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OBJECTIVE: To evaluate the association of Jewish cultural and religious identity and denominational affiliation with interest in, intention to undertake and uptake of population-based BRCA (Breast Cancer Gene)-testing. DESIGN: Cohort-study set within recruitment to GCaPPS-trial (ISRCTN73338115). SETTING: London Ashkenazi-Jewish (AJ) population. POPULATION OR SAMPLE: AJ men and women, >18 years. METHODS: Participants were self-referred, and attended recruitment clinics (clusters) for pre-test counselling. Subsequently consenting individuals underwent BRCA testing. Participants self-identified to one Jewish denomination: Conservative/Liberal/Reform/Traditional/Orthodox/Unaffiliated. Validated scales measured Jewish Cultural-Identity (JI) and Jewish Religious-identity (JR). Four-item Likert-scales analysed initial 'interest' and 'intention to test' pre-counselling. Item-Response-Theory and graded-response models, modelled responses to JI and JR scales. Ordered/multinomial logistic regression modelling evaluated association of JI-scale, JR-scale and Jewish Denominational affiliation on interest, intention and uptake of BRCA testing. MAIN OUTCOME MEASURES: Interest, intention, uptake of BRCA testing. RESULTS: In all, 935 AJ women/men of mean age = 53.8 (S.D = 15.02) years, received pre-test education and counselling through 256 recruitment clinic clusters (median cluster size = 3). Denominational affiliations included Conservative/Masorti = 91 (10.2%); Liberal = 82 (9.2%), Reform = 135 (15.1%), Traditional = 212 (23.7%), Orthodox = 239 (26.7%); and Unaffiliated/Non-practising = 135 (15.1%). Overall BRCA testing uptake was 88%. Pre-counselling, 96% expressed interest and 60% intention to test. JI and JR scores were highest for Orthodox, followed by Conservative/Masorti, Traditional, Reform, Liberal and Unaffiliated Jewish denominations. Regression modelling showed no significant association between overall Jewish Cultural or Religious Identity with either interest, intention or uptake of BRCA testing. Interest, intention and uptake of BRCA testing was not significantly associated with denominational affiliation. CONCLUSIONS: Jewish religious/cultural identity and denominational affiliation do not appear to influence interest, intention or uptake of population-based BRCA testing. BRCA testing was robust across all Jewish denominations. TWEETABLE ABSTRACT: Jewish cultural/religious factors do not affect BRCA testing, with robust uptake seen across all denominational affiliations.
Assuntos
Testes Genéticos , Judeus , Estudos de Coortes , Feminino , Humanos , Judeus/genética , Modelos Logísticos , Londres/epidemiologia , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: Unselected population-based BRCA testing provides the opportunity to apply genomics on a population-scale to maximise primary prevention for breast-and-ovarian cancer. We compare long-term outcomes of population-based and family-history (FH)/clinical-criteria-based BRCA testing on psychological health and quality of life. DESIGN: Randomised controlled trial (RCT) (ISRCTN73338115) GCaPPS, with two-arms: (i) population-screening (PS); (ii) FH/clinical-criteria-based testing. SETTING: North London Ashkenazi-Jewish (AJ) population. POPULATION/SAMPLE: AJ women/men. METHODS: Population-based RCT (1:1). Participants were recruited through self-referral, following pre-test genetic counselling from the North London AJ population. INCLUSION CRITERIA: AJ women/men >18 years old; exclusion-criteria: prior BRCA testing or first-degree relatives of BRCA-carriers. INTERVENTIONS: Genetic testing for three Jewish BRCA founder-mutations: 185delAG (c.68_69delAG), 5382insC (c.5266dupC) and 6174delT (c.5946delT), for (i) all participants in PS arm; (ii) those fulfilling FH/clinical criteria in FH arm. Linear mixed models and appropriate contrast tests were used to analyse the impact of BRCA testing on psychological and quality-of-life outcomes over 3 years. MAIN OUTCOME MEASURES: Validated questionnaires (HADS/MICRA/HAI/SF12) used to analyse psychological wellbeing/quality-of-life outcomes at baseline/1-year/2-year/3-year follow up. RESULTS: In all, 1034 individuals (691 women, 343 men) were randomised to PS (n = 530) or FH (n = 504) arms. There was a statistically significant decrease in anxiety (P = 0.046) and total anxiety-&-depression scores (P = 0.0.012) in the PS arm compared with the FH arm over 3 years. No significant difference was observed between the FH and PS arms for depression, health-anxiety, distress, uncertainty, quality-of-life or experience scores associated with BRCA testing. Contrast tests showed a decrease in anxiety (P = 0.018), health-anxiety (P < 0.0005) and quality-of-life (P = 0.004) scores in both PS and FH groups over time. Eighteen of 30 (60%) BRCA carriers identified did not fulfil clinical criteria for BRCA testing. Total BRCA prevalence was 2.9% (95% CI 1.97-4.12%), BRCA1 prevalence was 1.55% (95% CI 0.89-2.5%) and BRCA2 prevalence was 1.35% (95% CI 0.74-2.26%). CONCLUSION: Population-based AJ BRCA testing does not adversely affect long-term psychological wellbeing or quality-of-life, decreases anxiety and could identify up to 150% additional BRCA carriers. TWEETABLE ABSTRACT: Population BRCA testing in Ashkenazi Jews reduces anxiety and does not adversely affect psychological health or quality of life.
