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1.
Lancet Oncol ; 21(10): 1269-1282, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32861273

RESUMO

BACKGROUND: BRCA1 or BRCA2-mutated breast cancers are sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors and platinum agents owing to deficiency in homologous recombination repair of DNA damage. In this trial, we compared veliparib versus placebo in combination with carboplatin and paclitaxel, and continued as monotherapy if carboplatin and paclitaxel were discontinued before progression, in patients with HER2-negative advanced breast cancer and a germline BRCA1 or BRCA2 mutation. METHODS: BROCADE3 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 147 hospitals in 36 countries. Eligible patients (aged ≥18 years) had deleterious germline BRCA1 or BRCA2 mutation-associated, histologically or cytologically confirmed advanced HER2-negative breast cancer, an Eastern Cooperative Oncology Group performance status of 0-2, and had received up to two previous lines of chemotherapy for metastatic disease. Patients were randomly assigned (2:1) by interactive response technology by means of permuted blocks within strata (block size of 3 or 6) to carboplatin (area under the concentration curve 6 mg/mL per min intravenously) on day 1 and paclitaxel (80 mg/m2 intravenously) on days 1, 8, and 15 of 21-day cycles combined with either veliparib (120 mg orally twice daily, on days -2 to 5) or matching placebo. If patients discontinued carboplatin and paclitaxel before progression, they could continue veliparib or placebo at an intensified dose (300 mg twice daily continuously, escalating to 400 mg twice daily if tolerated) until disease progression. Patients in the control group could receive open-label veliparib monotherapy after disease progression. Randomisation was stratified by previous platinum use, history of CNS metastases, and oestrogen and progesterone receptor status. The primary endpoint was investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy analyses were done by intention to treat, which included all randomly assigned patients with a centrally confirmed BRCA mutation, and safety analyses included all patients who received at least one dose of velilparib or placebo. This study is ongoing and is registered with ClinicalTrials.gov, NCT02163694. FINDINGS: Between July 30, 2014, and Jan 17, 2018, 2202 patients were screened, of whom 513 eligible patients were enrolled and randomly assigned. In the intention-to-treat population (n=509), 337 patients were assigned to receive veliparib plus carboplatin-paclitaxel (veliparib group) and 172 were assigned to receive placebo plus carboplatin-paclitaxel (control group). Median follow-up at data cutoff (April 5, 2019) was 35·7 months (IQR 24·9-43·6) in the veliparib group and 35·5 months (23·1-45·9) in the control group. Median progression-free survival was 14·5 months (95% CI 12·5-17·7) in the veliparib group versus 12·6 months (10·6-14·4) in the control group (hazard ratio 0·71 [95% CI 0·57-0·88], p=0·0016). The most common grade 3 or worse adverse events were neutropenia (272 [81%] of 336 patients in the veliparib group vs 143 [84%] of 171 patients in the control group), anaemia (142 [42%] vs 68 [40%]), and thrombocytopenia (134 [40%] vs 48 [28%]). Serious adverse events occurred in 115 (34%) patients in the veliparib group versus 49 (29%) patients in the control group. There were no study drug-related deaths. INTERPRETATION: The addition of veliparib to a highly active platinum doublet, with continuation as monotherapy if the doublet were discontinued, resulted in significant and durable improvement in progression-free survival in patients with germline BRCA mutation-associated advanced breast cancer. These data indicate the utility of combining platinum and PARP inhibitors in this patient population. FUNDING: AbbVie.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carboplatina/uso terapêutico , Paclitaxel/uso terapêutico , Adulto , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Método Duplo-Cego , Esquema de Medicação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Intervalo Livre de Progressão , Resultado do Tratamento
3.
Mol Biol (Mosk) ; 54(4): 688-698, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32840490

