scholarly journals BRCA mutation in ovarian cancer: testing, implications and treatment considerations

2017 ◽  
Vol 9 (8) ◽  
pp. 519-531 ◽  
Author(s):  
Robert T. Neff ◽  
Leigha Senter ◽  
Ritu Salani
Keyword(s):  
Ovarian Cancer ◽  
Genetic Screening ◽  
Brca Mutation ◽  
High Grade ◽  
Brca Mutations ◽  
Recombination Proteins ◽  
Preventative Measures ◽  
Therapeutic Development ◽  
Treatment Considerations ◽  
Germline Brca Mutation

Ovarian cancer is a heterogeneous disease that encompasses a number of different cellular subtypes, the most common of which is high-grade serous ovarian cancer (HGSOC). Still today, ovarian cancer is primarily treated with chemotherapy and surgery. Recent advances in the hereditary understanding of this disease have shown a significant role for the BRCA gene. While only a minority of patients with HGSOC will have a germline BRCA mutation, many others may have tumor genetic aberrations within BRCA or other homologous recombination proteins. Genetic screening for these BRCA mutations has allowed improved preventative measures and therapeutic development. This review focuses on the understanding of BRCA mutations and their relationship with ovarian cancer development, as well as future therapeutic targets.

Germ-line BRCA mutations in high-grade ovarian cancer: A case for routine BRCA mutation screening after a diagnosis of invasive ovarian cancer.

2011 ◽  
Vol 29 (15_suppl) ◽  
pp. 5026-5026 ◽  
Author(s):  
K. Alsop ◽  
S. Fereday ◽  
C. Meldrum ◽  
A. deFazio ◽  
P. Webb ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Germ Line ◽  
Brca Mutation ◽  
Mutation Screening ◽  
High Grade ◽  
Brca Mutations

scholarly journals The Landscape and Therapeutic Implications of Molecular Profiles in Epithelial Ovarian Cancer

2020 ◽  
Vol 9 (7) ◽  
pp. 2239
Author(s):  
Ludivine Dion ◽  
Isis Carton ◽  
Sylvie Jaillard ◽  
Krystel Nyangoh Timoh ◽  
Sébastien Henno ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Genetic Alterations ◽  
High Grade ◽  
Dna Breaks ◽  
Brca Mutations ◽  
Platinum Based Chemotherapy

Epithelial ovarian cancer (EOC) affects 43,000 women worldwide every year and has a five-year survival rate of 30%. Mainstay treatment is extensive surgery and chemotherapy. Outcomes could be improved by molecular profiling. We conducted a review of the literature to identify relevant publications on molecular and genetic alterations in EOC. Approximately 15% of all EOCs are due to BRCA1 or BRCA2 mutations. Four histologic subtypes characterized by different mutations have been described: serous, endometrioid, mucinous, and clear-cell. Between 20–30% of high-grade serous EOCs have a BRCA mutation. Tumors with BRCA mutations are unable to repair double-strand DNA breaks, making them more sensitive to platinum-based chemotherapy and to PolyAdenosine Diphosphate-Ribose Polymerase (PARP) inhibitors. Olaparib is a PARP inhibitor with proven efficacy in BRCA-mutated ovarian cancer, but its effectiveness remains to be demonstrated in tumors with a BRCAness (breast cancer) profile (i.e., also including sporadic tumors in patients with deficient DNA repair genes). A universally accepted molecular definition of BRCAness is required to identify optimal theranostic strategies involving PARP inhibitors. Gene expression analyses have led to the identification of four subgroups of high-grade serous EOC: mesenchymal, proliferative, differentiated, and immunoreactive. These subtypes are not mutually exclusive but are correlated with prognosis. They are not yet used in routine clinical practice. A greater understanding of EOC subtypes could improve patient management.

