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1.
medRxiv ; 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33173903

RESUMO

Anti-Müllerian hormone (AMH) is expressed by antral stage ovarian follicles in women. Consequently, circulating AMH levels are detectable until menopause. Variation in age-specific AMH levels has been associated with breast cancer and polycystic ovary syndrome (PCOS), amongst other diseases. Identification of genetic variants underlying variation in AMH levels could provide clues about the physiological mechanisms that explain these AMH-disease associations. To date, only one variant in MCM8 has been identified to be associated with circulating AMH levels in women. We aimed to identify additional variants for AMH through a GWAS meta-analysis including data from 7049 premenopausal women of European ancestry, which more than doubles the sample size of the largest previous GWAS. We identified four loci associated with AMH levels at p < 5×10 -8 : the previously reported MCM8 locus and three novel signals in or near AMH, TEX41 , and CDCA7 . The strongest signal was a missense variant in the AMH gene (rs10417628). Most prioritized genes at the other three identified loci were involved in cell cycle regulation. Genetic correlation analyses indicated a strong positive correlation among SNPs for AMH levels and for age at menopause (r g = 0.82, FDR=0.003). Exploratory Mendelian randomization analyses did not support a causal effect of AMH on breast cancer or PCOS risk, but should be interpreted with caution as they may be underpowered and the validity of genetic instruments could not be extensively explored. In conclusion, we identified a variant in the AMH gene and three other loci that may affect circulating AMH levels in women.

2.
Lancet Diabetes Endocrinol ; 8(8): 683-692, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32707116

RESUMO

BACKGROUND: Recombinant human growth hormone has been used for more than 30 years and its indications have increased worldwide. There is concern that this treatment might increase mortality, but published data are scarce. We present data from the entire dataset of all eight countries of the Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) consortium, with the aim of studying long-term overall and cause-specific mortality in young adult patients treated with recombinant human growth hormone during childhood and relating this to the underlying diagnosis. METHODS: This cohort study was done in eight European countries (Belgium, France, Germany, Italy, The Netherlands, Sweden, Switzerland, and the UK). Patients were classified a priori based on pre-treatment perceived mortality risk from their underlying disease and followed up for cause-specific mortality. Person-years at risk of mortality and expected rates from general population data were used to calculate standardised mortality ratios (SMRs). FINDINGS: The cohort comprised 24 232 patients treated with recombinant human growth hormone during childhood, with more than 400 000 patient-years of follow-up. In low-risk patients with isolated growth hormone deficiency or idiopathic short stature, all-cause mortality was not significantly increased (SMR 1·1, 95% CI 0·9-1·3). In children born small for gestational age, all-cause mortality was significantly increased when analysed for all countries (SMR 1·5, CI 1·1-1·9), but this result was driven by the French subcohort. In patients at moderate or high risk, mortality was increased (SMR 3·8, 3·3-4·4; and 17·1, 15·6-18·7, respectively). Mortality was not associated with mean daily or cumulative doses of recombinant human growth hormone for any of the risk groups. Cause-specific mortality from diseases of the circulatory and haematological systems was increased in all risk groups. INTERPRETATION: In this cohort, the largest, to our knowledge, with long-term follow-up of patients treated with recombinant human growth hormone during childhood, all-cause mortality was associated with underlying diagnosis. In patients with isolated growth hormone deficiency or idiopathic short stature, recombinant human growth hormone treatment was not associated with increased all-cause mortality. However, mortality from certain causes was increased, emphasising the need for further long-term surveillance. FUNDING: European Union.