RESUMO

A majority of BRCA1/2 (BRCA) pathogenic variants (PVs) are single nucleotide substitutions or small insertions/deletions. Copy number variations (CNVs), also known as large genomic rearrangements (LGRs), have been identified in BRCA genes. LGRs detection is a mandatory analysis in hereditary breast and ovarian cancer families, if no predisposing PVs are found by sequencing. Next generation sequencing (NGS) may be used to detect structural variation, since quantitative analysis of sequencing reads, when coupled with appropriate bioinformatics tools, is capable of estimating and predicting germline LGRs (gLGRs). However, applying this approach to tumor tissue is challenging, and the pipelines for determination of CNV are yet to be optimized. The aim of this study was to validate the Next Generation Tumor Sequencing (NGTS) technology to detect various gLGRs of BRCA1 locus in surgical tumor tissue samples. In this study, seven different BRCA1 gLGRs, previously found in high-grade serous ovarian cancers (HGSOC) patients, were detected in tumor samples collected from the patients at a time of HGSOC surgery. This study demonstrated that NGS can accurately detect BRCA1 gLGRs in primary tumors, suggesting that gLGR evaluation in BRCA1 locus should be performed in cases when the screening for BRCA alterations starts from tumor instead of blood. NGS sequencing of tumor samples may become the preferred method to detect both somatic and germline gLGRs in BRCA-encoding loci.


Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Genes BRCA1 , Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias Ovarianas/genética , Variações do Número de Cópias de DNA/genética , Feminino , Células Germinativas/metabolismo , Mutação em Linhagem Germinativa , Humanos
4.
Mol Cell ; 78(6): 1152-1165.e8, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32516598

RESUMO

The APEX2 gene encodes APE2, a nuclease related to APE1, the apurinic/apyrimidinic endonuclease acting in base excision repair. Loss of APE2 is lethal in cells with mutated BRCA1 or BRCA2, making APE2 a prime target for homologous recombination-defective cancers. However, because the function of APE2 in DNA repair is poorly understood, it is unclear why BRCA-deficient cells require APE2 for viability. Here we present the genetic interaction profiles of APE2, APE1, and TDP1 deficiency coupled to biochemical and structural dissection of APE2. We conclude that the main role of APE2 is to reverse blocked 3' DNA ends, problematic lesions that preclude DNA synthesis. Our work also suggests that TOP1 processing of genomic ribonucleotides is the main source of 3'-blocking lesions relevant to APEX2-BRCA1/2 synthetic lethality. The exquisite sensitivity of BRCA-deficient cells to 3' blocks indicates that they represent a tractable vulnerability in homologous recombination-deficient tumor cells.


Assuntos
Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Endonucleases/metabolismo , Enzimas Multifuncionais/metabolismo , Proteína BRCA1/genética , Proteína BRCA2/genética , Linhagem Celular , DNA/metabolismo , Dano ao DNA , Reparo do DNA/genética , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Endonucleases/genética , Genes BRCA1/fisiologia , Humanos , Enzimas Multifuncionais/genética , Diester Fosfórico Hidrolases/genética , Diester Fosfórico Hidrolases/metabolismo
5.
Maturitas ; 137: 11-17, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32498931

RESUMO

Mutation of BRCA genes significantly increases the lifetime risk of breast, ovarian, fallopian tube and primary peritoneal cancers. In addition to the increased risk of these multiple malignancies, the recent literature suggests that mutations in BRCA genes may lead to decreased reproductive potential. In this systematic review, we focus on the effect of BRCA gene mutation on reproductive potential. The main outcomes included the rate of nulliparity, ovarian reserve, ovarian response, and the age at natural menopause. A total of 23 observational studies were included for quality analysis. The certainty of evidence was low to moderate: the main limitations were imprecision and statistically significant heterogeneity. Meta-analysis suggested that the rate of nulliparity, serum anti-müllerian hormone levels, antral follicle counts and ovarian response were not significantly affected in BRCA gene mutation carriers (P > 0.05). BRCA gene mutation carriers tended to have a lower number of primordial follicles (P = 0.0002) and lower age at natural menopause than non-carriers. In conclusion, there is no compelling evidence indicating that the rate of nulliparity, serum AMH, antral follicle counts and ovarian response are affected in BRCA mutation carriers.


