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1.
Nat Commun ; 15(1): 4021, 2024 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-38740751

RESUMEN

The unexplained protective effect of childhood adiposity on breast cancer risk may be mediated via mammographic density (MD). Here, we investigate a complex relationship between adiposity in childhood and adulthood, puberty onset, MD phenotypes (dense area (DA), non-dense area (NDA), percent density (PD)), and their effects on breast cancer. We use Mendelian randomization (MR) and multivariable MR to estimate the total and direct effects of adiposity and age at menarche on MD phenotypes. Childhood adiposity has a decreasing effect on DA, while adulthood adiposity increases NDA. Later menarche increases DA/PD, but when accounting for childhood adiposity, this effect is attenuated. Next, we examine the effect of MD on breast cancer risk. DA/PD have a risk-increasing effect on breast cancer across all subtypes. The MD SNPs estimates are heterogeneous, and additional analyses suggest that different mechanisms may be linking MD and breast cancer. Finally, we evaluate the role of MD in the protective effect of childhood adiposity on breast cancer. Mediation MR analysis shows that 56% (95% CIs [32%-79%]) of this effect is mediated via DA. Our finding suggests that higher childhood adiposity decreases mammographic DA, subsequently reducing breast cancer risk. Understanding this mechanism is important for identifying potential intervention targets.


Asunto(s)
Adiposidad , Densidad de la Mama , Neoplasias de la Mama , Mamografía , Menarquia , Análisis de la Aleatorización Mendeliana , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/diagnóstico por imagen , Femenino , Adiposidad/genética , Factores de Riesgo , Niño , Tamaño Corporal , Adulto , Polimorfismo de Nucleótido Simple , Persona de Mediana Edad
2.
medRxiv ; 2023 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-37693539

RESUMEN

Observational studies suggest that mammographic density (MD) may have a role in the unexplained protective effect of childhood adiposity on breast cancer risk. Here, we investigated a complex and interlinked relationship between puberty onset, adiposity, MD, and their effects on breast cancer using Mendelian randomization (MR). We estimated the effects of childhood and adulthood adiposity, and age at menarche on MD phenotypes (dense area (DA), non-dense area (NDA), percent density (PD)) using MR and multivariable MR (MVMR), allowing us to disentangle their total and direct effects. Next, we examined the effect of MD on breast cancer risk, including risk of molecular subtypes, and accounting for genetic pleiotropy. Finally, we used MVMR to evaluate whether the protective effect of childhood adiposity on breast cancer was mediated by MD. Childhood adiposity had a strong inverse effect on mammographic DA, while adulthood adiposity increased NDA. Later menarche had an effect of increasing DA and PD, but when accounting for childhood adiposity, this effect attenuated to the null. DA and PD had a risk-increasing effect on breast cancer across all subtypes. The MD single-nucleotide polymorphism (SNP) estimates were extremely heterogeneous, and examination of the SNPs suggested different mechanisms may be linking MD and breast cancer. Finally, MR mediation analysis estimated that 56% (95% CIs [32% - 79%]) of the childhood adiposity effect on breast cancer risk was mediated via DA. In this work, we sought to disentangle the relationship between factors affecting MD and breast cancer. We showed that higher childhood adiposity decreases mammographic DA, which subsequently leads to reduced breast cancer risk. Understanding this mechanism is of great importance for identifying potential targets of intervention, since advocating weight gain in childhood would not be recommended.

