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1.
JMIR Res Protoc ; 10(1): e24414, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33480862

RESUMO

BACKGROUND: BRCA1/2 mutation carriers are recommended to undergo risk-reducing salpingo-oophorectomy (RRSO) at 35 to 45 years of age. RRSO substantially decreases ovarian cancer risk, but at the cost of immediate menopause. Knowledge about the potential adverse effects of premenopausal RRSO, such as increased risk of cardiovascular disease, osteoporosis, cognitive dysfunction, and reduced health-related quality of life (HRQoL), is limited. OBJECTIVE: The aim of this study is to assess the long-term health effects of premenopausal RRSO on cardiovascular disease, bone health, cognitive functioning, urological complaints, sexual functioning, and HRQoL in women with high familial risk of breast or ovarian cancer. METHODS: We will conduct a multicenter cross-sectional study with prospective follow-up, nested in a nationwide cohort of women at high familial risk of breast or ovarian cancer. A total of 500 women who have undergone RRSO before 45 years of age, with a follow-up period of at least 10 years, will be compared with 250 women (frequency matched on current age) who have not undergone RRSO or who have undergone RRSO at over 55 years of age. Participants will complete an online questionnaire on lifestyle, medical history, cardiovascular risk factors, osteoporosis, cognitive function, urological complaints, and HRQoL. A full cardiovascular assessment and assessment of bone mineral density will be performed. Blood samples will be obtained for marker analysis. Cognitive functioning will be assessed objectively with an online neuropsychological test battery. RESULTS: This study was approved by the institutional review board in July 2018. In February 2019, we included our first participant. As of November 2020, we had enrolled 364 participants in our study. CONCLUSIONS: Knowledge from this study will contribute to counseling women with a high familial risk of breast/ovarian cancer about the long-term health effects of premenopausal RRSO. The results can also be used to offer health recommendations after RRSO. TRIAL REGISTRATION: ClinicalTrials.gov NCT03835793; https://clinicaltrials.gov/ct2/show/NCT03835793. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/24414.

2.
J Community Genet ; 2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32880035

RESUMO

Individuals having a genetic predisposition to cancer and their partners face challenging decisions regarding their wish to have children. This study aimed to determine the effects of an online decision aid to support couples in making an informed decision regarding their reproductive options. A nationwide pretest-posttest study was conducted in the Netherlands among 131 participants between November 2016 and May 2018. Couples were eligible for participation if one partner had a pathogenic variant predisposing for an autosomal dominant hereditary cancer syndrome. Participants completed a questionnaire before use (T0), and at 3 months (T3) after use of the decision aid to assess the primary outcome measure informed decision-making, and the secondary outcome measures decisional conflict, knowledge, realistic expectations, level of deliberation, and decision self-efficacy. T0-T3 comparisons show an overall positive effect for all outcome measures (all ps < 0.05; knowledge (ES = - 1.05), decisional conflict (ES = 0.99), participants' decision self-efficacy (ES = -0.55), level of deliberation (ES = - 0.50), and realistic expectations (ES = - 0.44). Informed decision-making increased over time and 58.0% of the participants made an informed reproductive decision at T3. The online decision aid seems to be an appropriate tool to complement standard reproductive counseling to support our target group in making an informed reproductive decision. Use of the decision aid may lessen the negative psychological impact of decision-making on couples' daily life and wellbeing.

