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1.
Mol Biol (Mosk) ; 55(3): 412-421, 2021.
Artigo em Russo | MEDLINE | ID: mdl-34097676

RESUMO

Molecular profiling of tumors may provide promising options for personalized treatment. We have examined the spectrum of germline and somatic mutations in 23 breast cancers (ВС) of various molecular subtypes, including tumors 1) with expression of estrogen, progesterone and/or epidermal growth factor receptor HER2/neu, and 2) with a triple negative phenotype. Genomic DNA specimens were isolated from archived tumor and normal tissue samples and subjected to targeted sequencing of the coding regions of 25 cancer-associated genes with a mean coverage of x 1000. In the triple negative subtype of ВС, the pathogenic germline mutations BRCA1 c.66_67delAG (185delAG) and BRCA1 c.3226_3227AG (3347delAG) were detected, while the germline mutation BRCA2 658_659del (886delGT) was found in patients with positive receptor staining. Mutations in BRCAl/2 were overrepresented by frequency (80%), pointing at common loss of heterozygosity affecting the normal allele. Somatic mutations in the TP53 gene were found in 7/10 (70%) patients with the triple negative subtype of ВС and in 3/13 (23%) in the group with positive receptor staining. Additionally, in both groups of patients, somatic mutations of the PTEN, MSH2, MSH6, and MUTYH genes were detected.


Assuntos
Neoplasias da Mama , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença , Células Germinativas , Mutação em Linhagem Germinativa , Humanos , Mutação
2.
BMC Med Inform Decis Mak ; 21(1): 180, 2021 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-34090422

RESUMO

BACKGROUND: Women with pathogenic BRCA1 and BRCA2 mutations possess a high risk of developing breast and ovarian cancer. They face difficult choices when considering preventive options. This study presents the development process of the first decision aids to support this complex decision-making process in the German healthcare system. METHODS: A six-step development process based on the International Patient Decision Aid Standards was used, including a systematic literature review of existing decision aids, a topical medical literature review, preparation of the decision aids, focus group discussions with women with BRCA1/2 mutations, internal and external reviews by clinical and self-help experts, and user tests. All reviews were followed by iterative revisions. RESULTS: No existing decision aids were transferable to the German setting. The medical research revealed a need to develop separate decision aids for women with BRCA1/2 mutations (A) without a history of cancer (previvors) and (B) with a history of unilateral breast cancer (survivors). The focus group discussions confirmed a high level of approval for the decision aids from both target groups. Additionally, previvors requested more information on risk-reducing breast surgery, risk-reducing removal of both ovaries and Fallopian tubes, and psychological aspects; survivors especially wanted more information on breast cancer on the affected side (e.g. biological parameters, treatment, and risk of recurrence). CONCLUSIONS: In a structured process, two target-group-specific DAs for previvors/survivors with BRCA1/2 mutations were developed to support decision-making on risk-adapted preventive options. These patient-oriented tools offer an important addition to existing specialist medical care in Germany.


Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Técnicas de Apoio para a Decisão , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Alemanha , Humanos , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/prevenção & controle
3.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073818

RESUMO

Approximately 23% of metastatic castration-resistant prostate cancers (mCRPC) harbor deleterious aberrations in DNA repair genes. Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) therapy has shown improvements in overall survival in patients with mCRPC who harbor somatic and/or germline alterations of homology recombination repair (HRR) genes. Peripheral blood samples are typically used for the germline mutation analysis test using the DNA extracted from peripheral blood leucocytes. Somatic alterations can be assessed by extracting DNA from a tumor tissue sample or using circulating tumor DNA (ctDNA) extracted from a plasma sample. Each of these genetic tests has its own benefits and limitations. The main advantages compared to the tissue test are that liquid biopsy is a non-invasive and easily repeatable test with the value of better representing tumor heterogeneity than primary biopsy and of capturing changes and/or resistance mutations in the genetic tumor profile during disease progression. Furthermore, ctDNA can inform about mutation status and guide treatment options in patients with mCRPC. Clinical validation and test implementation into routine clinical practice are currently very limited. In this review, we discuss the state of the art of the ctDNA test in prostate cancer compared to blood and tissue testing. We also illustrate the ctDNA testing workflow, the available techniques for ctDNA extraction, sequencing, and analysis, describing advantages and limits of each techniques.


