A comprehensive analysis of BRCA2 gene: focus on mechanistic aspects of its functions, spectrum of deleterious mutations, and therapeutic strategies targeting BRCA2-deficient tumors

Shailani, Anjali; Kaur, Raman Preet; Munshi, Anjana

doi:10.1007/s12032-018-1085-8

Cited by 13 publications

(12 citation statements)

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“…Moreover, this region is also the binding site of RAD51 and BRCA2, which causes the binding of BRCA1 to RAD51 and BRCA2 to be blocked. Furthermore, the 1342A>C mutation of BRCA2 gene leads to abnormal structure of BRCA2 protein, which cannot bind to RAD51, RAD52, P53, etc., so that the regulatory points of cell cycle cannot be accurately located, and the damaged DNA double strand cannot be repaired, which may lead to tumor occurrence [40]. Therefore, we speculated that the mutations between BRCA1 and BRCA2 synergistically lead to the occurrence of ovarian cancer in this family.…”

Section: Discussionmentioning

confidence: 99%

Case report: Analysis of BRCA1 and BRCA2 gene mutations in a hereditary ovarian cancer family

Liao

Song

et al. 2020

J Assist Reprod Genet

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Objective Breast cancer susceptibility gene 1/2 (BRCA1/2) is the most important susceptibility gene associated with hereditary ovarian cancer (HOC). We aimed to screen BRAC1 and BRAC2 gene mutations in a member of a hereditary ovarian cancer family in China, and to analyze the structure and function of the mutant protein. Methods A typical HOC family was selected. Blood samples and pathological tissue samples were taken from the female members of the family. Blood samples from two patients with sporadic ovaries of the same pathological type were taken as a control group. After RNA extraction, PCR amplification was applied and the PCR products were directly sequenced and aligned, prediction and analysis of protein structure and molecular conformation that may be caused by BRCA1/2 mutation. Results The whole gene analysis of BRCA1 and BRCA2 in ovarian cancer patients in the family showed that there were 8 mutations in BRCA1 whole gene sequencing, including 3 nonsense mutations (2314C>T, 2543T>C, 4540T>C); two mutations have been recorded, which are associated with cervical cancer (2844C>T) and endometriosis (3345A>G); three newly discovered mutations (3780A>G, 5069A>G, 3326A>T). Among them, 3780A>G and 5069A>G caused amino acid changes, while 3326A>T mutation caused Arg mutation to stop codon. A total of 7 mutations were detected in BRCA2 whole-genome sequencing, including 5 non-significant mutations (3623A>G, 4034T>C, 4790A>G, 6740G>C, 7469A>G); one no-record mutation (1716T>A), and 1 recorded mutation (1342A>C), which was associated with breast cancer and ovarian cancer. BRCA1 (3326A>T) and BRCA2 (1342A>C) mutations were co-existing in patients (II1, II3, and II5) identified as serous adenocarcinoma grade II. Two cases of ovarian serous cystadenocarcinoma with no history of family tumors were normalized for BRCA1/2 gene sequencing. In the gene detection of III generation female, four females with BRCA2 (1342A>C) mutation were found, and one of them also carried the BRCA1 (3326A>T) mutation, who can be considered a high-risk group of HOC in this family. Online protein structure predictions revealed that BRCA1 (3326A>T) mutations mutated AGA at this site to TGA resulting in a translated Arg (arginine) mutation as a stop codon, while BRCA2 (1342A>C) mutated AAT at this site to CAT resulting in a translated Asn mutation to His. Conclusion The BRCA1 (3326A>T) and BRCA2 (1342A>C) were detected in the HOC family, which may be the susceptibility gene of the family's HOC. The BRCA1/2 gene screening may be possible to obtain high-risk populations in this family.

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Section: Discussionmentioning

confidence: 99%

Case report: Analysis of BRCA1 and BRCA2 gene mutations in a hereditary ovarian cancer family

Liao

Song

et al. 2020

J Assist Reprod Genet

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“…To date, about 2000 different mutations have been identified in both genes, although not all of them are risk-associated. BRCA genetic alterations known to increase individual cancer susceptibility are referred to as “deleterious” mutations and, in the majority of cases, they introduce premature stop codons leading to truncated and nonfunctional proteins [4,5]. Thus, mutations may disturb BRCA1 and BRCA2 participation in DNA repair or interaction with repair proteins.…”

Section: Brca Genes and Cancer Susceptibilitymentioning

confidence: 99%

Role of BRCA Mutations in Cancer Treatment with Poly(ADP-ribose) Polymerase (PARP) Inhibitors

