  
Vol 28 (27) ◽  
pp. 4214-4220 ◽  
Author(s):  
Janice S. Kwon ◽  
Angelica M. Gutierrez-Barrera ◽  
Diana Young ◽  
Charlotte C. Sun ◽  
Molly S. Daniels ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Life Expectancy ◽  
Brca Mutation ◽  
Cost Effective ◽  
Mutation Testing ◽  
Breast Cancers ◽  
Brca Testing ◽  
Breast And Ovarian Cancer ◽  
Quality Adjusted Life

PurposeEvery year approximately 25% of women diagnosed with breast cancer are younger than 50 years of age, and almost 10% of them have a BRCA mutation. Not all potential carriers are identified by existing criteria for BRCA testing. We estimated the costs and benefits of different BRCA testing criteria for women with breast cancer younger than 50 years.MethodsWe developed a Markov Monte Carlo simulation to compare six criteria for BRCA mutation testing: (1) no testing (reference); (2) medullary breast cancer in patients younger than 50 years; (3) any breast cancer in patients younger than 40 years; (4) triple negative (TN) breast cancer in patients younger than 40 years; (5) TN breast cancer in patients younger than 50 years; (6) any breast cancer in patients younger than 50 years. Net health benefits were life expectancy and quality-adjusted life expectancy, and primary outcome was the incremental cost-effectiveness ratio (ICER). The model estimated the number of new breast and ovarian cancer cases.ResultsBRCA mutation testing for all women with breast cancer who were younger than 50 years could prevent the highest number of breast and ovarian cancer cases, but with unfavorable ICERs. Testing women with TN breast cancers who were younger than 50 years was cost-effective with an ICER of $8,027 per year of life gained ($9,084 per quality-adjusted life-year), and could reduce subsequent breast and ovarian cancer risks by 23% and 41%, respectively, compared with the reference strategy.ConclusionTesting women with TN breast cancers who were younger than 50 years for BRCA mutations is a cost-effective strategy and should be adopted into current guidelines for genetic testing.

scholarly journals Differences in Ovarian and Other Cancers Risks by Population and BRCA Mutation Location

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1050
Author(s):  
Masayuki Sekine ◽  
Koji Nishino ◽  
Takayuki Enomoto
Keyword(s):  
Ovarian Cancer ◽  
Cancer Risk ◽  
Cancer Patients ◽  
Brca Mutation ◽  
Parp Inhibitors ◽  
Individual Risk ◽  
Ovarian Cancer Risk ◽  
Founder Mutations ◽  
Brca Mutations ◽  
Germline Brca Mutation

Hereditary breast and ovarian cancer is caused by a germline mutation in BRCA1 or BRCA2 genes. The frequency of germline BRCA1/2 gene mutation carriers and the ratio of germline BRCA1 to BRCA2 mutations in BRCA-related cancer patients vary depending on the population. Genotype and phenotype correlations have been reported in BRCA mutant families, however, the correlations are rarely used for individual risk assessment and management. BRCA genetic testing has become a companion diagnostic for PARP inhibitors, and the number of families with germline BRCA mutation identified is growing rapidly. Therefore, it is expected that analysis of the risk of developing cancer will be possible in a large number of BRCA mutant carriers, and there is a possibility that personal and precision medicine for the carriers with specific common founder mutations will be realized. In this review, we investigated the association of ovarian cancer risk and BRCA mutation location, and differences of other BRCA-related cancer risks by BRCA1/2 mutation, and furthermore, we discussed the difference in the prevalence of germline BRCA mutation in ovarian cancer patients. As a result, although there are various discussions, there appear to be differences in ovarian cancer risk by population and BRCA mutation location. If it becomes possible to estimate the risk of developing BRCA-related cancer for each BRCA mutation type, the age at risk-reducing salpingo-oophorectomy can be determined individually. The decision would bring great benefits to young women with germline BRCA mutations.

scholarly journals Reliability of Tumor Testing Compared to Germline Testing for Detecting BRCA1 and BRCA2 Mutations in Patients with Epithelial Ovarian Cancer

2021 ◽  
Vol 11 (7) ◽  
pp. 593
Author(s):  
Christine Bekos ◽  
Christoph Grimm ◽  
Marlene Kranawetter ◽  
Stephan Polterauer ◽  
Felicitas Oberndorfer ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Brca Mutation ◽  
Treatment Decision ◽  
Concordance Rate ◽  
Brca1 And Brca2 ◽  
Brca Mutations ◽  
Uncertain Significance ◽  
Brca1 And Brca2 Mutations ◽  
Germline Testing

Background: BRCA 1/2 mutation status has become one of the most important parameters for treatment decision in patients with epithelial ovarian cancer (EOC). The aim of this study was to compare tumor DNA with blood DNA sequencing to evaluate the reliability of BRCA tumor testing results. Methods: Patients who were treated for EOC between 2003 and 2019 at the Medical University of Vienna and underwent both germline (gBRCA) and tumor (tBRCA) testing for BRCA mutations were identified. We calculated the concordance rate and further analyzed discordant cases. Results: Out of 140 patients with EOC, gBRCA mutation was found in 47 (33.6%) and tBRCA mutation in 53 (37.9%) patients. Tumor testing identified an additional 9/140 (6.4%) patients with somatic BRCA mutation and negative germline testing. The comparison of germline testing with tumor testing revealed a concordance rate of 93.5% and a negative predictive value of tumor testing of 96.0%. After BRCA variants of uncertain significance were included in the analysis, concordance rate decreased to 90.9%. Conclusion: Tumor testing identified the majority of pathogenic germline BRCA mutations but missed three (2.1%) patients. In contrast, nine (6.4%) patients harboring a somatic BRCA mutation would have been missed by gBRCA testing only.

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