3.
Breast Cancer Res Treat ; 177(3): 723-733, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31302855

RESUMO

BACKGROUND: In healthy BRCA1/2 mutation carriers, bilateral risk-reducing mastectomy (BRRM) strongly reduces the risk of developing breast cancer (BC); however, no clear survival benefit of BRRM over BC surveillance has been reported yet. METHODS: In this Dutch multicenter cohort study, we used multivariable Cox models with BRRM as a time-dependent covariable to estimate the associations between BRRM and the overall and BC-specific mortality rates, separately for BRCA1 and BRCA2 mutation carriers. RESULTS: During a mean follow-up of 10.3 years, 722 out of 1712 BRCA1 (42%) and 406 out of 1145 BRCA2 (35%) mutation carriers underwent BRRM. For BRCA1 mutation carriers, we observed 52 deaths (20 from BC) in the surveillance group, and 10 deaths (one from BC) after BRRM. The hazard ratios were 0.40 (95% CI 0.20-0.90) for overall mortality and 0.06 (95% CI 0.01-0.46) for BC-specific mortality. BC-specific survival at age 65 was 93% for surveillance and 99.7% for BRRM. For BRCA2 mutation carriers, we observed 29 deaths (7 from BC) in the surveillance group, and 4 deaths (no BC) after BRRM. The hazard ratio for overall mortality was 0.45 (95% CI 0.15-1.36). BC-specific survival at age 65 was 98% for surveillance and 100% for BRRM. CONCLUSION: BRRM was associated with lower mortality than surveillance for BRCA1 mutation carriers, but for BRCA2 mutation carriers, BRRM may lead to similar BC-specific survival as surveillance. Our findings support a more individualized counseling based on BRCA mutation type.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/etiologia , Neoplasias da Mama/prevenção & controle , Heterozigoto , Mutação , Mastectomia Profilática , Neoplasias da Mama/mortalidade , Neoplasias da Mama/cirurgia , Feminino , Mutação em Linhagem Germinativa , Humanos , Mortalidade , Países Baixos/epidemiologia , Prognóstico , Mastectomia Profilática/métodos , Vigilância em Saúde Pública , Comportamento de Redução do Risco
4.
J Genet Couns ; 28(3): 533-542, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30629779

RESUMO

A nationwide pretest-posttest study was conducted in all clinical genetic centres in the Netherlands, to evaluate the effects of an online decision aid to support persons who have a genetic predisposition to cancer and their partners in making an informed decision regarding reproductive options. Main outcomes (decisional conflict, knowledge, realistic expectations, level of deliberation, and decision self-efficacy) were measured before use (T0), immediately after use (T1), and at 2 weeks (T2) after use of the decision aid. Paired sample t tests were used to compute differences between the first and subsequent measurements. T0-T1 and T0-T2 comparisons indicate a significant reduction in mean decisional conflict scores with stronger effects for participants with high baseline decisional conflict. Furthermore, use of the decision aid resulted in increased knowledge levels and improved realistic expectations. Level of deliberation only increased for participants with lower baseline levels of deliberation. Decision self-efficacy increased for those with low baseline scores, whereas those with high baseline scores showed a reduction at T2. It can be concluded that use of the decision aid resulted in several positive outcomes indicative of informed decision-making. The decision aid is an appropriate and highly appreciated tool to be used in addition to reproductive counseling.


Assuntos
Técnicas de Apoio para a Decisão , Predisposição Genética para Doença , Neoplasias/genética , Sistemas On-Line , Participação do Paciente , Reprodução , Adulto , Feminino , Humanos , Masculino , Países Baixos , Parceiros Sexuais
5.
Fam Cancer ; 18(1): 137-146, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29846879

RESUMO

An online decision aid to support persons having a genetic predisposition to cancer and their partners during reproductive decision-making was developed. A two-phase usability test was conducted among 12 couples (N = 22; 2 persons participated without their partner) at risk for hereditary cancer and 15 health care providers. Couples and health care providers expressed similar suggestions for improvements, and evaluated the modified decision aid as acceptable, easy to use, and comprehensible. The final decision aid was pilot tested (N = 16) with paired sample t tests comparing main outcomes (decisional conflict, knowledge, realistic expectations regarding the reproductive options and decision self-efficacy) before (T0), immediately (T1) and 2 weeks after (T2) use of the decision aid. Pilot testing indicated decreased decisional conflict scores, increased knowledge, and improved realistic expectations regarding the reproductive options, at T1 and T2. No effect was found for couples' decision self-efficacy. The positive findings during usability testing were thus reflected in the pilot study. The decision aid will be further evaluated in a nationwide pretest-posttest study to facilitate implementation in the onco-genetic counselling setting. Ultimately, it is expected that the decision aid will enable end-users to make an informed decision.


Assuntos
Tomada de Decisões , Técnicas de Apoio para a Decisão , Predisposição Genética para Doença , Síndromes Neoplásicas Hereditárias/genética , Reprodução/genética , Adulto , Feminino , Aconselhamento Genético/métodos , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Internet , Masculino , Projetos Piloto
6.
Nat Genet ; 50(7): 968-978, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29915430

RESUMO

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10-6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.