Assuntos
DNA Tumoral Circulante/sangue , Mutação , Proteínas de Neoplasias/genética , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Reparo de DNA por Recombinação , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Humanos , Biópsia Líquida , Masculino , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/genética , Análise de Sequência de DNA
4.
World J Gastroenterol ; 27(17): 1943-1958, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34007132

RESUMO

Pancreatic cancer remains a leading cause of cancer-related death with few available therapies for advanced disease. Recently, patients with germline BRCA mutations have received increased attention due to advances in the management of BRCA mutated ovarian and breast tumors. Germline BRCA mutations significantly increase risk of developing pancreatic cancer and can be found in up to 8% of patients with sporadic pancreatic cancer. In patients with germline BRCA mutations, platinum-based chemotherapies and poly (ADP-ribose) polymerase inhibitors are effective treatment options which may offer survival benefits. This review will focus on the molecular biology, epidemiology, and management of BRCA-mutated pancreatic cancer. Furthermore, we will discuss future directions for this area of research and promising active areas of research.


Assuntos
Neoplasias Ovarianas , Neoplasias Pancreáticas , Proteína BRCA1/genética , Proteína BRCA2/genética , Feminino , Mutação em Linhagem Germinativa , Humanos , Mutação , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico
5.
Nat Commun ; 12(1): 2487, 2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-33941784

RESUMO

ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1/BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Indóis/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Proteína BRCA1/genética , Proteína BRCA2/genética , Metilação de DNA/genética , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Indóis/efeitos adversos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Platina/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Regiões Promotoras Genéticas/genética
6.
J Cancer Res Clin Oncol ; 147(7): 2035-2045, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33885953

RESUMO

PURPOSE: BRCA mutation carriers have an increased risk of developing breast or ovarian cancer. Risk-reducing bilateral salpingo-oophorectomy (RRBSO) is associated with a decrease in risk for tubal and ovarian cancer. Hormone replacement therapy (HRT) may increase breast, ovarian, and endometrial cancer risk in the general population. This review analyses the published data on HRT and risk of cancer in BRCA mutation carriers with and without RRBSO. METHODS: We included all relevant articles published in English from 1995 to October 2020. Sources were identified through a search on PubMed and Cochrane Library. RESULTS: We included one case-control and one retrospective cohort study on ovarian and one case-control study on endometrial cancer risk and HRT in BRCA mutation carriers. Regarding breast cancer risk, one case-control study on BRCA mutation carriers with and without RRBSO and one case-control study, one Markov chain decision model, two prospective cohort studies, and one metaanalysis on carriers after RRBSO were included. For ovarian cancer, results were ambiguous. For breast cancer, most studies did not find an adverse effect associated with HRT. However, some of the studies found a risk modification associated with different formulations and duration of use. CONCLUSION: Although data are limited, HRT does not seem to have a relevant effect on cancer risk in BRCA mutation carriers. RRBSO should not be postponed to avoid subsequent HRT in this population. Adequate HRT after RRBSO should be offered to avoid chronic diseases resulting from low estrogen levels. However, further data on the safety of different formulations are needed.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/etiologia , Neoplasias do Endométrio/etiologia , Terapia de Reposição Hormonal/efeitos adversos , Mutação , Neoplasias Ovarianas/etiologia , Neoplasias da Mama/patologia , Neoplasias do Endométrio/patologia , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Neoplasias Ovarianas/patologia
7.
Int J Mol Sci ; 22(8)2021 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-33919527

