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1.
Int J Cancer ; 148(2): 307-319, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32851660

RESUMO

Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two-sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P < 5 × 10-8 ) were identified as instrumental variables, and assessed using genome-wide association study data from the Endometrial Cancer Association Consortium (12 906 cases and 108 979 controls) and the Global Lipids Genetic Consortium (n = 188 578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non-endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non-endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non-endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non-endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings.

2.
Int J Audiol ; 59(5): 374-382, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32011194

RESUMO

Objective: The objective of this study was to provide proof-of-concept of a single session of tinnitus instruction and counselling with and without homework.Design: A mixed-method design using questionnaires and thematic evaluation of qualitative data was implemented.Study sample: Sixteen participants received instruction in a single, one-to-one counselling session; eight participants additionally undertook homework consisting of either positive visualisation augmented by sound or a workbook of written and drawing activities supporting the instruction provided in the counselling session. All participants completed questionnaires just before and 3 weeks after the intervention, half were interviewed 3 weeks following the intervention.Results: Average tinnitus functional index (TFI) scores were 45 (SD 25) before and 29 (SD 23) following counselling, with a change of 4.8 or greater recorded in 75% and change of 13 points or greater in 50% of participants. Both counselling and counselling with homework showed similar changes in the TFI. This finding was supported by the qualitative analysis from which a model consisting of the themes of counselling benefit, content, application and homework benefit was derived.Conclusions: This study provides proof-of-concept of a single tinnitus instruction and counselling session, based on an ecological model of tinnitus.

3.
J Med Genet ; 55(6): 384-394, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29386252

RESUMO

BACKGROUND: Germline pathogenic variants in SDHB/SDHC/SDHD are the most frequent causes of inherited phaeochromocytomas/paragangliomas. Insufficient information regarding penetrance and phenotypic variability hinders optimum management of mutation carriers. We estimate penetrance for symptomatic tumours and elucidate genotype-phenotype correlations in a large cohort of SDHB/SDHC/SDHD mutation carriers. METHODS: A retrospective survey of 1832 individuals referred for genetic testing due to a personal or family history of phaeochromocytoma/paraganglioma. 876 patients (401 previously reported) had a germline mutation in SDHB/SDHC/SDHD (n=673/43/160). Tumour risks were correlated with in silico structural prediction analyses. RESULTS: Tumour risks analysis provided novel penetrance estimates and genotype-phenotype correlations. In addition to tumour type susceptibility differences for individual genes, we confirmed that the SDHD:p.Pro81Leu mutation has a distinct phenotype and identified increased age-related tumour risks with highly destabilising SDHB missense mutations. By Kaplan-Meier analysis, the penetrance (cumulative risk of clinically apparent tumours) in SDHB and (paternally inherited) SDHD mutation-positive non-probands (n=371/67 with detailed clinical information) by age 60 years was 21.8% (95% CI 15.2% to 27.9%) and 43.2% (95% CI 25.4% to 56.7%), respectively. Risk of malignant disease at age 60 years in non-proband SDHB mutation carriers was 4.2%(95% CI 1.1% to 7.2%). With retrospective cohort analysis to adjust for ascertainment, cumulative tumour risks for SDHB mutation carriers at ages 60 years and 80 years were 23.9% (95% CI 20.9% to 27.4%) and 30.6% (95% CI 26.8% to 34.7%). CONCLUSIONS: Overall risks of clinically apparent tumours for SDHB mutation carriers are substantially lower than initially estimated and will improve counselling of affected families. Specific genotype-tumour risk associations provides a basis for novel investigative strategies into succinate dehydrogenase-related mechanisms of tumourigenesis and the development of personalised management for SDHB/SDHC/SDHD mutation carriers.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Proteínas de Membrana/genética , Paraganglioma/genética , Feocromocitoma/genética , Succinato Desidrogenase/genética , Neoplasias das Glândulas Suprarrenais/patologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Estudos de Associação Genética , Genótipo , Mutação em Linhagem Germinativa/genética , Heterozigoto , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Paraganglioma/patologia , Feocromocitoma/patologia , Fatores de Risco , Caracteres Sexuais
4.
Lancet Oncol ; 19(2): 169-180, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29337092