Assuntos
Genes BRCA1 , Genes BRCA2 , Fenômenos Reprodutivos Fisiológicos/genética , Hormônio Antimülleriano/sangue , Feminino , Humanos , Menopausa/genética , Mutação , Folículo Ovariano , Reserva Ovariana/genética , Paridade/genética
6.
Mol Biol (Mosk) ; 54(2): 212-223, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32392190

RESUMO

To clarify genetic differences between subspecies of the house mouse Mus musculus, their distribution, and hybridization, we first conducted a comparative analysis of variability of nucleotide sequences of fragments of the nuclear gene Brca1, exon 11 (2331 bp), and mitochondrial gene Cox1 (1260 bp) in 40 house mice from West and East Europe, Transcaucasia, Siberia, and Central and South Asia. Brca1 genotypes were divided into five main groups, which differed in a number of fixed substitutions. Genotypes of each group are characteristic for the certain geographical region and the following subspecies: M. m. musculus, M. m. domesticus, M. m. castaneus, and M. m. wagneri together with M. m. gansuensis; a fifth group corresponds to an unidentified subspecies or a distinct genetic form of M. musculus from India (Sikkim State). Besides the homozygous specimens, we revealed mice, which were heterozygous for all diagnostic loci simultaneously; these specimens were determined as hybrid. Hybrid mice were mainly found in the zones of contact of subspecies, but in some cases, quite far from one of the parent subspecies (possibly, due to transportation). In two hybrid mice (from Bakhtiari Province of Iran and Transbaikalia of Russia), unique Brca1 haplotypes were detected. It cannot be ruled out that, at least partly, they may be characteristic of the M. m. bactrianus and M. m. gansuensis subspecies, respectively. Thus, the results of the study showed that the nuclear Brca1 gene is a promising molecular genetic marker for the analysis of variability, differentiation, and hybridization of house mice as well for subspecific identification of M. musculus specimens. Despite more rapid evolution of the Cox1 gene, it is not well suited for discrimination of M. m. musculus, M. m. wagneri, M. m. gansuensis specimens and Transcaucasian representatives of M. m. domesticus due to introgression and long-term maintenance of foreign mitochondrial DNA in populations. However, Cox1 gene analysis (along with the diagnostics of animals by nuclear DNA) may be useful for estimation of population differences in M. m. castaneus and M. m. domesticus subspecies.


Assuntos
Ciclo-Oxigenase 1/genética , Éxons , Genes BRCA1 , Genes Mitocondriais , Variação Genética , Proteínas de Membrana/genética , Camundongos/genética , Animais , Proteína BRCA1/genética , Genética Populacional , Haplótipos , Irã (Geográfico) , Federação Russa , Sibéria
7.
Mol Cell ; 78(6): 1070-1085, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32459988

RESUMO

Anti-cancer drugs targeting the DNA damage response (DDR) exploit genetic or functional defects in this pathway through synthetic lethal mechanisms. For example, defects in homologous recombination (HR) repair arise in cancer cells through inherited or acquired mutations in BRCA1, BRCA2, or other genes in the Fanconi anemia/BRCA pathway, and these tumors have been shown to be particularly sensitive to inhibitors of the base excision repair (BER) protein poly (ADP-ribose) polymerase (PARP). Recent work has identified additional genomic and functional assays of DNA repair that provide new predictive and pharmacodynamic biomarkers for these targeted therapies. Here, we examine the development of selective agents targeting DNA repair, including PARP inhibitors; inhibitors of the DNA damage kinases ataxia-telangiectasia and Rad3 related (ATR), CHK1, WEE1, and ataxia-telangiectasia mutated (ATM); and inhibitors of classical non-homologous end joining (cNHEJ) and alternative end joining (Alt EJ). We also review the biomarkers that guide the use of these agents and current clinical trials with these therapies.