Assuntos
Nanismo Hipofisário/tratamento farmacológico , Nanismo Hipofisário/mortalidade , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/efeitos adversos , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Mortalidade/tendências , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Fatores de Tempo , Adulto Jovem
3.
Sci Rep ; 10(1): 11762, 2020 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-32678138

RESUMO

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype associated with a high rate of recurrence and poor prognosis. Recently we identified a hypermethylation in the long noncoding RNA 299 (LINC00299) gene in blood-derived DNA from TNBC patients compared with healthy controls implying that LINC00299 hypermethylation may serve as a circulating biomarker for TNBC. In the present study, we investigated whether LINC00299 methylation is associated with TNBC in a prospective nested breast cancer case-control study within the Generations Study. Methylation at cg06588802 in LINC00299 was measured in 154 TNBC cases and 159 breast cancer-free matched controls using MethyLight droplet digital PCR. To assess the association between methylation level and TNBC risk, logistic regression was used to calculate odd ratios and 95% confidence intervals, adjusted for smoking status. We found no evidence for association between methylation levels and TNBC overall (P = 0.062). Subgroup analysis according to age at diagnosis and age at blood draw revealed increased methylation levels in TNBC cases compared with controls in the young age groups [age 26-52 (P = 0.0025) and age 22-46 (P = 0.001), respectively]. Our results suggest a potential association of LINC00299 hypermethylation with TNBC in young women.

4.
Int J Cancer ; 147(5): 1306-1314, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32012248

RESUMO

Early-adulthood body size is strongly inversely associated with risk of premenopausal breast cancer. It is unclear whether subsequent changes in weight affect risk. We pooled individual-level data from 17 prospective studies to investigate the association of weight change with premenopausal breast cancer risk, considering strata of initial weight, timing of weight change, other breast cancer risk factors and breast cancer subtype. Hazard ratios (HR) and 95% confidence intervals (CI) were obtained using Cox regression. Among 628,463 women, 10,886 were diagnosed with breast cancer before menopause. Models adjusted for initial weight at ages 18-24 years and other breast cancer risk factors showed that weight gain from ages 18-24 to 35-44 or to 45-54 years was inversely associated with breast cancer overall (e.g., HR per 5 kg to ages 45-54: 0.96, 95% CI: 0.95-0.98) and with oestrogen-receptor(ER)-positive breast cancer (HR per 5 kg to ages 45-54: 0.96, 95% CI: 0.94-0.98). Weight gain from ages 25-34 was inversely associated with ER-positive breast cancer only and weight gain from ages 35-44 was not associated with risk. None of these weight gains were associated with ER-negative breast cancer. Weight loss was not consistently associated with overall or ER-specific risk after adjusting for initial weight. Weight increase from early-adulthood to ages 45-54 years is associated with a reduced premenopausal breast cancer risk independently of early-adulthood weight. Biological explanations are needed to account for these two separate factors.

5.
Breast Cancer Res ; 22(1): 19, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-32046759

RESUMO

As a consequence of responding to colleagues who asked about the publication of the original article [1], the authors have determined that the data published in Table 4 of the paper are incorrect.

6.
Cancer Res ; 80(5): 1210-1218, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31932455

RESUMO

Repeated exposure to the acute proinflammatory environment that follows ovulation at the ovarian surface and distal fallopian tube over a woman's reproductive years may increase ovarian cancer risk. To address this, analyses included individual-level data from 558,709 naturally menopausal women across 20 prospective cohorts, among whom 3,246 developed invasive epithelial ovarian cancer (2,045 serous, 319 endometrioid, 184 mucinous, 121 clear cell, 577 other/unknown). Cox models were used to estimate multivariable-adjusted HRs between lifetime ovulatory cycles (LOC) and its components and ovarian cancer risk overall and by histotype. Women in the 90th percentile of LOC (>514 cycles) were almost twice as likely to be diagnosed with ovarian cancer than women in the 10th percentile (<294) [HR (95% confidence interval): 1.92 (1.60-2.30)]. Risk increased 14% per 5-year increase in LOC (60 cycles) [(1.10-1.17)]; this association remained after adjustment for LOC components: number of pregnancies and oral contraceptive use [1.08 (1.04-1.12)]. The association varied by histotype, with increased risk of serous [1.13 (1.09-1.17)], endometrioid [1.20 (1.10-1.32)], and clear cell [1.37 (1.18-1.58)], but not mucinous [0.99 (0.88-1.10), P-heterogeneity = 0.01] tumors. Heterogeneity across histotypes was reduced [P-heterogeneity = 0.15] with adjustment for LOC components [1.08 serous, 1.11 endometrioid, 1.26 clear cell, 0.94 mucinous]. Although the 10-year absolute risk of ovarian cancer is small, it roughly doubles as the number of LOC rises from approximately 300 to 500. The consistency and linearity of effects strongly support the hypothesis that each ovulation leads to small increases in the risk of most ovarian cancers, a risk that cumulates through life, suggesting this as an important area for identifying intervention strategies. SIGNIFICANCE: Although ovarian cancer is rare, risk of most ovarian cancers doubles as the number of lifetime ovulatory cycles increases from approximately 300 to 500. Thus, identifying an important area for cancer prevention research.