RESUMO

BACKGROUND: Retrospective studies provide conflicting interpretations of the effect of inherited genetic factors on the prognosis of patients with breast cancer. The primary aim of this study was to determine the effect of a germline BRCA1 or BRCA2 mutation on breast cancer outcomes in patients with young-onset breast cancer. METHODS: We did a prospective cohort study of female patients recruited from 127 hospitals in the UK aged 40 years or younger at first diagnosis (by histological confirmation) of invasive breast cancer. Patients with a previous invasive malignancy (except non-melanomatous skin cancer) were excluded. Patients were identified within 12 months of initial diagnosis. BRCA1 and BRCA2 mutations were identified using blood DNA collected at recruitment. Clinicopathological data, and data regarding treatment and long-term outcomes, including date and site of disease recurrence, were collected from routine medical records at 6 months, 12 months, and then annually until death or loss to follow-up. The primary outcome was overall survival for all BRCA1 or BRCA2 mutation carriers (BRCA-positive) versus all non-carriers (BRCA-negative) at 2 years, 5 years, and 10 years after diagnosis. A prespecified subgroup analysis of overall survival was done in patients with triple-negative breast cancer. Recruitment was completed in 2008, and long-term follow-up is continuing. FINDINGS: Between Jan 24, 2000, and Jan 24, 2008, we recruited 2733 women. Genotyping detected a pathogenic BRCA mutation in 338 (12%) patients (201 with BRCA1, 137 with BRCA2). After a median follow-up of 8·2 years (IQR 6·0-9·9), 651 (96%) of 678 deaths were due to breast cancer. There was no significant difference in overall survival between BRCA-positive and BRCA-negative patients in multivariable analyses at any timepoint (at 2 years: 97·0% [95% CI 94·5-98·4] vs 96·6% [95·8-97·3]; at 5 years: 83·8% [79·3-87·5] vs 85·0% [83·5-86·4]; at 10 years: 73·4% [67·4-78·5] vs 70·1% [67·7-72·3]; hazard ratio [HR] 0·96 [95% CI 0·76-1·22]; p=0·76). Of 558 patients with triple-negative breast cancer, BRCA mutation carriers had better overall survival than non-carriers at 2 years (95% [95% CI 89-97] vs 91% [88-94]; HR 0·59 [95% CI 0·35-0·99]; p=0·047) but not 5 years (81% [73-87] vs 74% [70-78]; HR 1·13 [0·70-1·84]; p=0·62) or 10 years (72% [62-80] vs 69% [63-74]; HR 2·12 [0·82-5·49]; p= 0·12). INTERPRETATION: Patients with young-onset breast cancer who carry a BRCA mutation have similar survival as non-carriers. However, BRCA mutation carriers with triple-negative breast cancer might have a survival advantage during the first few years after diagnosis compared with non-carriers. Decisions about timing of additional surgery aimed at reducing future second primary-cancer risks should take into account patient prognosis associated with the first malignancy and patient preferences. FUNDING: Cancer Research UK, the UK National Cancer Research Network, the Wessex Cancer Trust, Breast Cancer Now, and the PPP Healthcare Medical Trust Grant.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença/epidemiologia , Mutação em Linhagem Germinativa/genética , Adulto , Fatores Etários , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Estudos de Coortes , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Análise Multivariada , Avaliação de Resultados da Assistência ao Paciente , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Análise de Sobrevida , Neoplasias de Mama Triplo Negativas , Reino Unido , Adulto Jovem
5.
Med Confl Surviv ; 33(4): 320-323, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29214839
6.
JAMA ; 317(23): 2402-2416, 2017 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-28632866