Assuntos
Reparo do DNA/efeitos dos fármacos , Reparo do DNA/fisiologia , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/uso terapêutico , Biomarcadores Farmacológicos , Dano ao DNA/efeitos dos fármacos , Reparo do DNA por Junção de Extremidades/efeitos dos fármacos , Reparo do DNA/genética , Genes BRCA1/efeitos dos fármacos , Recombinação Homóloga , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo
9.
Best Pract Res Clin Obstet Gynaecol ; 65: 139-153, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32245629

RESUMO

Germline mutations in cancer-susceptibility-genes (CSG) can dramatically increase womens' lifetime risk of ovarian, endometrial, breast and bowel cancers. Identification of unaffected carriers is important to enable proactive engagement with highly effective screening and preventive options to minimise cancer risk. Currently, a family-history model is used to identify individuals with CSGs. Complex regional referral guidelines specify the family-history criteria required before an individual is eligible for genetic-testing. This model is ineffective, resource intense, misses >50% CSG carriers, is associated with underutilisation of genetic-testing services and delays detection of mutation carriers. Although awareness and detection of CSG-carriers has improved, over 97% carriers remain unidentified. This reflects significant missed opportunities for precision-prevention. Population-based genetic-testing (PBGT) represents a novel healthcare strategy with the potential to dramatically improve detection of unaffected CSG-carriers along with enabling population risk-stratification for cancer precision-prevention. Several research studies have assessed the impact, feasibility, acceptability, long-term psychological outcomes and cost-effectiveness of population-based BRCA-testing in the Ashkenazi-Jewish population. Initial data on PBGT in the general-population is beginning to emerge and large implementation studies investigating PBGT in the general-population are needed. This review will summarise the current research into the clinical, psycho-social, health-economic, societal and ethical consequences of a PBGT model for women's cancer precision-prevention.


Assuntos
Neoplasias da Mama/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Predisposição Genética para Doença/etnologia , Testes Genéticos/métodos , Genética Populacional , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Neoplasias Ovarianas/genética , Neoplasias da Mama/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/etnologia , Detecção Precoce de Câncer , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença/genética , Síndrome Hereditária de Câncer de Mama e Ovário/etnologia , Humanos , Mutação , Neoplasias , Neoplasias Ovarianas/diagnóstico
10.
N Engl J Med ; 382(22): 2091-2102, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32343890

RESUMO

BACKGROUND: Multiple loss-of-function alterations in genes that are involved in DNA repair, including homologous recombination repair, are associated with response to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition in patients with prostate and other cancers. METHODS: We conducted a randomized, open-label, phase 3 trial evaluating the PARP inhibitor olaparib in men with metastatic castration-resistant prostate cancer who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). All the men had a qualifying alteration in prespecified genes with a direct or indirect role in homologous recombination repair. Cohort A (245 patients) had at least one alteration in BRCA1, BRCA2, or ATM; cohort B (142 patients) had alterations in any of 12 other prespecified genes, prospectively and centrally determined from tumor tissue. Patients were randomly assigned (in a 2:1 ratio) to receive olaparib or the physician's choice of enzalutamide or abiraterone (control). The primary end point was imaging-based progression-free survival in cohort A according to blinded independent central review. RESULTS: In cohort A, imaging-based progression-free survival was significantly longer in the olaparib group than in the control group (median, 7.4 months vs. 3.6 months; hazard ratio for progression or death, 0.34; 95% confidence interval, 0.25 to 0.47; P<0.001); a significant benefit was also observed with respect to the confirmed objective response rate and the time to pain progression. The median overall survival in cohort A was 18.5 months in the olaparib group and 15.1 months in the control group; 81% of the patients in the control group who had progression crossed over to receive olaparib. A significant benefit for olaparib was also seen for imaging-based progression-free survival in the overall population (cohorts A and B). Anemia and nausea were the main toxic effects in patients who received olaparib. CONCLUSIONS: In men with metastatic castration-resistant prostate cancer who had disease progression while receiving enzalutamide or abiraterone and who had alterations in genes with a role in homologous recombination repair, olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone. (Funded by AstraZeneca and Merck Sharp & Dohme; PROfound ClinicalTrials.gov number, NCT02987543.).