RESUMO

BACKGROUND: Perioperative cisplatin-based chemotherapy (CBC) can improve the outcome of patients with muscle-invasive bladder cancer (MIBC), but it is still to be defined which patients benefit. Mutations in DNA damage response genes (DDRG) can predict the response to CBC. The value of DDRG expression as a marker of CBC treatment effect remains unclear. MATERIAL AND METHODS: RNA expression of the nine key DDRG (BCL2, BRCA1, BRCA2, ERCC2, ERCC6, FOXM1, RAD50, RAD51, and RAD52) was assessed by qRT-PCR in a cohort of 61 MICB patients (median age 66 y, 48 males, 13 females) who underwent radical cystectomy in a tertiary care center. The results were validated in the The Cancer Genome Atlas (TCGA) cohort of MIBC (n = 383). Gene expression was correlated with disease-free survival (DFS) and overall survival (OS). Subgroup analyses were performed in patients who received adjuvant cisplatin-based chemotherapy (ACBC) (Mannheim n = 20 and TCGA n = 75). RESULTS: Low expression of RAD52 was associated with low DFS in both the Mannheim and the TCGA cohorts (Mannheim: p = 0.039; TCGA: p = 0.017). This was especially apparent in subgroups treated with ACBC (Mannheim: p = 0.0059; TCGA: p = 0.012). Several other genes showed an influence on DFS in the Mannheim cohort (BRCA2, ERCC2, FOXM1) where low expression was associated with poor DFS (p < 0.05 for all). This finding was not fully supported by the data in the TCGA cohort, where high expression of FOXM1 and BRCA2 correlated with poor DFS. CONCLUSION: Low expression of RAD52 correlated with decreased DFS in the Mannheim and the TCGA cohort. This effect was especially pronounced in the subset of patients who received ACBC, making it a promising indicator for response to ACBC on the level of gene expression.


Assuntos
Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Biomarcadores Tumorais , Quimioterapia Adjuvante , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/genética , Feminino , Proteína Forkhead Box M1/genética , Proteína Forkhead Box M1/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/prevenção & controle , Neoplasias da Bexiga Urinária/genética
8.
Int J Mol Sci ; 22(9)2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33922657

RESUMO

BRCA mutation, one of the most common types of mutations in breast and ovarian cancer, has been suggested to be synthetically lethal with depletion of RAD52. Pharmacologically inhibiting RAD52 specifically eradicates BRCA-deficient cancer cells. In this study, we demonstrated that curcumin, a plant polyphenol, sensitizes BRCA2-deficient cells to CPT-11 by impairing RAD52 recombinase in MCF7 cells. More specifically, in MCF7-siBRCA2 cells, curcumin reduced homologous recombination, resulting in tumor growth suppression. Furthermore, a BRCA2-deficient cell line, Capan1, became resistant to CPT-11 when BRCA2 was reintroduced. In vivo, xenograft model studies showed that curcumin combined with CPT-11 reduced the growth of BRCA2-knockout MCF7 tumors but not MCF7 tumors. In conclusion, our data indicate that curcumin, which has RAD52 inhibitor activity, is a promising candidate for sensitizing BRCA2-deficient cells to DNA damage-based cancer therapies.


Assuntos
Proteína BRCA2/deficiência , Neoplasias da Mama/tratamento farmacológico , Curcumina/farmacologia , Dano ao DNA , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Recombinação Homóloga , Proteína Rad52 de Recombinação e Reparo de DNA/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Apoptose , Proteína BRCA2/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Reparo do DNA , Feminino , Humanos , Irinotecano/farmacologia , Camundongos , Camundongos Nus , Mutação , Inibidores da Topoisomerase I/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
9.
BMC Cancer ; 21(1): 217, 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33653301

RESUMO

BACKGROUND: Certain sequences of genomic mutations can lead to cancer formation and affect treatment outcomes and drug resistance. We constructed a cancer evolutionary tree using bulk-targeted deep sequencing to explore the impact of sequential and co-occurring somatic mutations on patients with stage III colorectal cancer (CRC). METHODS: A total of 108 stage III CRC patients from National Cheng Kung University Hospital (NCKUH) were recruited for this study between Jan. 2014 and Jan. 2019. Clinical information and tumor-targeted deep sequencing data were collected. Phylogenetic trees were reconstructed for evolutionary trajectories. We used a machine learning model for survival analysis. RESULTS: Six sequential somatic mutations stratified patients into seven subgroups based on survival. Patients carrying sequential germline followed by DNA damage response-related ATM or BRCA2 somatic mutations or non-TP53, APC somatic mutations had a better outcome than those without such mutations. The 4-year recurrence-free survival (RFS) probability was 88% in the low-risk group (G1) and 46% in the high-risk group (G2) (log-rank p-value 2e-05). The predictive efficacy by the area under the curve (AUC) was 0.73, 0.7, 0.797, and 0.88 at 2, 4, 6, and 8 years, respectively. The mutation status of mismatch repair (MMR) genes was not associated with RFS. Different genomic features were found between the groups. The orders of APC, KRAS and APC, BRCA2 sequential somatic mutations were associated with clinical outcomes. The occurrence of somatic mutations in BRCA2, such as TP53 somatic mutations, affected recurrence-free survival. CONCLUSIONS: According to the evolution model, DNA damage response (DDR)-related ATM or BRCA2 somatic mutations are promising biomarkers for assessing the response of stage III CRC patients to oxaliplatin-based chemotherapy. The sequential order and co-occurring DDR somatic mutations are associated with recurrence-free survival.