Faraoni

Graziani

2018

Cancers

180

125

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Inhibition of poly(ADP-ribose) polymerase (PARP) activity induces synthetic lethality in mutated BRCA1/2 cancers by selectively targeting tumor cells that fail to repair DNA double strand breaks (DSBs). Clinical studies have confirmed the validity of the synthetic lethality approach and four different PARP inhibitors (PARPi; olaparib, rucaparib, niraparib and talazoparib) have been approved as monotherapies for BRCA-mutated or platinum-sensitive recurrent ovarian cancer and/or for BRCA-mutated HER2-negative metastatic breast cancer. PARPi therapeutic efficacy is higher against tumors harboring deleterious germline or somatic BRCA mutations than in BRCA wild-type tumors. BRCA mutations or intrinsic tumor sensitivity to platinum compounds are both regarded as indicators of deficiency in DSB repair by homologous recombination as well as of favorable response to PARPi. However, not all BRCA-mutated or platinum-responsive patients obtain clinical benefit from these agents. Conversely, a certain percentage of patients with wild-type BRCA or platinum-resistant tumors can still get benefit from PARPi. Thus, additional reliable markers need to be validated in clinical trials to select patients potentially eligible for PARPi-based therapies, in the absence of deleterious BRCA mutations or platinum sensitivity. In this review, we summarize the mechanisms of action of PARPi and the clinical evidence supporting their use as anticancer drugs as well as the additional synthetic lethal partners that might confer sensitivity to PARPi in patients with wild-type BRCA tumors.

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“…BRCA2 then localizes RAD51 to the DNA, and RAD51 is loaded onto RPA-coated DNA to invade the DNA double helix. When the BRCA2 gene is mutated, and therefore the BRCA2 protein deficient, RAD51 cannot be efficiently localized onto DNA (figure based on: Wooster R. et al, 1995; Prakash R. et al, 2015; Shailani A. et al, 2018 [25,27,28])…”

Section: Main Textmentioning

confidence: 99%

“…1). BRCA2 binds to RAD51 and localizes it to the nucleus, which is the site of DNA damage [25,27,28]. In BRCA2-mutated (deficient) cells, RAD51 is not transported into the nucleus and remains aberrantly in the cell.…”

Section: Introductionmentioning

confidence: 99%

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Mutations of BRCA2 in canine mammary tumors and their targeting potential in clinical therapy

2020

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Dogs develop cancer spontaneously with age, with breed-specific risk underlying differences in genetics. Mammary tumors are reported as the most frequent neoplasia in intact female dogs. Their high prevalence in certain breeds suggests a genetic component, as it is the case in human familial breast cancer, distinctly in BRCA2-associated cancers. However, the molecular genetics of BRCA2 in the pathogenesis of canine cancer are still under investigation. Genetic variations of canine BRCA2 comprised single nucleotide polymorphisms, insertions and deletions. The BRCA2 level has been shown to be reduced in tumor gland samples, suggesting that low expression of BRCA2 is contributing to mammary tumor development in dogs. Additionally, specific variations of the BRCA2 gene affect RAD51 binding strength, critically damage the BRCA2-RAD51 binding and further provoke a defective repair. In humans, preclinical and clinical data revealed a synthetic lethality interaction between BRCA2 mutations and PARP inhibition. PARP inhibitors are successfully used to increase chemo-and radiotherapy sensitivity, although they are also associated with numerous side effects and acquired resistance. Cancer treatment of canine patients could benefit from increased chemo-and radiosensitivity, as their cancer therapy protocols usually include only low doses of drugs or radiation. Early investigations show tolerability of iniparib in dogs. PARP inhibitors also imply higher therapy costs and consequently are less likely to be accepted by pet owners. We summarized the current evidence of canine BRCA2 gene alterations and their association with mammary tumors. Mutations in the canine BRCA2 gene have the potential to be exploited in clinical therapy through the usage of PARP inhibitors. However, further investigations are needed before introducing PARP inhibitors in veterinary clinical practice.

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A comprehensive analysis of BRCA2 gene: focus on mechanistic aspects of its functions, spectrum of deleterious mutations, and therapeutic strategies targeting BRCA2-deficient tumors

Cited by 13 publications

References 58 publications

Case report: Analysis of BRCA1 and BRCA2 gene mutations in a hereditary ovarian cancer family

Case report: Analysis of BRCA1 and BRCA2 gene mutations in a hereditary ovarian cancer family

Role of BRCA Mutations in Cancer Treatment with Poly(ADP-ribose) Polymerase (PARP) Inhibitors

Mutations of BRCA2 in canine mammary tumors and their targeting potential in clinical therapy

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