Assuntos
Neoplasias da Mama/genética , Estudos de Casos e Controles , Feminino , Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Humanos , Polimorfismo de Nucleotídeo Único , Risco , Transcriptoma
7.
Br J Cancer ; 119: 357-363, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29937543

RESUMO

BACKGROUND: The effect of in vitro fertilisation (IVF) on breast cancer risk for BRCA1/2 mutation carriers is rarely examined. As carriers may increasingly undergo IVF as part of preimplantation genetic diagnosis (PGD), we examined the impact of ovarian stimulation for IVF on breast cancer risk in BRCA1/2 mutation carriers. METHODS: The study population consisted of 1550 BRCA1 and 964 BRCA2 mutation carriers, derived from the nationwide HEBON study and the nationwide PGD registry. Questionnaires, clinical records and linkages with the Netherlands Cancer Registry were used to collect data on IVF exposure, risk-reducing surgeries and cancer diagnosis, respectively. Time-dependent Cox regression analyses were conducted, stratified for birth cohort and adjusted for subfertility. RESULTS: Of the 2514 BRCA1/2 mutation carriers, 3% (n = 76) were exposed to ovarian stimulation for IVF. In total, 938 BRCA1/2 mutation carriers (37.3%) were diagnosed with breast cancer. IVF exposure was not associated with risk of breast cancer (HR: 0.79, 95% CI: 0.46-1.36). Similar results were found for the subgroups of subfertile women (n = 232; HR: 0.73, 95% CI: 0.39-1.37) and BRCA1 mutation carriers (HR: 1.12, 95% CI: 0.60-2.09). In addition, age at and recency of first IVF treatment were not associated with breast cancer risk. CONCLUSION: No evidence was found for an association between ovarian stimulation for IVF and breast cancer risk in BRCA1/2 mutation carriers.


Assuntos
Neoplasias da Mama/etiologia , Fertilização In Vitro/efeitos adversos , Genes BRCA1 , Genes BRCA2 , Heterozigoto , Mutação , Indução da Ovulação , Adulto , Idoso , Neoplasias da Mama/genética , Feminino , Humanos , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Risco
8.
J Med Genet ; 55(1): 15-20, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28490613

RESUMO

BACKGROUND: We previously showed that the BRCA1 variant c.5096G>A p.Arg1699Gln (R1699Q) was associated with an intermediate risk of breast cancer (BC) and ovarian cancer (OC). This study aimed to assess these cancer risks for R1699Q carriers in a larger cohort, including follow-up of previously studied families, to further define cancer risks and to propose adjusted clinical management of female BRCA1*R1699Q carriers. METHODS: Data were collected from 129 BRCA1*R1699Q families ascertained internationally by ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium members. A modified segregation analysis was used to calculate BC and OC risks. Relative risks were calculated under both monogenic model and major gene plus polygenic model assumptions. RESULTS: In this cohort the cumulative risk of BC and OC by age 70 years was 20% and 6%, respectively. The relative risk for developing cancer was higher when using a model that included the effects of both the R1699Q variant and a residual polygenic component compared with monogenic model (for BC 3.67 vs 2.83, and for OC 6.41 vs 5.83). CONCLUSION: Our results confirm that BRCA1*R1699Q confers an intermediate risk for BC and OC. Breast surveillance for female carriers based on mammogram annually from age 40 is advised. Bilateral salpingo-oophorectomy should be considered based on family history.


Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença , Mutação/genética , Neoplasias Ovarianas/genética , Segregação de Cromossomos , Feminino , Humanos , Fatores de Risco
9.
Cancer Epidemiol Biomarkers Prev ; 23(11): 2482-91, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25103822

RESUMO

BACKGROUND: We aimed to quantify previously observed relatively high cancer risks in BRCA2 mutation carriers (BRCA2 carriers) older than 60 in the Northern Netherlands, and to analyze whether these could be explained by mutation spectrum or population background risk. METHODS: This consecutive cohort study included all known pathogenic BRCA1/2 carriers in the Northern Netherlands (N = 1,050). Carrier and general reference populations were: BRCA1/2 carriers in the rest of the Netherlands (N = 2,013) and the general population in both regions. Regional differences were assessed with HRs and ORs. HRs were adjusted for birth year and mutation spectrum. RESULTS: All BRCA1 carriers and BRCA2 carriers younger than 60 had a significantly lower breast cancer risk in the Northern Netherlands; HRs were 0.66 and 0.64, respectively. Above age 60, the breast cancer risk in BRCA2 carriers in the Northern Netherlands was higher than in the rest of the Netherlands [HR, 3.99; 95% confidence interval (CI), 1.11-14.35]. Adjustment for mutational spectrum changed the HRs for BRCA1, BRCA2 <60, and BRCA2 ≥60 years by -3%, +32%, and +11% to 0.75, 0.50, and 2.61, respectively. There was no difference in background breast cancer incidence between the two regions (OR, 1.03; 95% CI, 0.97-1.09). CONCLUSIONS: Differences in mutation spectrum only partly explain the regional differences in breast cancer risk in BRCA2 carriers, and for an even smaller part in BRCA1 carriers. IMPACT: The increased risk in BRCA2 carriers older than 60 may warrant extension of intensive breast screening beyond age 60.