Assuntos
Neoplasias Colorretais/genética , Dano ao DNA , Mutação , Oxaliplatina/administração & dosagem , Proteína da Polipose Adenomatosa do Colo/genética , Idoso , Proteína BRCA2/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Filogenia , Proteínas Proto-Oncogênicas p21(ras)/genética
10.
J Med Life ; 14(1): 17-20, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33767780

RESUMO

The use of the PARP inhibitors (PARPi) in the treatment of breast cancer (BC) with germine mutations has evolved over the years, and further research has been done in order to broaden the horizon of this treatment strategy. Therefore the aim of this paper is to review the efficiency of PARPi in the treatment of BRCA 1/2-mutated locally advanced and metastatic Her-2/net negative BC mentioning their side effects, mechanism of resistance and future directions. Inhibition of PARP transforms single-strand breaks into double-strand breaks (DBS), the accumulation of the latter causing cell death (cell apoptosis). The Olympia AD phase III trial demonstrated a statistically significant progression-free survival rate (PFS) when using the PARPi olaparib in metastatic BC with germline BRCA1/2 mutations without any benefit of the overall survival rate. PARPi therapy is associated with acceptable responsive rates and progression-free survival rates in locally advanced and metastatic BRCA1/2 associated BC through mechanisms that enhance and increase the sensitivity to chemotherapeutic or target agents as they induce a synthetic lethality and cell apoptosis. The side effects are not significant, the most adverse effects being related to the hematological and gastrointestinal systems. Olaparib is currently approved in the first-line treatment of BRCA1/2 mutated Her-2/neu negative metastatic BC at an oral dose of 300 mg twice daily, while Talazoparib represents a category one recommendation in locally advanced and metastatic Her-2/neu negative BC in women with central nervous system metastases.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Mutação em Linhagem Germinativa/genética , Poli Adenosina Difosfato Ribose/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Metástase Neoplásica , Poli Adenosina Difosfato Ribose/uso terapêutico
11.
Methods Mol Biol ; 2212: 347-376, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33733367

RESUMO

As practitioners, we aim to provide a consolidated introduction of tidy data science along with routine packages for relational data representation and interpretation, with the focus on analytics related to human genetic interactions. We describe three showcases (also made available at https://23verse.github.io/gini ), all done so via the R one-liner, in this chapter defined as a sequential pipeline of elementary functions chained together achieving a complex task. We guide the readers through step-by-step instructions on (case 1) performing network module analysis of genetic interactions, followed by visualization and interpretation; (case 2) implementing a practical strategy of how to identify and interpret tissue-specific genetic interactions; and (case 3) carrying out interaction-based tissue clustering and differential interaction analysis. All showcases demonstrate simplistic beauty and efficient nature of this analytics. We anticipate that mastering a dozen of one-liners to efficiently interpret genetic interactions is very timely now; opportunities for computational translational research are arising for data scientists to harness therapeutic potential of human genetic interaction data that are ever-increasingly available.


Assuntos
Algoritmos , Ciência de Dados/estatística & dados numéricos , Epistasia Genética , Redes Reguladoras de Genes , Software , Animais , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Interpretação Estatística de Dados , Genoma Humano , Genótipo , Humanos , Camundongos , Especificidade de Órgãos , Fenótipo , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Mapeamento de Interação de Proteínas
12.
J Transl Med ; 19(1): 108, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33726785

