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1.
Blood ; 133(10): 1130-1139, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30573632

RESUMO

Female Hodgkin lymphoma (HL) patients treated with chest radiotherapy (RT) have a very high risk of breast cancer. The contribution of genetic factors to this risk is unclear. We therefore examined 211 155 germline single-nucleotide polymorphisms (SNPs) for gene-radiation interaction on breast cancer risk in a case-only analysis including 327 breast cancer patients after chest RT for HL and 4671 first primary breast cancer patients. Nine SNPs showed statistically significant interaction with RT on breast cancer risk (false discovery rate, <20%), of which 1 SNP in the PVT1 oncogene attained the Bonferroni threshold for statistical significance. A polygenic risk score (PRS) composed of these SNPs (RT-interaction-PRS) and a previously published breast cancer PRS (BC-PRS) derived in the general population were evaluated in a case-control analysis comprising the 327 chest-irradiated HL patients with breast cancer and 491 chest-irradiated HL patients without breast cancer. Patients in the highest tertile of the RT-interaction-PRS had a 1.6-fold higher breast cancer risk than those in the lowest tertile. Remarkably, we observed a fourfold increased RT-induced breast cancer risk in the highest compared with the lowest decile of the BC-PRS. On a continuous scale, breast cancer risk increased 1.4-fold per standard deviation of the BC-PRS, similar to the effect size found in the general population. This study demonstrates that genetic factors influence breast cancer risk after chest RT for HL. Given the high absolute breast cancer risk in radiation-exposed women, these results can have important implications for the management of current HL survivors and future patients.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Doença de Hodgkin/genética , Doença de Hodgkin/radioterapia , Neoplasias Induzidas por Radiação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/etiologia , Sobreviventes de Câncer , Estudos de Casos e Controles , Feminino , Genótipo , Doença de Hodgkin/complicações , Humanos , Pessoa de Meia-Idade , Segunda Neoplasia Primária/genética , Razão de Chances , Polimorfismo de Nucleotídeo Único , Controle de Qualidade , Dosagem Radioterapêutica , Análise de Regressão , Risco , Adulto Jovem
2.
Gynecol Oncol ; 141(2): 386-401, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-25940428

RESUMO

OBJECTIVE: Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. METHODS: Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). RESULTS: We found no association with risk of ovarian cancer (OR=0.99, 95% CI 0.94-1.04, p=0.74) or breast cancer (OR=0.98, 95% CI 0.94-1.01, p=0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR=1.09, 95% CI 0.97-1.23, p=0.14, breast cancer HR=1.04, 95% CI 0.97-1.12, p=0.27; BRCA2, ovarian cancer HR=0.89, 95% CI 0.71-1.13, p=0.34, breast cancer HR=1.06, 95% CI 0.94-1.19, p=0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR=0.94, 95% CI 0.83-1.07, p=0.38), breast cancer (HR=0.96, 95% CI 0.87-1.06, p=0.38), and all other previously-reported associations. CONCLUSIONS: rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.


Assuntos
Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias Epiteliais e Glandulares/enzimologia , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Carcinoma Epitelial do Ovário , Feminino , Humanos
3.
Cancer Epidemiol Biomarkers Prev ; 24(1): 308-16, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25336561

RESUMO

BACKGROUND: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. METHODS: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. RESULTS: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. CONCLUSION: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. IMPACT: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.


Assuntos
Neoplasias da Mama/genética , Genes BRCA1/fisiologia , Genes BRCA2/fisiologia , Neoplasias Ovarianas/genética , Adulto , Estudos de Coortes , Feminino , Humanos , Mutação , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Adulto Jovem
4.
Int J Neuropsychopharmacol ; 16(3): 677-82, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22607776

RESUMO

In psychiatric practice, pharmacogenetics has the potential to identify patients with an increased risk of unsatisfactory drug responses. Genotype-guided treatment adjustments may increase benefits and reduce harm in these patients; however, pharmacogenetic testing is not (yet) common practice and more pharmacogenetic research in psychiatric patients is warranted. An important precondition for this type of research is the establishment of biobanks. In this paper, we argue that, for the storage of samples in psychiatric biobanks, waiving of consent is not ethically justifiable since the risks cannot be considered minimal and the argument of impracticability does not apply. An opt-out consent procedure is also not justifiable, since it presumes competence while the decisional competence of psychiatric patients needs to be carefully evaluated. We state that an enhanced opt-in consent procedure is ethically necessary, i.e. a procedure that supports the patients' decision-making at the time when the patient is most competent. Nevertheless, such a procedure is not the traditional exhaustive informed consent procedure, since this is not feasible in the case of biobanking.