RESUMO

Importance: The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. Objectives: To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location. Design, Setting, and Participants: Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years. Exposures: BRCA1/2 mutations, family cancer history, and mutation location. Main Outcomes and Measures: Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer. Results: Among 3886 women (median age, 38 years; interquartile range [IQR], 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2 carriers. For contralateral breast cancer, the cumulative risk 20 years after breast cancer diagnosis was 40% (95% CI, 35%-45%) for BRCA1 and 26% (95% CI, 20%-33%) for BRCA2 carriers (hazard ratio [HR] for comparing BRCA2 vs BRCA1, 0.62; 95% CI, 0.47-0.82; P=.001 for difference). Breast cancer risk increased with increasing number of first- and second-degree relatives diagnosed as having breast cancer for both BRCA1 (HR for ≥2 vs 0 affected relatives, 1.99; 95% CI, 1.41-2.82; P<.001 for trend) and BRCA2 carriers (HR, 1.91; 95% CI, 1.08-3.37; P=.02 for trend). Breast cancer risk was higher if mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 (HR, 1.46; 95% CI, 1.11-1.93; P=.007) and c.2831-c.6401 in BRCA2 (HR, 1.93; 95% CI, 1.36-2.74; P<.001). Conclusions and Relevance: These findings provide estimates of cancer risk based on BRCA1 and BRCA2 mutation carrier status using prospective data collection and demonstrate the potential importance of family history and mutation location in risk assessment.


Assuntos
Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Mutação , Segunda Neoplasia Primária/genética , Neoplasias Ovarianas/genética , Adulto , Distribuição por Idade , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/epidemiologia , Família , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Segunda Neoplasia Primária/epidemiologia , Neoplasias Ovarianas/epidemiologia , Estudos Prospectivos , Medição de Risco , Fatores de Tempo
7.
Histopathology ; 71(1): 42-52, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28165631

RESUMO

AIMS: Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a high-grade, aggressive tubulopapillary carcinoma, arising predominantly in the setting of the hereditary leiomyomatosis-RCC syndrome of familial uterocutaneous leiomyomatosis and deficiency of FH. In contrast, succinate dehydrogenase (SDH)-deficient RCC is a lower-grade oncocytic carcinoma with cytoplasmic flocculence/vacuolation and inclusions, arising mostly in individuals harbouring germline mutations of subunit B of the SDH complex (SDHB). Herein we aim to report the clinicopathologic features of a novel form of FH-deficient RCC showing a low grade oncocytic morphology, reminiscent of SDH-deficient RCC. METHODS AND RESULTS: These distinctive, low-grade oncocytic neoplasms, with solid, nested and focally tubular architecture (2-90 mm), arose in four males (aged 11-41 years). Uniform cytology of polygonal cells, with flocculent, vacuolated eosinophilic cytoplasm with scattered inclusions, fine chromatin, and inconspicuous nucleoli, was apparent. Despite these features suggestive of SDH-deficient RCC, each tumour was confirmed as an FH-deficient carcinoma with retained SDHB expression. One case showed a synchronous, anatomically separate, typical high-grade FH-deficient RCC; one other showed such a tumour at nephrectomy 4 years later. No progression has been noted at 3 and 7 years in the cases with only the SDH-like lesions; the two cases with separate, typical FH-deficient RCCs progressed. CONCLUSIONS: In summary, we characterize a novel oncocytic type of FH-deficient RCC with a striking resemblance to SDH-deficient RCC, posing a diagnostic challenge and raising concerns about sampling and multifocality for syndrome-associated cases under surveillance protocols.


Assuntos
Carcinoma de Células Renais/patologia , Fumarato Hidratase/deficiência , Neoplasias Renais/patologia , Adulto , Carcinoma de Células Renais/enzimologia , Criança , Humanos , Neoplasias Renais/enzimologia , Masculino , Succinato Desidrogenase
8.
Disabil Rehabil Assist Technol ; 12(1): 97-103, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27915580