Assuntos
Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/epidemiologia , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Humanos , Mutação , Países Baixos , Fatores de Risco
10.
J Med Genet ; 51(2): 98-107, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24285858

RESUMO

BACKGROUND: BRCA1 or BRCA2 mutations confer increased risks of breast and ovarian cancer, but risks have been found to vary across studies and populations. METHODS: We ascertained pedigree data of 582 BRCA1 and 176 BRCA2 families and studied the variation in breast and ovarian cancer risks using a modified segregation analysis model. RESULTS: The average cumulative breast cancer risk by age 70 years was estimated to be 45% (95% CI 36 to 52%) for BRCA1 and 27% (95% CI 14 to 38%) for BRCA2 mutation carriers. The corresponding cumulative risks for ovarian cancer were 31% (95% CI 17 to 43%) for BRCA1 and 6% (95% CI 2 to 11%) for BRCA2 mutation carriers. In BRCA1 families, breast cancer relative risk (RR) increased with more recent birth cohort (p heterogeneity = 0.0006) and stronger family histories of breast cancer (p heterogeneity < 0.001). For BRCA1, our data suggest a significant association between the location of the mutation and the ratio of breast to ovarian cancer (p<0.001). By contrast, in BRCA2 families, no evidence was found for risk heterogeneity by birth cohort, family history or mutation location. CONCLUSIONS: BRCA1 mutation carriers conferred lower overall breast and ovarian cancer risks than reported so far, while the estimates of BRCA2 mutations were among the lowest. The low estimates for BRCA1 might be due to older birth cohorts, a moderate family history, or founder mutations located within specific regions of the gene. These results are important for a more accurate counselling of BRCA1/2 mutation carriers.


Assuntos
Efeito Fundador , Genes BRCA1 , Genes BRCA2 , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Adulto , Distribuição por Idade , Idade de Início , Idoso , Estudos de Coortes , Feminino , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Humanos , Pessoa de Meia-Idade , Mutação , Países Baixos/epidemiologia , Linhagem , Risco , Adulto Jovem
11.
Cancer ; 119(5): 955-62, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23165859

RESUMO

BACKGROUND: The objective of this study was to assess the incidence of primary breast cancer (PBC) and contralateral breast cancer (CBC) in patients who had BRCA1/BRCA2-associated epithelial ovarian cancer (OC). METHODS: From the database of the Rotterdam Family Cancer Clinic, patients who had BRCA-associated OC without a history of unilateral breast cancer (BC) (at risk of PBC; n = 79) or with a history of unilateral BC (at risk of CBC; n = 37) were selected. The control groups consisted of unaffected BRCA mutation carriers (n = 351) or mutation carriers who had a previous unilateral BC (n = 294), respectively. The risks of PBC and CBC were calculated using the Kaplan-Meier survival method with death considered as a competing risk event. RESULTS: Women with BRCA-associated OC had lower 2-year, 5-year, and 10-year risks of PBC (3%, 6%, and 11%, respectively) compared with unaffected mutation carriers (6%, 16%, and 28%, respectively; P = .03), although they had a considerably higher mortality rate at similar time points (13%, 33%, and 61%, respectively, vs 1%, 2%, and 2%, respectively; P < .001). In BRCA mutation carriers with a previous unilateral BC, the 2-year, 5-year, and 10-year risks of CBC were nonsignificantly lower in patients with OC than in those without OC (0%, 7%, and 7%, respectively, vs 6%, 16%, and 34%, respectively; P = .06), whereas the mortality rate was higher in patients with OC (19%, 34%, and 55%, respectively, vs 4%, 11%, and 21%, respectively; P < .001). CONCLUSIONS: Patients with BRCA-associated OC had a lower risk of developing a subsequent PBC or CBC than mutation carriers without OC, whereas the risk of dying from OC was greater than the risk of developing BC. These data may facilitate more tailored counseling for this patient subgroup, although confirmative studies are warranted.