Assuntos
Antineoplásicos/uso terapêutico , Mutação com Perda de Função , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Androstenos/efeitos adversos , Androstenos/uso terapêutico , Antineoplásicos/efeitos adversos , Proteínas Mutadas de Ataxia Telangiectasia/genética , Genes BRCA1 , Genes BRCA2 , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Feniltioidantoína/efeitos adversos , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Intervalo Livre de Progressão , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia
11.
Best Pract Res Clin Obstet Gynaecol ; 65: 125-138, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32122773

RESUMO

As the treatment of epithelial ovarian cancer (OC) moves further into personalised medicine, the importance of determining the presence or absence of inherited mutations in cancer susceptibility genes has grown. It is now becoming routine to test for germline mutations in the BRCA1 and BRCA2 genes, which are responsible for a significant proportion of hereditary epithelial OC and are established predictive biomarkers of potential benefit from poly ADP ribose polymerase (PARP) inhibitors. The identification of patients with hereditary OC allows the patient to benefit from personalised treatment, while allowing family members to undergo cascade testing, where identification of unaffected carriers can allow early detection, risk-reduction or prevention for both breast and OC, and ultimately improve long-term outcomes. Other susceptibility genes, include the Lynch Syndrome (mismatch repair) genes and several other genes involved in the homologous recombination pathway (HRD genes), are implicated in OC genesis, and are also becoming of increasing interest as therapeutic options grow for these patients. This review will highlight the importance of the early detection of a germline gene pathogenic variant, which informs on the clinical course of disease in a particular patient, and therefore, guides therapeutic management including risk reducing and personalised treatment.


Assuntos
Carcinoma Epitelial do Ovário/genética , Predisposição Genética para Doença , Testes Genéticos/métodos , Neoplasias Ovarianas/genética , Carcinoma Epitelial do Ovário/diagnóstico , Feminino , Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Humanos , Neoplasias Ovarianas/diagnóstico
12.
Magy Onkol ; 64(1): 13-24, 2020 Mar 17.
Artigo em Húngaro | MEDLINE | ID: mdl-32181758

RESUMO

Germinal or somatic mutations of the BRCA genes may serve as therapeutic targets. Deficient functioning of the BRCA genes render the cancer vulnerable to such therapeutic interventions as chemotherapy with DNA-targeted agents and PARP inhibitors targeting DNA repair capacity. Although BRCA mutations may be detected in a large variety of cancers, the mentioned specific therapies are efficient in the so called BRCA-associated cancers only including ovarian, breast, pancreatic, prostate cancers and the rare uterine sarcomas. While in ovarian and prostate carcinomas both germinal and somatic, in breast and pancreatic cancers exclusively germinal, and in uterine sarcomas mostly somatic mutations specify the tumor as BRCA-dependent; platinum-sensitivity in ovarian cancer may replace BRCA testing by indicating the presence of frequent DNA repair deficiency. Platinum-based chemotherapy is frequently efficient in BRCA-dependent cancers, while PARP inhibitors yet registered for ovarian, breast and pancreatic cancers bring paradigm change in the treatment of ovarian cancer and provide an additional treatment option of the others.


Assuntos
Genes BRCA1 , Genes BRCA2 , Mutação/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Platina/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Humanos
14.
Obstet Gynecol ; 135(4): 853-868, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32168205

RESUMO

Increasing numbers of women experience early menopause due in part to surgical treatment for benign gynecologic disorders and the rise in risk-reducing bilateral salpingo-oophorectomy in women with BRCA mutations. Unfortunately, the adverse health consequences of early loss of ovarian function accelerate the menopausal state and affect multiple systems, including cardiovascular, neurologic, bone, and connective tissue, and affect quality of life owing to vasomotor symptoms, mood, sleep, and sexual function. Yet many clinicians and women remain reluctant to use hormone therapy because of the Women's Health Initiative's adverse findings, even though they are not applicable to women with early menopause. This review examines the effects of early menopause and highlights the critical role of hormone therapy in this population.