Assuntos
Ansiedade , Detecção Precoce de Câncer , Genes BRCA1 , Genes BRCA2 , Síndrome Hereditária de Câncer de Mama e Ovário , Qualidade de Vida , Adulto , Ansiedade/fisiopatologia , Ansiedade/prevenção & controle , Detecção Precoce de Câncer/métodos , Detecção Precoce de Câncer/psicologia , Feminino , Predisposição Genética para Doença/psicologia , Testes Genéticos/métodos , Testes Genéticos/estatística & dados numéricos , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Síndrome Hereditária de Câncer de Mama e Ovário/etnologia , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Síndrome Hereditária de Câncer de Mama e Ovário/psicologia , Humanos , Judeus/genética , Judeus/estatística & dados numéricos , Londres/epidemiologia , Masculino , Anamnese/estatística & dados numéricos , IncertezaRESUMO
OBJECTIVE: To evaluate factors affecting unselected population-based BRCA testing in Ashkenazi Jews (AJ). DESIGN: Cohort-study set within recruitment to the GCaPPS trial (ISRCTN73338115). SETTING: North London AJ population. POPULATION OR SAMPLE: Ashkenazi Jews women/men >18 years, recruited through self-referral. METHODS: Ashkenazi Jews women/men underwent pre-test counselling for BRCA testing through recruitment clinics (clusters). Consenting individuals provided blood samples for BRCA testing. Data were collected on socio-demographic/family history/knowledge/psychological well-being along with benefits/risks/cultural influences (18-item questionnaire measuring 'attitude'). Four-item Likert-scales analysed initial 'interest' and 'intention-to-test' pre-counselling. Uni- and multivariable logistic regression models evaluated factors affecting uptake/interest/intention to undergo BRCA testing. Statistical inference was based on cluster robust standard errors and joint Wald tests for significance. Item-Response Theory and graded-response models modelled responses to 18-item questionnaire. MAIN OUTCOME MEASURES: Interest, intention, uptake, attitude towards BRCA testing. RESULTS: A total of 935 individuals (women = 67%/men = 33%; mean age = 53.8 (SD = 15.02) years) underwent pre-test genetic-counselling. During the pre-counselling, 96% expressed interest in and 60% indicated a clear intention to undergo BRCA testing. Subsequently, 88% opted for BRCA testing. BRCA-related knowledge (P = 0.013) and degree-level education (P = 0.01) were positively and negatively (respectively) associated with intention-to-test. Being married/cohabiting had four-fold higher odds for BRCA testing uptake (P = 0.009). Perceived benefits were associated with higher pre-counselling odds for interest in and intention to undergo BRCA testing. Reduced uncertainty/reassurance were the most important factors contributing to decision-making. Increased importance/concern towards risks/limitations (confidentiality/insurance/emotional impact/inability to prevent cancer/marriage ability/ethnic focus/stigmatisation) were significantly associated with lower odds of uptake of BRCA testing, and discriminated between acceptors and decliners. Male gender/degree-level education (P = 0.001) had weaker correlations, whereas having children showed stronger (P = 0.005) associations with attitudes towards BRCA testing. CONCLUSIONS: BRCA testing in the AJ population has high acceptability. Pre-test counselling increases awareness of disadvantages/limitations of BRCA testing, influencing final cost-benefit perception and decision-making on undergoing testing. TWEETABLE ABSTRACT: BRCA testing in Ashkenazi Jews has high acceptability and uptake. Pre-test counselling facilitates informed decision-making.