RESUMO

BACKGROUND: The incidence of breast cancer (BC) and/or ovarian cancer (OC) is increasing in Tunisia especially in young women and mostly those with family history. However, the spectrum of BRCA mutations remains little explored in Tunisian patients in particular in the southern region. METHODS: We sequenced the entire coding regions of BRCA1and BRCA2 genes using next generation sequencing (NGS) in 134 selected patients with BC and/or OC. RESULTS: Among the 134 patients, 19 (14.17%) carried pathogenic mutations (10 are BRCA1 mutation carriers and 9 are BRCA2 mutation carriers) that are mainly frameshift index (76.9%). Interestingly, 5 out of the 13 variants (38.46%) were found at least twice in unrelated patients, as the c.1310-1313 delAAGA in BRCA2 and the c.5030_5033 delCTAA that has been identified in 4/98 BC patients and in 3/15 OC patients from unrelated families with strong history of cancer. Besides recurrent mutations, 6 variant (4 in BRCA1 and 2 in BRCA2) were not reported previously. Furthermore, 3 unrelated patients carried the VUS c.9976A > T, (K3326*) in BRCA2 exon 27. BRCA carriers correlated significantly with tumor site (p = 0.029) and TNBC cases (p = 0.008). In the groups of patients aged between 31 and 40, and 41-50 years, BRCA1 mutations occurred more frequently in patients with OC than those with BC, and conversely BRCA2 carriers are mostly affected with BC (p = 0.001, and p = 0.044 respectively). CONCLUSIONS: The overall frequency of the BRCA germline mutations was 14.17% in patients with high risk of breast/ovarian cancer. We identified recurrent mutations as the c.1310_1313 delAAGA in BRCA2 gene and the c.5030_5033 delCTAA in BRCA1 gene that were found in 4% and 20% of familial BC and OC respectively. Our data will contribute in the implementation of genetic counseling and testing for families with high-risk of BC and/or OC.


Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Adulto , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Feminino , Genes BRCA2 , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Humanos , Mutação/genética , Neoplasias Ovarianas/genética , Tunísia
13.
Nucleic Acids Res ; 49(8): 4239-4257, 2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33744950

RESUMO

Tumours with mutations in the BRCA1/BRCA2 genes have impaired double-stranded DNA break repair, compromised replication fork protection and increased sensitivity to replication blocking agents, a phenotype collectively known as 'BRCAness'. Tumours with a BRCAness phenotype become dependent on alternative repair pathways that are error-prone and introduce specific patterns of somatic mutations across the genome. The increasing availability of next-generation sequencing data of tumour samples has enabled identification of distinct mutational signatures associated with BRCAness. These signatures reveal that alternative repair pathways, including Polymerase θ-mediated alternative end-joining and RAD52-mediated single strand annealing are active in BRCA1/2-deficient tumours, pointing towards potential therapeutic targets in these tumours. Additionally, insight into the mutations and consequences of unrepaired DNA lesions may also aid in the identification of BRCA-like tumours lacking BRCA1/BRCA2 gene inactivation. This is clinically relevant, as these tumours respond favourably to treatment with DNA-damaging agents, including PARP inhibitors or cisplatin, which have been successfully used to treat patients with BRCA1/2-defective tumours. In this review, we aim to provide insight in the origins of the mutational landscape associated with BRCAness by exploring the molecular biology of alternative DNA repair pathways, which may represent actionable therapeutic targets in in these cells.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Quebras de DNA de Cadeia Dupla , Reparo do DNA/genética , Neoplasias/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Humanos , Mutação , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico
14.
Int J Mol Sci ; 22(4)2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33671579

RESUMO

DNA double-strand breaks (DSBs) are among the most serious forms of DNA damage. In humans, DSBs are repaired mainly by non-homologous end joining (NHEJ) and homologous recombination repair (HRR). Single-strand annealing (SSA), another DSB repair system, uses homologous repeats flanking a DSB to join DNA ends and is error-prone, as it removes DNA fragments between repeats along with one repeat. Many DNA deletions observed in cancer cells display homology at breakpoint junctions, suggesting the involvement of SSA. When multiple DSBs occur in different chromosomes, SSA may result in chromosomal translocations, essential in the pathogenesis of many cancers. Inhibition of RAD52 (RAD52 Homolog, DNA Repair Protein), the master regulator of SSA, results in decreased proliferation of BRCA1/2 (BRCA1/2 DNA Repair Associated)-deficient cells, occurring in many hereditary breast and ovarian cancer cases. Therefore, RAD52 may be targeted in synthetic lethality in cancer. SSA may modulate the response to platinum-based anticancer drugs and radiation. SSA may increase the efficacy of the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9 (CRISPR associated 9) genome editing and reduce its off-target effect. Several basic problems associated with SSA, including its evolutionary role, interplay with HRR and NHEJ and should be addressed to better understand its role in cancer pathogenesis and therapy.