RESUMO

PURPOSE: It has been suggested that frequency lowering may be a superior tinnitus reducing digital signal processing (DSP) strategy in hearing aids than conventional amplification. A crossover trial was undertaken to determine if frequency compression (FC) was superior to wide dynamic range compression (WDRC) in reducing tinnitus. METHOD: A 6-8-week crossover trial of two digital signal-processing techniques (WDRC and 2 WDRC with FC) was undertaken in 16 persons with high-frequency sensorineural hearing loss and chronic tinnitus. RESULTS: WDRC resulted in larger improvements in Tinnitus Functional Index and rating scale scores than WDRC with FC. The tinnitus improvements obtained with both processing types appear to be due to reduced hearing handicap and possibly decreased tinnitus audibility. CONCLUSIONS: Hearing aids are useful assistive devices in the rehabilitation of tinnitus. FC was very successful in a few individuals but was not superior to WDRC across the sample. It is recommended that WDRC remain as the default first choice tinnitus hearing aid processing strategy for tinnitus. FC should be considered as one of the many other options for selection based on individual hearing needs. Implications of Rehabilitation Hearing aids can significantly reduce the effects of tinnitus after 6-8 weeks of use. Addition of frequency compression digital signal processing does not appear superior to standard amplitude compression alone. Improvements in tinnitus were correlated with reductions in hearing handicap.


Assuntos
Auxiliares de Audição , Zumbido/reabilitação , Estudos Cross-Over , Humanos , Método Simples-Cego
9.
Cancer Epidemiol Biomarkers Prev ; 25(11): 1503-1510, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27550749

RESUMO

BACKGROUND: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist-hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls. METHODS: Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable. RESULTS: The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10-17). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m2 of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89-2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55; 95% CI, 1.44-1.68, per 5 kg/m2). The association attenuated but remained significant after adjusting for BMI (OR = 1.22; 95% CI, 1.10-1.39; P = 5.3 × 10-4). There was evidence of directional pleiotropy (P = 1.5 × 10-4). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P < 4.0 × 10-4), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS. CONCLUSIONS: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI. IMPACT: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling. Cancer Epidemiol Biomarkers Prev; 25(11); 1503-10. ©2016 AACR.


Assuntos
Índice de Massa Corporal , Neoplasias do Endométrio/etiologia , Predisposição Genética para Doença , Análise da Randomização Mendeliana , Obesidade/complicações , Polimorfismo de Nucleotídeo Único , Neoplasias do Endométrio/genética , Feminino , Humanos , Obesidade/genética , Relação Cintura-Quadril
10.
Nat Genet ; 48(6): 667-674, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27135401

RESUMO

We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r(2) = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.


Assuntos
Neoplasias do Endométrio/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Cromossomos Humanos Par 8 , Feminino , Humanos , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas
11.
Recent Results Cancer Res ; 205: 29-44, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27075347

RESUMO

Thyroid cancers are largely divided into medullary (MTC) and non-medullary (NMTC) cancers , depending on the cell type of origin. Familial non-medullary thyroid cancer (FNMTC) comprises about 5-15% of NMTC and is a heterogeneous group of diseases, including both non-syndromic and syndromic forms. Non-syndromic FNMTC tends to manifest papillary thyroid carcinoma , usually multifocal and bilateral . Several high-penetrance genes for FNMTC have been identified, but they are often confined to a few or single families, and other susceptibility loci appear to play a small part, conferring only small increments in risk. Familial susceptibility is likely to be due to a combination of genetic and environmental influences. The current focus of research in FNMTC is to characterise the susceptibility genes and their role in carcinogenesis. FNMTC can also occur as a part of multitumour genetic syndromes such as familial adenomatous polyposis , Cowden's disease , Werner's syndrome and Carney complex . These tend to present at an early age and are multicentric and bilateral with distinct pathology. The clinical evaluation of these patients is similar to that for most patients with a thyroid nodule. Medullary thyroid cancer (MTC) arises from the parafollicular cells of the thyroid which release calcitonin. The familial form of MTC accounts for 20-25% of cases and presents as a part of the multiple endocrine neoplasia type 2 (MEN 2) syndromes or as a pure familial MTC (FMTC). They are caused by germline point mutations in the RET oncogene on chromosome 10q11.2. There is a clear genotype-phenotype correlation, and the aggressiveness of FMTC depends on the specific genetic mutation, which should determine the timing of surgery.