Assuntos
Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Testes Genéticos , Síndrome Hereditária de Câncer de Mama e Ovário , Judeus , Adulto , Atitude Frente a Saúde/etnologia , Características Culturais , Feminino , Aconselhamento Genético/psicologia , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/psicologia , Testes Genéticos/economia , Testes Genéticos/estatística & dados numéricos , Síndrome Hereditária de Câncer de Mama e Ovário/etnologia , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Síndrome Hereditária de Câncer de Mama e Ovário/psicologia , Humanos , Judeus/genética , Judeus/psicologia , Londres , Masculino , Mutação , Participação do Paciente/estatística & dados numéricos , Fatores SocioeconômicosRESUMO
OBJECTIVE: To evaluate the role of targeted prostate cancer screening in men with BRCA1 or BRCA2 mutations, an international study, IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls), was established. This is the first multicentre screening study targeted at men with a known genetic predisposition to prostate cancer. A preliminary analysis of the data is reported. PATIENTS AND METHODS: Men aged 40-69 years from families with BRCA1 or BRCA2 mutations were offered annual prostate specific antigen (PSA) testing, and those with PSA > 3 ng/mL, were offered a prostate biopsy. Controls were men age-matched (± 5 years) who were negative for the familial mutation. RESULTS: In total, 300 men were recruited (205 mutation carriers; 89 BRCA1, 116 BRCA2 and 95 controls) over 33 months. At the baseline screen (year 1), 7.0% (21/300) underwent a prostate biopsy. Prostate cancer was diagnosed in ten individuals, a prevalence of 3.3%. The positive predictive value of PSA screening in this cohort was 47·6% (10/21). One prostate cancer was diagnosed at year 2. Of the 11 prostate cancers diagnosed, nine were in mutation carriers, two in controls, and eight were clinically significant. CONCLUSIONS: The present study shows that the positive predictive value of PSA screening in BRCA mutation carriers is high and that screening detects clinically significant prostate cancer. These results support the rationale for continued screening in such men.
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Detecção Precoce de Câncer/métodos , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença/genética , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/diagnóstico , Adulto , Idoso , Detecção Precoce de Câncer/normas , Métodos Epidemiológicos , Predisposição Genética para Doença/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias da Próstata/sangue , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genéticaRESUMO
BACKGROUND: A novel oncogenetic clinic was established in 2002 at the Royal Marsden NHS Foundation Trust offering advice and specialist follow-up for families with a germline mutation in BRCA1 or BRCA2. The remit of this multidisciplinary clinic, staffed by individuals in both oncology and genetics, is to provide individualised screening recommendations, support in decision making, risk reducing strategies, cascade testing, and an extensive research portfolio. METHODS: A retrospective analysis was performed to evaluate uptake of genetic testing, risk reducing surgery and cancer prevalence in 346 BRCA1/BRCA2 families seen between January 1996 and December 2006. RESULTS: 661 individuals attended the clinic and 406 mutation carriers were identified; 85.8% mutation carriers have chosen to attend for annual follow-up. 70% of mutation carriers elected for risk reducing bilateral salpingo-oophorectomy (RRBSO). 32% of unaffected women chose risk reducing bilateral mastectomy. 32% of women with breast cancer chose contralateral risk reducing mastectomy at time of diagnosis. Some women took over 8 years to decide to have surgery. 91% of individuals approached agreed to participate in research programmes. INTERPRETATION: A novel specialist clinic for BRCA1/2 mutation carriers has been successfully established. The number of mutation positive families is increasing. This, and the high demand for RRBSO in women over 40, is inevitably going to place an increasing demand on existing health resources. Our clinic model has subsequently been adopted in other centres and this will greatly facilitate translational studies and provide a healthcare structure for management and follow-up of such people who are at a high cancer risk.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/prevenção & controle , Neoplasias Ovarianas/prevenção & controle , Adulto , Idoso , Proteínas Reguladoras de Apoptose , Neoplasias da Mama/cirurgia , Coleta de Dados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/cirurgia , Medicina Preventiva , Estudos Retrospectivos , Comportamento de Redução do RiscoRESUMO