Assuntos
Bancos de Espécimes Biológicos/ética , Pesquisa Biomédica/ética , Consentimento Livre e Esclarecido/ética , Transtornos Mentais/genética , Farmacogenética/ética , Adulto , Bancos de Espécimes Biológicos/tendências , Pesquisa Biomédica/tendências , Feminino , Humanos , Transtornos Mentais/diagnóstico , Transtornos Mentais/tratamento farmacológico , Farmacogenética/tendências
5.
Pharmacogenomics ; 13(5): 571-8, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22462749

RESUMO

Adaptive trial designs can be beneficial in pharmacogenetic research when prior uncertainty exists regarding the exact role and clinical relevance of genetic variability in drug response. This type of design enables us to learn about the effect of the genetic variability on drug response and to immediately use this information for the remainder of the study. For different types of adaptive trial designs, we discuss when and how the designs are suitable for pharmacogenetic research: adaptation of randomization, adaptation of patient enrollment and adaptive enrichment. To illustrate the potential benefits of an adaptive design over a fixed design, we simulated an adaptive trial based on the results of the IPASS trial. With a simple model we show that for this example an adaptive enrichment design would have led to a smaller trial, with less EGF receptor mutation-negative patients unnecessarily exposed to the drug, without compromising the α level or reducing power.


Assuntos
Simulação por Computador , Relação Dose-Resposta a Droga , Farmacogenética/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Avaliação de Medicamentos , Determinação de Ponto Final , Humanos , Tamanho da Amostra
6.
Pharmacogenomics ; 12(10): 1485-92, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22008051

RESUMO

Pharmacogenetic analyses of clinical trials aim to either detect whether a subgroup of patients identified by genetic characteristics responds differently to the treatment or to verify whether a proposed genotype-guided treatment is beneficial over standard care. This article describes three different trial designs, differing in the timing of randomization and genotyping. Each design has its own advantages, and the objectives and conditions under which each one is most suited are discussed.


Assuntos
Farmacogenética , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Genótipo , Técnicas de Genotipagem , Humanos , Pesquisa Médica Translacional
7.
Int J Artif Organs ; 32(11): 787-93, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20020410

RESUMO

PURPOSE: Hemoglobin cycling has been reported in hemodialysis patients treated with erythropoiesis-stimulating agents (ESA) and is associated with increased mortality. Information on hemoglobin cycling in Europe is limited. We investigated hemoglobin variability in the Netherlands. Hemodialysis and peritoneal dialysis patients were studied and pre-dialysis patients were enrolled. METHODS: This observational retrospective study was executed in a Dutch dialysis center. We studied 157 patients from 2005 to 2007: 56 hemodialysis, 12 peritoneal dialysis and 29 pre-dialysis patients, all treated with ESA; and 60 pre-dialysis patients without ESA. Patients were divided on the basis of their pattern of hemoglobin fluctuation around a range of 11-12 g/dL. In dialysis patients, the amount of time that hemoglobin remained within that range was calculated. For all patients, the magnitude of hemoglobin fluctuations was assessed (i.e. the difference between hemoglobin maximum and minimum) and data on ESA dose changes and hospitalizations were collected. RESULTS: None of the ESA treated patients had hemoglobin levels stable within the target range over a one-year period. Pre-dialysis patients without ESA also showed variable hemoglobin levels. A stepwise decrease in the magnitudes of hemoglobin fluctuation was observed in the hemodialysis patients, peritoneal dialysis patients, pre-dialysis patients using ESA, and the pre-dialysis patients without ESA, respectively. CONCLUSION: In the Netherlands, hemoglobin variability is common in hemodialysis and peritoneal dialysis patients, but also in pre-dialysis patients. The results of this study warrant further research into the relationship between hemoglobin variability and clinical outcomes.


Assuntos
Hematínicos/uso terapêutico , Hemoglobinas/metabolismo , Falência Renal Crônica/terapia , Diálise Peritoneal , Diálise Renal , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Humanos , Falência Renal Crônica/sangue , Masculino , Pessoa de Meia-Idade , Países Baixos , Guias de Prática Clínica como Assunto , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
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