Assuntos
Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/terapia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/terapia , Predisposição Genética para Doença , Testes Genéticos , Genótipo , Humanos , Síndromes Neoplásicas Hereditárias/genética , Fenótipo , Neoplasias da Glândula Tireoide/genética
12.
Hum Mol Genet ; 25(12): 2612-2620, 2016 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-27008869

RESUMO

Endometrial cancer is the most common gynecological malignancy in the developed world. Although there is evidence of genetic predisposition to the disease, most of the genetic risk remains unexplained. We present the meta-analysis results of four genome-wide association studies (4907 cases and 11 945 controls total) in women of European ancestry. We describe one new locus reaching genome-wide significance (P < 5 × 10 -8) at 6p22.3 (rs1740828; P = 2.29 × 10 -8, OR = 1.20), providing evidence of an additional region of interest for genetic susceptibility to endometrial cancer.


Assuntos
Neoplasias do Endométrio/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Cromossomos Humanos Par 6/genética , Neoplasias do Endométrio/patologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único
13.
Assist Technol ; 28(2): 115-25, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26817495

RESUMO

Masking is widely used in the management of tinnitus, however, masking at the perceived spatial location of tinnitus has not been investigated. This article examines the development of a method for the spatial masking of tinnitus. This report consists of three studies: Study I is a proof of concept study comparing customized spatial masking to conventional bilateral masking; Study II is a prototype evaluation in which the spatial masking paradigm was compared to a bilaterally equal masker using iPods connected to hearing aids in a 4-week cross-over trial; and Study III is a 4-month crossover pilot study-using prototype hearing aid-based maskers, and in which three-dimensional (3D) masking (2 months) was compared to a Tinnitus Retraining Therapy (2 months). There was a preference for the 3D masking stimulus across all three studies. Individual changes in the Tinnitus Handicap Inventory (THI) after 2 weeks of trial (Study II) and Tinnitus Functional Index (TFI) after 2 months of trial (Study III) were observed without large group differences. The spatial masking concept was piloted successfully. The qualitative and quantitative results obtained indicate directions for future clinical trials and therapy development. This study indicates that spatial masking of tinnitus is feasible, of benefit to many participants, and warrants further trials.


Assuntos
Auxiliares de Audição , Zumbido/terapia , Adulto , Idoso , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Inquéritos e Questionários , Adulto Jovem
14.
Endocr Relat Cancer ; 23(2): 77-91, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26574572

RESUMO

Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E2) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8×10(-11)). SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4×10(-8)). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11-1.21) is compatible with that predicted by the observed effect on E2 concentrations (1.09, CI=1.03-1.21), consistent with the hypothesis that endometrial cancer risk is driven by E2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (Pinteraction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.


Assuntos
Aromatase/genética , Neoplasias do Endométrio/etiologia , Estradiol/sangue , Interação Gene-Ambiente , Predisposição Genética para Doença , Genótipo , Polimorfismo de Nucleotídeo Único , Fatores Etários , Alelos , Índice de Massa Corporal , Estudos de Casos e Controles , Neoplasias do Endométrio/sangue , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Estudos de Associação Genética , Humanos , Fenótipo
15.
Endocr Relat Cancer ; 22(5): 851-61, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26330482

RESUMO

Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded by ESR1. Consequently, several studies have investigated whether variation at the ESR1 locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3633 genotyped and imputed single nucleotide polymorphisms (SNPs) in 6607 EC cases and 37 925 controls. There was evidence of an EC risk signal located at a potential alternative promoter of the ESR1 gene (lead SNP rs79575945, P=1.86×10(-5)), which was stronger for cancers of endometrioid subtype (P=3.76×10(-6)). Bioinformatic analysis suggests that this risk signal is in a functionally important region targeting ESR1, and eQTL analysis found that rs79575945 was associated with expression of SYNE1, a neighbouring gene. In summary, we have identified a single EC risk signal located at ESR1, at study-wide significance. Given SNPs located at this locus have been associated with risk for breast cancer, also a hormonally driven cancer, this study adds weight to the rationale for performing informed candidate fine-scale genetic studies across cancer types.