Assuntos
Reparo do DNA/genética , DNA de Cadeia Simples/genética , Edição de Genes/métodos , Instabilidade Genômica , Neoplasias/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Quebras de DNA de Cadeia Dupla , Reparo do DNA/fisiologia , Feminino , Humanos , Neoplasias/terapia
15.
J Int Med Res ; 49(2): 300060521991019, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33541181

RESUMO

OBJECTIVE: Nearly 5% of patients with breast cancer carry germline BRCA mutations, which are more common in triple-negative breast cancer (TNBC). Previous clinical trials demonstrated the therapeutic efficacy of poly (ADP-ribose) polymerase inhibitors (PARPis) against BRCA-mutated metastatic breast cancer. The current study conducted a systemic review and meta-analysis of the clinical efficiency and safety of PARPis, either alone or combined with chemotherapy, in patients with TNBC. METHODS: We searched PubMed, EMBASE, and ClinicalTrials.gov to identify randomized controlled trials comparing PARPi therapy with chemotherapy, and comparisons of chemotherapy plus PARPis with chemotherapy alone were included. The study endpoints included the clinical response, progression-free survival, and adverse event rates. RESULTS: PARPi therapy was revealed to improve progression-free survival in patients with advanced breast cancer, either alone or in combination with chemotherapy. Subgroup analysis illustrated that patients with mutant BRCA1 and mutant BRCA2 and those who had not been treated with platinum-based agents could specifically benefit from PARPis. CONCLUSION: PARPi monotherapy can significantly improve clinical outcomes in patients with advanced breast cancer, especially those with TNBC, those who had not previously received platinum therapy, and those with mutant BRCA1/2. PARPis combined with chemotherapy represent new treatment options for patients with advanced cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Proteína BRCA1/genética , Proteína BRCA2/genética , Feminino , Humanos , Mutação , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia
16.
Menopause ; 28(3): 263-270, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33534430

RESUMO

OBJECTIVE: BRCA carriers are recommended to undergo prophylactic risk-reducing salpingo-oophorectomy (RRSO). Possible adverse health impacts of RRSO, particularly when done before natural menopause, can reduce the long-term satisfaction with this risk-reducing strategy. The aim of this study was to prospectively evaluate the level of satisfaction of women undergoing RRSO, also in relation to some specific characteristics at RRSO. METHODS: A prospective cohort study was performed in the Modena Family Cancer Clinic of the University Hospital of Modena (Italy). All BRCA1/2 confirmed mutation carriers who decided to undergo RRSO were recruited between 2016 and 2019. RESULTS: Fifty-five women (29 BRCA1 and 26 BRCA2) (mean age: 50.4 ±â€Š7.7 years [range 35-79]) were included with a mean follow-up after RRSO of 660.9 days (1.8 years) (range 35-1,688 days) (median: 549 days). No intraepithelial (Serous Tubal Intraepithelial Carcinoma)/invasive cancers were found (0%) at RRSO. No vasomotor symptoms at 1 month after surgery were reported by 11/22 (50%) premenopausal women at RRSO. All women (100%) with new "RRSO-caused" vasomotor symptoms with no previous breast cancer initiated postmenopausal hormone therapy. At the final follow-up the satisfaction rate (0-100 visual analog scale points) of the participants was 96.4 ±â€Š8.6 points (range 62-100). To the question "Would you undergo RRSO again if it was proposed today? (0-100 visual analog scale points)" the answer was 99.4 ±â€Š3.2 points (range 79-100). These scores were in general very high and did not change in the different groups according to pre/postmenopausal status at RRSO, cancer survivors versus healthy women at RRSO, BRCA status, hormone therapy users/nonusers after RRSO, "RRSO-caused" symptoms versus not RRSO-caused (P > 0.05). CONCLUSIONS: Findings from this prospective study suggest that satisfaction with RRSO is very high and little dependent on the participants' characteristics at surgery. Women at high risk for ovarian cancer are very satisfied with their choice of risk-reduction strategy.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/prevenção & controle , Ovariectomia/efeitos adversos , Ovariectomia/métodos , Satisfação Pessoal , Procedimentos Cirúrgicos Profiláticos/efeitos adversos , Salpingectomia/métodos , Salpingo-Ooforectomia/efeitos adversos , Adulto , Idoso , Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Itália , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/patologia , Estudos Prospectivos , Comportamento de Redução do Risco , Resultado do Tratamento
17.
BMC Cancer ; 21(1): 199, 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33632156