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 Tumour Versus Germline BRCA Testing in Ovarian Cancer: A Single-Site Institution Experience in the United Kingdom

Diagnostics ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 547
Author(s):  
Iolia Akaev ◽  
Siavash Rahimi ◽  
Olubukola Onifade ◽  
Francis John Edward Gardner ◽  
David Castells-Rufas ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Unknown Origin ◽  
Parp Inhibitors ◽  
Serous Carcinoma ◽  
High Grade ◽  
Brca1 And Brca2 ◽  
Brca Mutations ◽  
Epithelial Cancers ◽  
Pathogenic Variants ◽  
Pathogenic Mutations

The aim of this audit was to evaluate the usefulness and serviceability of testing for pathogenic mutations in BRCA1 or BRCA2 (BRCA1/2) genes in ovarian cancer (OC) patients. One hundred and thirty-five patients with more common histological sub-types of OC were retrospectively identified between 2011 and 2019. The fail rate of the molecular analysis was 7.4% (10/135). One hundred and twenty-five records were evaluated: 99 (79.2%) patients had wild-type BRCA (both somatic and germline); tumour BRCA1/2 (tBRCA1/2) pathogenic mutations were found in 20 (16%) patients with distribution between BRCA1 and BRCA2 being 40% and 60%, respectively; 13 (10.4%) patients with pathogenic variants had germline mutations; and tBRCA1/2 with variant of unknown significance (VUS), in the absence of pathogenic BRCA1 or BRCA2 variants, was detected in 6 (4.8%) patients. Our data show that expanding the molecular service to the routine first-tumour testing for patients with OC will potentially increase the detection rate of BRCA mutations, thereby providing early benefits of PARP inhibitors therapy. The tumour testing service should continue to be offered to newly diagnosed patients with high-grade epithelial cancers, including high-grade serous carcinoma, but also with carcinosarcomas and poorly-differentiated metastatic adenocarcinomas of unknown origin.

scholarly journals High-Grade Serous Ovarian Cancer: Associations between BRCA Mutation Status, CT Imaging Phenotypes, and Clinical Outcomes

Radiology ◽  
2017 ◽  
Vol 285 (2) ◽  
pp. 472-481 ◽  
Author(s):  
Stephanie Nougaret ◽  
Yulia Lakhman ◽  
Mithat Gönen ◽  
Debra A. Goldman ◽  
Maura Miccò ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Outcomes ◽  
Brca Mutation ◽  
Ct Imaging ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Mutation Status

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.

scholarly journals Gynecologic Cancers: Emerging Novel Strategies for Targeting DNA Repair Deficiency

2016 ◽  
pp. e259-e268 ◽  
Author(s):  
Rebecca S. Kristeleit ◽  
Rowan E. Miller ◽  
Elise C. Kohn
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Inhibitor Therapy ◽  
Molecular Therapy ◽  
Parp Inhibition ◽  
Gynecologic Cancers ◽  
Brca Mutations ◽  
Individual Gene

The presence of a BRCA mutation, somatic or germline, is now established as a standard of care for selecting patients with ovarian cancer for treatment with a PARP inhibitor. During the clinical development of the PARP inhibitor class of agents, a subset of women without BRCA mutations were shown to respond to these drugs (termed “ BRCAness”). It was hypothesized that other genetic abnormalities causing a homologous recombinant deficiency (HRD) were sensitizing the BRCA wild-type cancers to PARP inhibition. The molecular basis for these other causes of HRD are being defined. They include individual gene defects (e.g., RAD51 mutation, CHEK2 mutation), homozygous somatic loss, and whole genome properties such as genomic scarring. Testing this knowledge is possible when selecting patients to receive molecular therapy targeting DNA repair, not only for patients with ovarian cancer but also endometrial and cervical cancers. The validity of HRD assays and multiple gene sequencing panels to select a broader population of patients for treatment with PARP inhibitor therapy is under evaluation. Other non-HRD targets for exploiting DNA repair defects in gynecologic cancers include mismatch repair (MMR), checkpoint signaling, and nonhomologous end-joining (NHEJ) DNA repair. This article describes recent evidence supporting strategies in addition to BRCA mutation for selecting patients for treatment with PARP inhibitor therapy. Additionally, the challenges and opportunities of exploiting DNA repair pathways other than homologous recombination for molecular therapy in gynecologic cancers is discussed.

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