Assuntos
Neoplasias da Mama/genética , Neoplasias do Endométrio/genética , Receptor alfa de Estrogênio/genética , Predisposição Genética para Doença , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Biologia Computacional , Proteínas do Citoesqueleto , Bases de Dados Genéticas , Feminino , Loci Gênicos , Genótipo , Humanos , Metanálise como Assunto , Prognóstico , Regiões Promotoras Genéticas/genética , Fatores de Risco
16.
J Clin Oncol ; 33(31): 3591-7, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-26282643

RESUMO

PURPOSE: In the general population, increased adiposity is a significant risk factor for colorectal cancer (CRC), but whether obesity has similar effects in those with hereditary CRC is uncertain. This prospective study investigated the association between body mass index and cancer risk in patients with Lynch syndrome (LS). PATIENTS AND METHODS: Participants with LS were recruited to the CAPP2 study, in which they were randomly assigned to receive aspirin 600 mg per day or aspirin placebo, plus resistant starch 30 g per day or starch placebo (2 × 2 factorial design). Mean intervention period was 25.0 months, and mean follow-up was 55.7 months. RESULTS: During follow-up, 55 of 937 participants developed CRC. For obese participants, CRC risk was 2.41× (95% CI, 1.22 to 4.85) greater than for underweight and normal-weight participants (reference group), and CRC risk increased by 7% for each 1-kg/m(2) increase in body mass index. The risk of all LS-related cancers in obese people was 1.77× (95% CI, 1.06 to 2.96; P = .03) greater than for the reference group. In subgroup analysis, obesity was associated with 3.72× (95% CI, 1.41 to 9.81) greater CRC risk in patients with LS with MLH1 mutation, but no excess risk was observed in those with MSH2 or MSH6 mutation (P = .5). The obesity-related excess CRC risk was confined to those randomly assigned to the aspirin placebo group (adjusted hazard ratio, 2.75; 95% CI, 1.12 to 6.79; P = .03). CONCLUSION: Obesity is associated with substantially increased CRC risk in patients with LS, but this risk is abrogated in those taking aspirin. Such patients are likely to benefit from obesity prevention and/or regular aspirin.


Assuntos
Aspirina/uso terapêutico , Índice de Massa Corporal , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Colorretais/complicações , Neoplasias Colorretais/prevenção & controle , Obesidade/complicações , Proteínas Adaptadoras de Transdução de Sinal/genética , Adiposidade , Adulto , Anti-Inflamatórios não Esteroides/uso terapêutico , Peso Corporal , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Proteínas de Ligação a DNA/genética , Feminino , Seguimentos , Heterozigoto , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS/genética , Mutação , Proteínas Nucleares/genética , Estudos Prospectivos , Fatores de Risco
18.
19.
Hum Genet ; 134(2): 231-45, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25487306

RESUMO

Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT-CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 × 10(-6) to P = 7.7 × 10(-5)). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERT P = 1.5 × 10(-18), CLPTM1L P = 1.5 × 10(-19)). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility.


Assuntos
Cromossomos Humanos Par 5/genética , Loci Gênicos , Proteínas de Membrana/genética , Modelos Genéticos , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Telomerase/genética , Cromossomos Humanos Par 5/metabolismo , Bases de Dados de Ácidos Nucleicos , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Haplótipos , Humanos , Proteínas de Membrana/biossíntese , Proteínas de Neoplasias/biossíntese , Regiões Promotoras Genéticas , Fatores de Risco , Telomerase/biossíntese
20.
Hum Mol Genet ; 24(5): 1478-92, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25378557

RESUMO

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.


Assuntos
Mapeamento Cromossômico , Neoplasias do Endométrio/genética , Loci Gênicos , Fator 1-beta Nuclear de Hepatócito/genética , Alelos , Estudos de Casos e Controles , Linhagem Celular Tumoral , Biologia Computacional , Bases de Dados Genéticas , Epigênese Genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos , Fator 1-beta Nuclear de Hepatócito/metabolismo , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Risco
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