Assuntos
Neoplasias Ovarianas/epidemiologia , Ovário/imunologia , Ovulação/imunologia , Idoso , Anticoncepcionais/administração & dosagem , Tubas Uterinas/imunologia , Tubas Uterinas/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/prevenção & controle , Ovário/patologia , Ovulação/efeitos dos fármacos , Modelos de Riscos Proporcionais , Estudos Prospectivos , História Reprodutiva , Medição de Risco , Fatores de Risco
7.
J Natl Cancer Inst ; 112(3): 278-285, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31165158

RESUMO

BACKGROUND: External validation of risk models is critical for risk-stratified breast cancer prevention. We used the Individualized Coherent Absolute Risk Estimation (iCARE) as a flexible tool for risk model development and comparative model validation and to make projections for population risk stratification. METHODS: Performance of two recently developed models, one based on the Breast and Prostate Cancer Cohort Consortium analysis (iCARE-BPC3) and another based on a literature review (iCARE-Lit), were compared with two established models (Breast Cancer Risk Assessment Tool and International Breast Cancer Intervention Study Model) based on classical risk factors in a UK-based cohort of 64 874 white non-Hispanic women (863 patients) age 35-74 years. Risk projections in a target population of US white non-Hispanic women age 50-70 years assessed potential improvements in risk stratification by adding mammographic breast density (MD) and polygenic risk score (PRS). RESULTS: The best calibrated models were iCARE-Lit (expected to observed number of cases [E/O] = 0.98, 95% confidence interval [CI] = 0.87 to 1.11) for women younger than 50 years, and iCARE-BPC3 (E/O = 1.00, 95% CI = 0.93 to 1.09) for women 50 years or older. Risk projections using iCARE-BPC3 indicated classical risk factors can identify approximately 500 000 women at moderate to high risk (>3% 5-year risk) in the target population. Addition of MD and a 313-variant PRS is expected to increase this number to approximately 3.5 million women, and among them, approximately 153 000 are expected to develop invasive breast cancer within 5 years. CONCLUSIONS: iCARE models based on classical risk factors perform similarly to or better than BCRAT or IBIS in white non-Hispanic women. Addition of MD and PRS can lead to substantial improvements in risk stratification. However, these integrated models require independent prospective validation before broad clinical applications.


Assuntos
Neoplasias da Mama/epidemiologia , Modelos Estatísticos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Risco , Adulto Jovem
9.
Mod Pathol ; 32(12): 1834-1846, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31239549