BACKGROUND: Rapp-Hodgkin syndrome (RHS) and Hay-Wells [also known as ankyloblepharon-ectodermal defects-cleft lip/palate (AEC)] syndrome have been designated as distinct ectodermal dysplasia syndromes despite both disorders having overlapping clinical features and the same mutated gene, TP63. OBJECTIVES: To search for TP63 mutations in two unrelated cases of RHS and two of AEC syndrome and to review the TP63 mutation database and clinical descriptions of affected individuals, the goal being to refine genotype-phenotype correlation and to determine the clinical/molecular justification for RHS and AEC continuing to exist as separate entities. METHODS: Clinical examination of four affected cases and sequencing of genomic DNA using TP63-specific primers. Literature review of published clinical descriptions of RHS and AEC syndrome cases containing TP63 mutation data. RESULTS: Cases of RHS and AEC show considerable clinical overlap, particularly with regard to hypotrichosis and mid-face hypoplasia, and the clinical feature of ankyloblepharon in AEC is often subtle, transient and a poor distinguishing clinical sign. We identified two new and two recurrent heterozygous mutations in TP63: c.1456insA (p.Leu486fsX52), RHS; c.1537T>G (p.Phe513Val), RHS; c.1787delG (p.Gly596fsX68), AEC; and c.1682G>A (p.Gly561Asp), AEC. Including this study, 42 different mutations in TP63 in RHS and AEC have now been reported, three of which are exactly the same in both syndromes. CONCLUSIONS: Our clinicopathological and molecular findings indicate that there is no justification for the continued use of eponyms in referring to these particular ectodermal dysplasia syndromes. We support the view that the terms 'Hay-Wells' and 'Rapp-Hodgkin' should be abandoned in favour of the all-inclusive diagnosis 'AEC syndrome', notwithstanding the inconsistency or often transient nature of the ankyloblepharon.
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Anormalidades Múltiplas/genética , Mutação , Transativadores/genética , Proteínas Supressoras de Tumor/genética , Adulto , Fenda Labial/genética , Fenda Labial/patologia , Fissura Palatina/genética , Fissura Palatina/patologia , Análise Mutacional de DNA , Displasia Ectodérmica/genética , Displasia Ectodérmica/patologia , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Pálpebras/anormalidades , Pálpebras/patologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Síndrome , Fatores de TranscriçãoRESUMO
Previous studies have reported that malignant hyperthermia susceptibility is caused in some families by inherited variation in a gene located on the short arm of chromosome 19 near to, or identical with, the ryanodine receptor gene (RYR1); this is expressed in skeletal muscle as a calcium release channel of the sarcoplasm reticulum. In other families, a gene in this location is excluded, but the locations of the genes involved have not yet been defined. We have analysed DNA samples from members of three large British families in whom in vitro muscle contracture tests for malignant hyperthermia susceptibility have been carried out in accordance with the procedure recommended by the European Malignant Hyperthermia Group. The results presented here strongly suggest that the gene for malignant hyperthermia susceptibility in one or more of these three British families is located in the same region of chromosome 19q, although further work is required to decide whether or not the RYR1 gene itself is causative in these families. As genetic heterogeneity could not be excluded, we cannot yet recommend the use of DNA markers to replace in vitro contracture tests in the diagnosis of malignant hyperthermia susceptibility.
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Cromossomos Humanos Par 19 , Ligação Genética/genética , Hipertermia Maligna/genética , Mapeamento Cromossômico , Suscetibilidade a Doenças , Marcadores Genéticos , Humanos , LinhagemRESUMO
The gene encoding a tissue inhibitor of metallo-proteinases, TIMP, has previously been shown to be X-linked in both the human and mouse genomes. We have used a series of somatic cell hybrids segregating translocation and deletion X chromosomes to map the TIMP gene on the human X chromosome. In combination with previous data, the gene can be assigned to Xp11.23----Xp11.4. Genetic linkage analyses demonstrate that TIMP is linked to the more distal ornithine transcarbamylase (OTC) locus at a distance of about 22 centimorgans. The data are consistent with the conclusion that TIMP maps to a conserved synteny and linkage group on the proximal short arm of the human X chromosome and on the pericentric region of the mouse X chromosome, including loci for synapsin-1, a member of the raf oncogene family, OTC, and TIMP.