Assuntos
Neoplasias da Mama/secundário , Neoplasias Ovarianas/genética , Adolescente , Adulto , Idoso , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/prevenção & controle , Criança , Pré-Escolar , Feminino , Genes BRCA1 , Genes BRCA2 , Aconselhamento Genético , Heterozigoto , Humanos , Lactente , Pessoa de Meia-Idade , Mutação , Neoplasias Primárias Múltiplas/epidemiologia , Neoplasias Ovarianas/patologia , Risco , Adulto Jovem
12.
Psychooncology ; 22(4): 902-10, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22740372

RESUMO

BACKGROUND: Several studies have shown that counselees do not experience psychopathological levels of distress after DNA test result disclosure. However, it has not systematically been studied whether the absence of psychopathology also means that counselees do not want to receive help. Their self-reported request for help may be related not only with psychopathology/distress but also with other psychological needs (e.g., surgery decisions), genetics-specific needs (e.g., feeling vulnerable/stigmatized), and existential concerns (e.g., meaning in life). METHODS: Questionnaires were filled in by Dutch cancer patients, before and after disclosure of BRCA1/2 test results for hereditary breast/ovarian cancer: pathogenic mutation results (n = 30), uninformative results (n = 202), or unclassified variants (n = 16). Newly developed questions measured request for help, psychopathology was estimated with factor analyses on distress/psychopathology instruments, and several validated questionnaires measured other needs/concerns. RESULTS: One-third of all counselees who reported a request for psychological help had actually received help. The level of psychopathology correlated between 0.34 and 0.44 with this self-reported need-for-help. Other needs, genetics-specific distress, and existential concerns correlated strongly/moderately with the counselees' self-reported need-for-help. Examples of other needs were intention to undergo surgery, inaccuracy of their interpretation, the impact of cancer, and family communication difficulties. Genetics-specific distress was for instance feeling vulnerable to develop cancer, stigma, and lack of mastery. Existential concerns were, among others, lack of purpose in life, low self-acceptance, and an unfulfilled wish for certainty. CONCLUSIONS: The request for help is related to multiple factors. Referral to psychosocial professionals may be improved by not only discussing psychopathology during genetic-counseling sessions but also by other needs and existential concerns. Questions about other needs and existential issues may be added to psychological screening instruments.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/psicologia , Aconselhamento Genético/psicologia , Predisposição Genética para Doença/psicologia , Neoplasias Ovarianas/psicologia , Estresse Psicológico , Proteína BRCA1/genética , Proteína BRCA2/genética , Comunicação , Análise Fatorial , Feminino , Testes Genéticos , Conhecimentos, Atitudes e Prática em Saúde , Necessidades e Demandas de Serviços de Saúde , Humanos , Países Baixos , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Educação de Pacientes como Assunto , Psicopatologia , Autorrelato , Inquéritos e Questionários
13.
J Med Genet ; 49(10): 618-20, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23054243

RESUMO

BACKGROUND: Recently, rare germline variants in XRCC2 were detected in non-BRCA1/2 familial breast cancer cases, and a significant association with breast cancer was reported. However, the breast cancer risk associated with these variants needs further evaluation. METHODS: The coding regions and exon-intron boundaries of XRCC2 were scanned for mutations in an international cohort of 3548 non-BRCA1/2 familial breast cancer cases and 1435 healthy controls using various mutation scanning methods. Predictions on functional relevance of detected missense variants were obtained from three different prediction algorithms. RESULTS: The only protein-truncating variant detected was found in a control. Rare non-protein-truncating variants were detected in 20 familial cases (0.6%) and nine healthy controls (0.6%). Although the number of variants predicted to be damaging or neutral differed between prediction algorithms, in all instances these categories were evenly represented among cases and controls. CONCLUSIONS: Our data do not confirm an association between XRCC2 variants and breast cancer risk, although a relative risk smaller than two could not be excluded. Variants in XRCC2 are unlikely to explain a substantial proportion of familial breast cancer.


Assuntos
Alelos , Neoplasias da Mama/genética , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Mutação , Feminino , Humanos , Fases de Leitura Aberta
14.
Patient Educ Couns ; 86(2): 239-51, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21684708