RESUMO

Primary ovarian mucinous tumors can be difficult to distinguish from metastatic gastrointestinal neoplasms by histology alone. The expected immunoprofile of a suspected metastatic lower gastrointestinal tumor is CK7-/CK20+/CDX2+/PAX8-. This study assesses the addition of a novel marker SATB2, to improve the diagnostic algorithm. A test cohort included 155 ovarian mucinous tumors (105 carcinomas and 50 borderline tumors) and 230 primary lower gastrointestinal neoplasms (123 colorectal adenocarcinomas and 107 appendiceal neoplasms). All cases were assessed for SATB2, PAX8 CK7, CK20, and CDX2 expression on tissue microarrays. Expression was scored in a 3-tier system as absent, focal (1-50% of tumor cells) and diffuse ( >50% of tumor cells) and then categorized into either absent/present or nondiffuse/diffuse. SATB2 and PAX8 expression was further evaluated in ovarian tumors from an international cohort of 2876 patients (expansion cohort, including 159 mucinous carcinomas and 46 borderline mucinous tumors). The highest accuracy of an individual marker in distinguishing lower gastrointestinal from ovarian mucinous tumors was CK7 (91.7%, nondiffuse/diffuse cut-off) followed by SATB2 (88.8%, present/absent cut-off). The most effective combination was CK7 and SATB2 with accuracy of 95.3% using the 3-tier interpretation, absent/focal/diffuse. This combination outperformed the standard clinical set of CK7, CK20 and CDX2 (87.5%). Re-evaluation of outlier cases confirmed ovarian origin for all but one case. The accuracy of SATB2 was confirmed in the expansion cohort (91.5%). SATB2 expression was also detected in 15% of ovarian endometrioid carcinoma but less than 5% of other ovarian histotypes. A simple two marker combination of CK7 and SATB2 can distinguish lower gastrointestinal from ovarian primary mucinous tumors with greater than 95% accuracy. PAX8 and CDX2 have value as second-line markers. The utility of CK20 in this setting is low and this warrants replacement of this marker with SATB2 in clinical practice.


Assuntos
Adenocarcinoma Mucinoso/diagnóstico , Biomarcadores Tumorais/análise , Queratina-7/análise , Proteínas de Ligação à Região de Interação com a Matriz/análise , Neoplasias Ovarianas/diagnóstico , Fatores de Transcrição/análise , Neoplasias do Apêndice/diagnóstico , Neoplasias do Apêndice/patologia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Masculino , Metástase Neoplásica/diagnóstico , Sensibilidade e Especificidade
10.
Clin Epigenetics ; 11(1): 66, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-31039828

RESUMO

BACKGROUND: It is well established that estrogens and other hormonal factors influence breast cancer susceptibility. We hypothesized that a woman's total lifetime estrogen exposure accumulates changes in DNA methylation, detectable in the blood, which could be used in risk assessment for breast cancer. METHODS: An estimated lifetime estrogen exposure (ELEE) model was defined using epidemiological data from EPIC-Italy (n = 31,864). An epigenome-wide association study (EWAS) of ELEE was performed using existing Illumina HumanMethylation450K Beadchip (HM450K) methylation data obtained from EPIC-Italy blood DNA samples (n = 216). A methylation index (MI) of ELEE based on 31 CpG sites was developed using HM450K data from EPIC-Italy and the Generations Study and evaluated for association with breast cancer risk in an independent dataset from the Generations Study (n = 440 incident breast cancer cases matched to 440 healthy controls) using targeted bisulfite sequencing. Lastly, a meta-analysis was conducted including three additional cohorts, consisting of 1187 case-control pairs. RESULTS: We observed an estimated 5% increase in breast cancer risk per 1-year longer ELEE (OR = 1.05, 95% CI 1.04-1.07, P = 3 × 10-12) in EPIC-Italy. The EWAS identified 694 CpG sites associated with ELEE (FDR Q < 0.05). We report a DNA methylation index (MI) associated with breast cancer risk that is validated in the Generations Study targeted bisulfite sequencing data (ORQ4_vs_Q1 = 1.77, 95% CI 1.07-2.93, P = 0.027) and in the meta-analysis (ORQ4_vs_Q1 = 1.43, 95% CI 1.05-2.00, P = 0.024); however, the correlation between the MI and ELEE was not validated across study cohorts. CONCLUSION: We have identified a blood DNA methylation signature associated with breast cancer risk in this study. Further investigation is required to confirm the interaction between estrogen exposure and DNA methylation in the blood.