Assuntos
Terapia de Reposição de Estrogênios , Menopausa Precoce , Neoplasias Ovarianas/genética , Salpingo-Ooforectomia/efeitos adversos , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos
18.
JAMA ; 323(7): 646-655, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32068819

RESUMO

Importance: Preclinical and epidemiological studies indicate a potential chemopreventive role of statins in epithelial ovarian cancer risk. Objective: To evaluate the association of genetically proxied inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (ie, genetic variants related to lower function of HMG-CoA reductase, target of statins) with epithelial ovarian cancer among the general population and in BRCA1/2 mutation carriers. Design, Setting, and Participants: Single-nucleotide polymorphisms (SNPs) in HMGCR, NPC1L1, and PCSK9 associated with low-density lipoprotein (LDL) cholesterol in a genome-wide association study (GWAS) meta-analysis (N ≤196 475) were used to proxy therapeutic inhibition of HMG-CoA reductase, Niemann-Pick C1-Like 1 (NPC1L1) and proprotein convertase subtilisin/kexin type 9 (PCSK9), respectively. Summary statistics were obtained for these SNPs from a GWAS meta-analysis of case-control analyses of invasive epithelial ovarian cancer in the Ovarian Cancer Association Consortium (OCAC; N = 63 347) and from a GWAS meta-analysis of retrospective cohort analyses of epithelial ovarian cancer among BRCA1/2 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA; N = 31 448). Across the 2 consortia, participants were enrolled between 1973 and 2014 and followed up through 2015. OCAC participants came from 14 countries and CIMBA participants came from 25 countries. SNPs were combined into multi-allelic models and mendelian randomization estimates representing lifelong inhibition of targets were generated using inverse-variance weighted random-effects models. Exposures: Primary exposure was genetically proxied inhibition of HMG-CoA reductase and secondary exposures were genetically proxied inhibition of NPC1L1 and PCSK9 and genetically proxied circulating LDL cholesterol levels. Main Outcomes and Measures: Overall and histotype-specific invasive epithelial ovarian cancer (general population) and epithelial ovarian cancer (BRCA1/2 mutation carriers), measured as ovarian cancer odds (general population) and hazard ratio (BRCA1/2 mutation carriers). Results: The OCAC sample included 22 406 women with invasive epithelial ovarian cancer and 40 941 control individuals and the CIMBA sample included 3887 women with epithelial ovarian cancer and 27 561 control individuals. Median ages for the cohorts ranged from 41.5 to 59.0 years and all participants were of European ancestry. In the primary analysis, genetically proxied HMG-CoA reductase inhibition equivalent to a 1-mmol/L (38.7-mg/dL) reduction in LDL cholesterol was associated with lower odds of epithelial ovarian cancer (odds ratio [OR], 0.60 [95% CI, 0.43-0.83]; P = .002). In BRCA1/2 mutation carriers, genetically proxied HMG-CoA reductase inhibition was associated with lower ovarian cancer risk (hazard ratio, 0.69 [95% CI, 0.51-0.93]; P = .01). In secondary analyses, there were no significant associations of genetically proxied inhibition of NPC1L1 (OR, 0.97 [95% CI, 0.53-1.75]; P = .91), PCSK9 (OR, 0.98 [95% CI, 0.85-1.13]; P = .80), or circulating LDL cholesterol (OR, 0.98 [95% CI, 0.91-1.05]; P = .55) with epithelial ovarian cancer. Conclusions and Relevance: Genetically proxied inhibition of HMG-CoA reductase was significantly associated with lower odds of epithelial ovarian cancer. However, these findings do not indicate risk reduction from medications that inhibit HMG-CoA reductase; further research is needed to understand whether there is a similar association with such medications.


Assuntos
Carcinoma Epitelial do Ovário/prevenção & controle , Hidroximetilglutaril-CoA Redutases/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Neoplasias Ovarianas/prevenção & controle , Polimorfismo de Nucleotídeo Único , Adulto , Carcinoma Epitelial do Ovário/genética , Estudos de Casos e Controles , LDL-Colesterol/sangue , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Proteínas de Membrana Transportadoras/genética , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Mutação , Razão de Chances , Neoplasias Ovarianas/genética , Pró-Proteína Convertase 9/genética , Estudos Retrospectivos , Risco
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