RESUMO

OBJECTIVE: Previous studies suggest that learning a DNA-test-result has no direct impact on the medical-decisions and psychological well-being of counselees. Their perception, especially their recollections and interpretations of their cancer-risks and heredity, predict and/or mediate this impact. These studies were criticized for their small range of predictors, mediators, outcomes and contextual factors. We studied the short-term impact of DNA-testing with an extended model. METHODS: Three months after disclosure of BRCA1/2-test-results, we sent counselees a questionnaire about their perception, medical and psychological outcomes, and medical, familial and psychological contexts. 248 affected women participated; 30 had received pathogenic-mutations, 16 unclassified-variants and 202 uninformative-results. RESULTS: The actually communicated genetic-information and the contextual variables predicted the counselees' perception, but did not directly predict any outcomes. The counselees' perception predicted and/or completely mediated the counselees' medical intentions and behavior, physical and psychological life-changes, stigma, mastery, negativity and cancer-worries. Short-term distress was related to the perception not only of their own risks, but also of their relatives' risks and heredity-likelihood. Effect sizes were medium to large. CONCLUSIONS AND IMPLICATIONS: The outcomes of DNA-testing were better predicted by the counselees' perception than by the actually given genetic-information. We recommend genetic-counselors to have tailored, interactive dialogues about the counselees' perception.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/psicologia , Rememoração Mental , Percepção , Adulto , Idoso , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Tomada de Decisões , Feminino , Aconselhamento Genético , Predisposição Genética para Doença , Testes Genéticos , Humanos , Pessoa de Meia-Idade , Modelos Teóricos , Análise de Regressão , Risco , Inquéritos e Questionários
15.
Nat Genet ; 43(2): 121-6, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21217753

RESUMO

Thoracic aortic aneurysms and dissections are a main feature of connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome. We delineated a new syndrome presenting with aneurysms, dissections and tortuosity throughout the arterial tree in association with mild craniofacial features and skeletal and cutaneous anomalies. In contrast with other aneurysm syndromes, most of these affected individuals presented with early-onset osteoarthritis. We mapped the genetic locus to chromosome 15q22.2-24.2 and show that the disease is caused by mutations in SMAD3. This gene encodes a member of the TGF-ß pathway that is essential for TGF-ß signal transmission. SMAD3 mutations lead to increased aortic expression of several key players in the TGF-ß pathway, including SMAD3. Molecular diagnosis will allow early and reliable identification of cases and relatives at risk for major cardiovascular complications. Our findings endorse the TGF-ß pathway as the primary pharmacological target for the development of new treatments for aortic aneurysms and osteoarthritis.


Assuntos
Aneurisma Aórtico/genética , Mutação , Osteoartrite/genética , Proteína Smad3/genética , Idade de Início , Aorta Torácica/metabolismo , Aneurisma Aórtico/complicações , Aneurisma Aórtico/diagnóstico por imagem , Cromossomos Humanos Par 15 , Saúde da Família , Feminino , Humanos , Imuno-Histoquímica/métodos , Masculino , Osteoartrite/complicações , Osteoartrite/metabolismo , Radiografia , Transdução de Sinais , Síndrome , Fator de Crescimento Transformador beta/metabolismo
16.
Eur J Hum Genet ; 18(9): 999-1005, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20531442

RESUMO

Holoprosencephaly is a severe malformation of the brain characterized by abnormal formation and separation of the developing central nervous system. The prevalence is 1:250 during early embryogenesis, the live-born prevalence is 1:16 000. The etiology of HPE is extremely heterogeneous and can be teratogenic or genetic. We screened four known HPE genes in a Dutch cohort of 86 non-syndromic HPE index cases, including 53 family members. We detected 21 mutations (24.4%), 3 in SHH, 9 in ZIC2 and 9 in SIX3. Eight mutations involved amino-acid substitutions, 7 ins/del mutations, 1 frame-shift, 3 identical poly-alanine tract expansions and 2 gene deletions. Pathogenicity of mutations was presumed based on de novo character, predicted non-functionality of mutated proteins, segregation of mutations with affected family-members or combinations of these features. Two mutations were reported previously. SNP array confirmed detected deletions; one spanning the ZIC2/ZIC5 genes (approx. 100 kb) the other a 1.45 Mb deletion including SIX2/SIX3 genes. The mutation percentage (24%) is comparable with previous reports, but we detected significantly less mutations in SHH: 3.5 vs 10.7% (P=0.043) and significantly more in SIX3: 10.5 vs 4.3% (P=0.018). For TGIF1 and ZIC2 mutation the rate was in conformity with earlier reports. About half of the mutations were de novo, one was a germ line mosaic. The familial mutations displayed extensive heterogeneity in clinical manifestation. Of seven familial index patients only two parental carriers showed minor HPE signs, five were completely asymptomatic. Therefore, each novel mutation should be considered as a risk factor for clinically manifest HPE, with the caveat of reduced clinical penetrance.


Assuntos
Proteínas do Olho/genética , Proteínas Hedgehog/genética , Holoprosencefalia/genética , Proteínas de Homeodomínio/genética , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Feminino , Humanos , Masculino , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único
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