Assuntos
Neoplasias da Mama/genética , Metilação de DNA , Estrogênios/efeitos adversos , Estudo de Associação Genômica Ampla/métodos , Estudos de Casos e Controles , Ilhas de CpG , Metilação de DNA/efeitos dos fármacos , Epigênese Genética , Feminino , Predisposição Genética para Doença , Humanos , Itália , Pessoa de Meia-Idade , Estudos Prospectivos
11.
Br J Cancer ; 121(2): 172-179, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31138896

RESUMO

BACKGROUND: It is plausible that night shift work could affect breast cancer risk, possibly by melatonin suppression or circadian clock disruption, but epidemiological evidence is inconclusive. METHODS: Using serial questionnaires from the Generations Study cohort, we estimated hazard ratios (HR) and 95% confidence intervals (95%CI) for breast cancer in relation to being a night shift worker within the last 10 years, adjusted for potential confounders. RESULTS: Among 102,869 women recruited in 2003-2014, median follow-up 9.5 years, 2059 developed invasive breast cancer. The HR in relation to night shift work was 1.00 (95%CI: 0.86-1.15). There was a significant trend with average hours of night work per week (P = 0.035), but no significantly raised risks for hours worked per night, nights worked per week, average hours worked per week, cumulative years of employment, cumulative hours, time since cessation, type of occupation, age starting night shift work, or age starting in relation to first pregnancy. CONCLUSIONS: The lack of overall association, and no association with all but one measure of dose, duration, and intensity in our data, does not support an increased risk of breast cancer from night shift work in women.


Assuntos
Neoplasias da Mama/etiologia , Jornada de Trabalho em Turnos/efeitos adversos , Adulto , Neoplasias da Mama/química , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/análise , Fatores de Risco
12.
Breast Cancer Res ; 21(1): 42, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30890167

RESUMO

BACKGROUND: Models that accurately predict risk of breast cancer are needed to help younger women make decisions about when to begin screening. Premenopausal concentrations of circulating anti-Müllerian hormone (AMH), a biomarker of ovarian reserve, and testosterone have been positively associated with breast cancer risk in prospective studies. We assessed whether adding AMH and/or testosterone to the Gail model improves its prediction performance for women aged 35-50. METHODS: In a nested case-control study including ten prospective cohorts (1762 invasive cases/1890 matched controls) with pre-diagnostic serum/plasma samples, we estimated relative risks (RR) for the biomarkers and Gail risk factors using conditional logistic regression and random-effects meta-analysis. Absolute risk models were developed using these RR estimates, attributable risk fractions calculated using the distributions of the risk factors in the cases from the consortium, and population-based incidence and mortality rates. The area under the receiver operating characteristic curve (AUC) was used to compare the discriminatory accuracy of the models with and without biomarkers. RESULTS: The AUC for invasive breast cancer including only the Gail risk factor variables was 55.3 (95% CI 53.4, 57.1). The AUC increased moderately with the addition of AMH (AUC 57.6, 95% CI 55.7, 59.5), testosterone (AUC 56.2, 95% CI 54.4, 58.1), or both (AUC 58.1, 95% CI 56.2, 59.9). The largest AUC improvement (4.0) was among women without a family history of breast cancer. CONCLUSIONS: AMH and testosterone moderately increase the discriminatory accuracy of the Gail model among women aged 35-50. We observed the largest AUC increase for women without a family history of breast cancer, the group that would benefit most from improved risk prediction because early screening is already recommended for women with a family history.