RESUMO

BACKGROUND: Breast cancer is one of the leading causes of cancer-related deaths in women, and there is a demand in developing an Asian-based genetic profiling database for breast cancer in improving the treatment response. This study aimed to determine molecular alternations and identify potential therapeutic targets by analyzing the genetic profiling from a cohort of Taiwanese breast cancers using a commercialized next-generation sequencing (NGS) targeted panel. METHODS: The study population comprised a broad spectrum of breast cancer patients in Taiwan, including Group 1: planned to receive first-line surgery and followed by adjuvant therapy, or early relapse within three years, Group 2: planned to receive first-line neoadjuvant therapy and followed by surgery, and Group 3: de novo stage IV, or stage IV with recurrence beyond three years. Molecular profiles were determined using Thermo Fisher™ Oncomine™ Comprehensive Assay version 3 (TMO comprehensive assay) from Formalin-Fixed Paraffin-Embedded (FFPE) tissues. Level of actionability was evaluated with the ESMO Scale of clinical actionability of molecular targets (ESCAT). RESULTS: A total of 380 TMO comprehensive assays were conducted on 372 patients, and we presented targeted sequencing analyses of Tier I: alteration-drug match associated with improved outcome in clinical trials including ERBB2 amplification, BRCA1/2 germline mutation, PIK3CA mutation, and NTRK translocation, and Tier II: antitumor activity associated with the matched alteration-drug but lack of prospective outcome data including PTEN loss, ESR1 mutation, AKT1 mutation, and ERBB2 mutation, and Tier III: matched drug-alteration that led to clinical benefit in another tumor type including MDM2 amplification, and ERBB3 mutation. Among them, 249 (66%) showed at least one actionable alternation based on the ESCAT criteria. The most frequent impacted genes (all variants combined within each sample) were PIK3CA (38%), followed by ERBB2 (23%), ESR1 (10%), AKT1 (6%), and BRCA2 (5%), and the remaining rare variants (less than 5% of assayed cohort) were BRCA1 (3%), MDM2 (2.2%), and ERBB3 (1.1%). CONCLUSION: Targeted sequencing of actionable genes is believed to provide clinical applicability and substantial benefits for Taiwanese breast cancer patients. A valid scale of clinical actionability should be adopted for precision medicine practice under multidisciplinary molecular tumor board.


Assuntos
Neoplasias da Mama/genética , Mutação , Adulto , Idoso , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/genética , Receptor ErbB-3/genética
18.
Expert Rev Pharmacoecon Outcomes Res ; 21(3): 441-448, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33593205

RESUMO

Objectives: To determine whether olaparib maintenance therapy, used with and without restriction by BRCA1/2 mutation status, is cost-effective at the population level for platinum-sensitive relapsed ovarian cancer in Singapore.Methods: A partitioned survival model compared three management strategies: 1) treat all patients with olaparib; 2) test for germline BRCA1/2 mutation, followed by targeted olaparib use in mutation carriers only; 3) observe all patients. Mature overall survival (OS) data from Study 19 and a 15-year time horizon were used and direct medical costs were applied. Sensitivity analyses were conducted to explore uncertainties.Results: Treating all patients with olaparib was the most costly and effective strategy, followed by targeted olaparib use, and observation of all patients. Base-case incremental cost-effectiveness ratios (ICERs) for all-olaparib and targeted use strategies were SGD133,394 (USD100,926) and SGD115,736 (USD87,566) per quality-adjusted life year (QALY) gained, respectively, compared to observation. ICERs were most sensitive to the cost of olaparib, time horizon and discount rate for outcomes. When these parameters were varied, ICERs remained above SGD92,000 (USD69,607)/QALY.Conclusions: At the current price, olaparib is not cost-effective when used with or without restriction by BRCA1/2 mutation status in Singapore, despite taking into account potential OS improvement over a long time horizon.