Assuntos
Neoplasias da Mama/epidemiologia , Adulto , Fatores Etários , Animais , Área Sob a Curva , Neoplasias da Mama/etiologia , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Análise Discriminante , Suscetibilidade a Doenças , Feminino , Hormônios Esteroides Gonadais/sangue , Hormônios Esteroides Gonadais/metabolismo , Humanos , Pessoa de Meia-Idade , Modelos Teóricos , Curva ROC , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Testosterona/sangue , Testosterona/metabolismo
13.
Cancer Res ; 79(8): 2065-2071, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30709929

RESUMO

Genome-wide association studies (GWAS) have so far identified 25 loci associated with glioma risk, with most showing specificity for either glioblastoma (GBM) or non-GBM tumors. The majority of these GWAS susceptibility variants reside in noncoding regions and the causal genes underlying the associations are largely unknown. Here we performed a transcriptome-wide association study to search for novel risk loci and candidate causal genes at known GWAS loci using Genotype-Tissue Expression Project (GTEx) data to predict cis-predicted gene expression in relation to GBM and non-GBM risk in conjunction with GWAS summary statistics on 12,488 glioma cases (6,183 GBM and 5,820 non-GBM) and 18,169 controls. Imposing a Bonferroni-corrected significance level of P < 5.69 × 10-6, we identified 31 genes, including GALNT6 at 12q13.33, as a candidate novel risk locus for GBM (mean Z = 4.43; P = 5.68 × 10-6). GALNT6 resides at least 55 Mb away from any previously identified glioma risk variant, while all other 30 significantly associated genes were located within 1 Mb of known GWAS-identified loci and were not significant after conditioning on the known GWAS-identified variants. These data identify a novel locus (GALNT6 at 12q13.33) and 30 genes at 12 known glioma risk loci associated with glioma risk, providing further insights into glioma tumorigenesis. SIGNIFICANCE: This study identifies new genes associated with glioma risk, increasing understanding of how these tumors develop.


Assuntos
Biomarcadores Tumorais/genética , Predisposição Genética para Doença , Glioma/genética , Glioma/patologia , Polimorfismo de Nucleotídeo Único , Transcriptoma , Estudos de Casos e Controles , Regulação Neoplásica da Expressão Gênica , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Prognóstico , Locos de Características Quantitativas
14.
Scand J Work Environ Health ; 45(2): 183-193, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30614502

RESUMO

Objective Studies of loud noise exposure and vestibular schwannomas (VS) have shown conflicting results. The population-based INTERPHONE case‒control study was conducted in 13 countries during 2000-2004. In this paper, we report the results of analyses on the association between VS and self-reported loud noise exposure. Methods Self-reported noise exposure was analyzed in 1024 VS cases and 1984 matched controls. Life-long noise exposure was estimated through detailed questions. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using adjusted conditional logistic regression for matched sets. Results The OR for total work and leisure noise exposure was 1.6 (95% CI 1.4-1.9). OR were 1.5 (95% CI 1.3-1.9) for only occupational noise, 1.9 (95% CI 1.4-2.6) for only leisure noise and 1.7 (95% CI 1.2-2.2) for exposure in both contexts. OR increased slightly with increasing lag-time. For occupational exposures, duration, time since exposure start and a metric combining lifetime duration and weekly exposure showed significant trends of increasing risk with increasing exposure. OR did not differ markedly by source or other characteristics of noise. Conclusion The consistent associations seen are likely to reflect either recall bias or a causal association, or potentially indicate a mixture of both.


Assuntos
Neuroma Acústico/epidemiologia , Ruído Ocupacional/estatística & dados numéricos , Exposição Ocupacional/estatística & dados numéricos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
16.
Hum Mol Genet ; 28(8): 1392-1401, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30649302

RESUMO

Anti-Müllerian hormone (AMH) is required for sexual differentiation in the fetus, and in adult females AMH is produced by growing ovarian follicles. Consequently, AMH levels are correlated with ovarian reserve, declining towards menopause when the oocyte pool is exhausted. A previous genome-wide association study identified three genetic variants in and around the AMH gene that explained 25% of variation in AMH levels in adolescent males but did not identify any genetic associations reaching genome-wide significance in adolescent females. To explore the role of genetic variation in determining AMH levels in women of late reproductive age, we carried out a genome-wide meta-analysis in 3344 pre-menopausal women from five cohorts (median age 44-48 years at blood draw). A single genetic variant, rs16991615, previously associated with age at menopause, reached genome-wide significance at P = 3.48 × 10-10, with a per allele difference in age-adjusted inverse normal AMH of 0.26 standard deviations (SD) (95% confidence interval (CI) [0.18,0.34]). We investigated whether genetic determinants of female reproductive lifespan were more generally associated with pre-menopausal AMH levels. Genetically-predicted age at menarche had no robust association but genetically-predicted age at menopause was associated with lower AMH levels by 0.18 SD (95% CI [0.14,0.21]) in age-adjusted inverse normal AMH per one-year earlier age at menopause. Our findings provide genetic support for the well-established use of AMH as a marker of ovarian reserve.


Assuntos
Hormônio Antimülleriano/genética , Pré-Menopausa/fisiologia , Adulto , Fatores Etários , Hormônio Antimülleriano/sangue , Hormônio Antimülleriano/fisiologia , Sequência de Bases , Feminino , Expressão Gênica , Regulação da Expressão Gênica/genética , Estudos de Associação Genética/métodos , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Haplótipos , Humanos , Longevidade , Menarca/genética , Pessoa de Meia-Idade , Mitocôndrias/genética , Folículo Ovariano , Ovário , Polimorfismo de Nucleotídeo Único/genética , Pré-Menopausa/genética , Reprodução/genética , Análise de Sequência de DNA , Transcriptoma/genética
17.
Am J Epidemiol ; 188(3): 500-508, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30535276

RESUMO

A balanced robertsonian translocation (rob) results from fusion of 2 acrocentric chromosomes. Carriers are phenotypically normal and are often diagnosed because of recurrent miscarriages, infertility, or aneuploid offspring. Mortality and site-specific cancer risks in carriers have not been prospectively investigated. We followed 1,987 carriers diagnosed in Great Britain for deaths and cancer risk, over an average of 24.1 years. Standardized mortality and incidence ratios were calculated comparing the number of observed events against population rates. Overall mortality was higher for carriers diagnosed before age 15 years (standardized mortality ratio (SMR) = 2.00, 95% confidence interval (CI): 1.09, 3.35), similar for those diagnosed aged 15-44 years (SMR = 1.06, 95% CI: 0.86-1.28), and lower for those diagnosed aged 45-84 years (SMR = 0.81, 95% CI: 0.68, 0.95). Cancer incidence was higher for non-Hodgkin lymphoma (standardized incidence ratio (SIR) = 1.90, 95% CI: 1.01, 3.24) and childhood leukemia (SIR = 14.5, 95% CI: 1.75, 52.2), the latter particularly in rob(15;21) carriers (SIR = 447.8, 95% CI: 11.3, 2,495). Rob(13;14) carriers had a higher breast cancer risk (SIR = 1.58, 95% CI: 1.12, 2.15). Mortality risks relative to the population in diagnosed carriers depend on age at cytogenetic diagnosis, possibly reflecting age-specific cytogenetic referral reasons. Carriers might be at greater risk of childhood leukemia and non-Hodgkin lymphoma and those diagnosed with rob(13;14) of breast cancer.