Assuntos
Terapia de Alvo Molecular , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Proteína BRCA1/genética , Proteína BRCA2/genética , Análise Custo-Benefício , Feminino , Humanos , Mutação , Recidiva Local de Neoplasia , Neoplasias Ovarianas/economia , Neoplasias Ovarianas/genética , Ftalazinas/economia , Piperazinas/economia , Inibidores de Poli(ADP-Ribose) Polimerases/economia , Anos de Vida Ajustados por Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Singapura , Análise de Sobrevida , Fatores de Tempo
19.
Value Health ; 24(2): 303-312, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33518037

RESUMO

BACKGROUND: Targeted genetic testing is a tool to identify women at increased risk of gynaecological cancer. OBJECTIVE: This systematic review evaluates the results and quality of cost-effectiveness modeling studies that assessed targeted genetic-based screen-and-treat strategies to prevent breast and ovarian cancer. METHODS: Using MEDLINE and databases of the Centre for Reviews and Dissemination, we searched for health economic modeling evaluations of targeted genetic-based screen-and-treat strategies to prevent inheritable breast and ovarian cancer (until August 2020). The incremental cost-effectiveness ratios (ICERs) were compared. Methodological variations were addressed by evaluating the model conceptualizations, the modeling techniques, parameter estimation and uncertainty, and transparency and validation of the models. Additionally, the reporting quality of each study was assessed. RESULTS: Eighteen studies met our inclusion criteria. From a payer perspective, the ICERs of (1) BRCA screening for high-risk women without cancer ranged from dominating the no test strategy to an ICER of $21 700/quality-adjusted life years (QALY). In studies that evaluated (2) BRCA cascade screening (ie, screening of women with cancer plus their unaffected relatives) compared with no test, the ICERs were between $6500/QALY and $50 200/QALY. Compared with BRCA alone, (3) multigene testing in women without cancer had an ICER of $51 800/QALY (one study), while for (4) multigene-cascade screening the ICERs were $15 600/QALY, $56.500/QALY, and $69 600/QALY for women in the United Kingdom, Norway, and the United States, respectively (2 studies). More recently published studies showed a higher methodological and reporting quality. CONCLUSIONS: Targeted BRCA or multiple gene screening is likely to be cost-effective. Methodological variations could be decreased by the development of a reference model, which may serve as a tool for validation of present and future cost-effectiveness models.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/psicologia , Testes Genéticos/economia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/psicologia , Proteína BRCA1/genética , Proteína BRCA2/genética , Análise Custo-Benefício , Feminino , Humanos
20.
Am J Hum Genet ; 108(3): 458-468, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33609447

RESUMO

Determination of the clinical relevance of rare germline variants of uncertain significance (VUSs) in the BRCA2 cancer predisposition gene remains a challenge as a result of limited availability of data for use in classification models. However, laboratory-based functional data derived from validated functional assays of known sensitivity and specificity may influence the interpretation of VUSs. We evaluated 252 missense VUSs from the BRCA2 DNA-binding domain by using a homology-directed DNA repair (HDR) assay and identified 90 as non-functional and 162 as functional. The functional assay results were integrated with other available data sources into an ACMG/AMP rules-based classification framework used by a hereditary cancer testing laboratory. Of the 186 missense variants observed by the testing laboratory, 154 were classified as VUSs without functional data. However, after applying protein functional data, 86% (132/154) of the VUSs were reclassified as either likely pathogenic/pathogenic (39/132) or likely benign/benign (93/132), which impacted testing results for 1,900 individuals. These results indicate that validated functional assay data can have a substantial impact on VUS classification and associated clinical management for many individuals with inherited alterations in BRCA2.


Assuntos
Proteína BRCA2/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença , Reparo de DNA por Recombinação/genética , Neoplasias da Mama/patologia , Feminino , Variação Genética/genética , Humanos , Mutação de Sentido Incorreto/genética , Relação Estrutura-Atividade
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