Assuntos
Neoplasias/genética , Neoplasias/mortalidade , Sistemas de Translocação de Proteínas/análise , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Estudos de Coortes , Feminino , Heterozigoto , Humanos , Incidência , Leucemia/genética , Leucemia/mortalidade , Linfoma não Hodgkin/genética , Linfoma não Hodgkin/mortalidade , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Reino Unido/epidemiologia , Adulto Jovem
19.
Int J Cancer ; 145(6): 1493-1498, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30496607

RESUMO

The constitutional t(11;22)(q23;q11) translocation is the only recurrent non-Robertsonian translocation known in humans. Carriers are phenotypically normal and are usually referred for cytogenetic testing because of multiple miscarriages, infertility, or having aneuploidy in offspring. A breast cancer predisposition has been suggested, but previous studies have been small and had methodological shortcomings. We therefore conducted a long-term prospective study of cancer and mortality risk in carriers. We followed 65 male and 101 female carriers of t(11;22)(q23;q11) diagnosed in cytogenetic laboratories in Britain during 1976-2005 for cancer and deaths for an average of 21.4 years per subject. Standardised mortality (SMR) and incidence (SIR) ratios were calculated comparing the numbers of observed events with those expected from national age-, sex-, country- and calendar-period-specific population rates. Cancer incidence was borderline significantly raised for cancer overall (SIR = 1.56, 95% CI: 0.98-2.36, n = 22), and significantly raised for invasive breast cancer (SIR = 2.74, 95% CI: 1.18-5.40, n = 8) and in situ breast cancer (SIR = 13.0, 95% CI: 3.55-33.4, n = 4). Breast cancer risks were particularly increased at ages <50 (SIR = 4.37, 95% CI: 1.42-10.2 for invasive, SIR = 22.8, 95% CI: 2.76-82.5 for in situ). Mortality was borderline significantly raised for breast cancer (SMR = 4.82, 95% CI: 0.99-14.1) but not significantly raised for other cancers or causes. Individuals diagnosed with t(11;22)(q23;q11) appear to be at several-fold increased breast cancer risk, with the greatest risks at premenopausal ages. Further research is required to understand the genetic mechanism involving 11q23 and 22q11 and there may be a need for enhanced breast cancer surveillance among female carriers.


Assuntos
Cromossomos Humanos Par 11 , Cromossomos Humanos Par 22 , Neoplasias/genética , Neoplasias/mortalidade , Translocação Genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Predisposição Genética para Doença , Heterozigoto , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Estudos Prospectivos , Reino Unido/epidemiologia , Adulto Jovem
20.
J Clin Endocrinol Metab ; 104(3): 658-664, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30137467

RESUMO

Context: There has been concern that GH treatment of children might increase meningioma risk. Results of published studies have been inconsistent and limited. Objective: To examine meningioma risks in relation to GH treatment. Design: Cohort study with follow-up via cancer registries and other registers. Setting: Population-based. Patients: A cohort of 10,403 patients treated in childhood with recombinant GH in five European countries since this treatment was first used in 1984. Expected rates from national cancer registration statistics. Main Outcome Measures: Risk of meningioma incidence. Results: During follow-up, 38 meningiomas occurred. Meningioma risk was greatly raised in the cohort overall [standardized incidence ratio (SIR) = 75.4; 95% CI: 54.9 to 103.6], as a consequence of high risk in subjects who had received radiotherapy for underlying malignancy (SIR = 658.4; 95% CI: 460.4 to 941.7). Risk was not significantly raised in patients who did not receive radiotherapy. Risk in radiotherapy-treated patients was not significantly related to mean daily dose of GH, duration of GH treatment, or cumulative dose of GH. Conclusions: Our data add to evidence of very high risk of meningioma in patients treated in childhood with GH after cranial radiotherapy, but suggest that GH may not affect radiotherapy-related risk, and that there is no material raised risk of meningioma in GH-treated patients who did not receive radiotherapy.


Assuntos
Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/efeitos adversos , Neoplasias Meníngeas/epidemiologia , Meningioma/epidemiologia , Segunda Neoplasia Primária/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Irradiação Craniana/efeitos adversos , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Neoplasias Meníngeas/etiologia , Meningioma/etiologia , Segunda Neoplasia Primária/etiologia , Proteínas Recombinantes/efeitos adversos , Sistema de Registros/estatística & dados numéricos , Medição de Risco , Adulto Jovem
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