3.
Obesity (Silver Spring) ; 31(3): 861-870, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36790827

RESUMEN

OBJECTIVE: The aim of this study was to systematically evaluate the direction of any potential causal effect between sleep and adiposity traits. METHODS: Two-sample Mendelian randomization was used to assess the association of genetically predicted sleep traits with adiposity and vice versa. Using data from UK Biobank and 23andMe, the sleep traits explored were morning preference (chronotype; N = 697,828), insomnia (N = 1,331,010), sleep duration (N = 446,118), napping (N = 452,633), and daytime sleepiness (N = 452,071). Using data from the Genetic Investigation of ANthropometric Traits (GIANT) and Early Growth Genetics (EGG) consortia, the adiposity traits explored were adult BMI, hip circumference (HC), waist circumference (WC), waist-hip ratio (WHR; N = 322,154), and childhood BMI (N = 35,668). RESULTS: This study found evidence that insomnia symptoms increased mean WC, BMI, and WHR (difference in means, WC = 0.39 SD [95% CI: 0.13-0.64], BMI = 0.47 SD [95% CI: 0.22-0.73], and WHR = 0.34 SD [95% CI: 0.16-0.52]). Napping increased mean WHR (0.23 SD [95% CI: 0.08-0.39]). Higher HC, WC, and adult BMI increased odds of daytime sleepiness (HC = 0.02 SD [95% CI: 0.01-0.04], WC = 0.04 SD [95% CI: 0.01-0.06], and BMI 0.02 SD [95% CI: 0.00-0.04]). This study also found that higher mean childhood BMI resulted in lower odds of napping (-0.01 SD [95% CI: 0.02-0.00]). CONCLUSIONS: The effects of insomnia on adiposity and of adiposity on daytime sleepiness suggest that poor sleep and weight gain may contribute to a feedback loop that could be detrimental to overall health.


Asunto(s)
Trastornos de Somnolencia Excesiva , Trastornos del Inicio y del Mantenimiento del Sueño , Adulto , Niño , Humanos , Adiposidad/genética , Índice de Masa Corporal , Análisis de la Aleatorización Mendeliana , Obesidad/genética , Factores de Riesgo , Sueño , Relación Cintura-Cadera
4.
J Mol Biol ; 434(17): 167663, 2022 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-35659507

RESUMEN

The tumor protein 53 (p53) is involved in transcription-dependent and independent processes. Several p53 variants related to cancer have been found to impact protein stability. Other variants, on the contrary, might have little impact on structural stability and have local or long-range effects on the p53 interactome. Our group previously identified a loop in the DNA binding domain (DBD) of p53 (residues 207-213) which can recruit different interactors. Experimental structures of p53 in complex with other proteins strengthen the importance of this interface for protein-protein interactions. We here characterized with structure-based approaches somatic and germline variants of p53 which could have a marginal effect in terms of stability and act locally or allosterically on the region 207-213 with consequences on the cytosolic functions of this protein. To this goal, we studied 1132 variants in the p53 DBD with structure-based approaches, accounting also for protein dynamics. We focused on variants predicted with marginal effects on structural stability. We then investigated each of these variants for their impact on DNA binding, dimerization of the p53 DBD, and intramolecular contacts with the 207-213 region. Furthermore, we identified variants that could modulate long-range the conformation of the region 207-213 using a coarse-grain model for allostery and all-atom molecular dynamics simulations. Our predictions have been further validated using enhanced sampling methods for 15 variants. The methodologies used in this study could be more broadly applied to other p53 variants or cases where conformational changes of loop regions are essential in the function of disease-related proteins.


Asunto(s)
Neoplasias , Proteína p53 Supresora de Tumor , Regulación Alostérica/genética , ADN/química , Humanos , Simulación de Dinámica Molecular , Mutación , Neoplasias/genética , Unión Proteica , Dominios Proteicos , Proteína p53 Supresora de Tumor/química , Proteína p53 Supresora de Tumor/genética
5.
Commun Biol ; 5(1): 337, 2022 04 08.
Artículo en Inglés | MEDLINE | ID: mdl-35396499

RESUMEN

Studies suggest that adiposity in childhood may reduce the risk of breast cancer in later life. The biological mechanism underlying this effect is unclear but is likely to be independent of body size in adulthood. Using a Mendelian randomization framework, we investigate 18 hypothesised mediators of the protective effect of childhood adiposity on later-life breast cancer, including hormonal, reproductive, physical, and glycaemic traits. Our results indicate that, while most of the hypothesised mediators are affected by childhood adiposity, only IGF-1 (OR: 1.08 [1.03: 1.15]), testosterone (total/free/bioavailable ~ OR: 1.12 [1.05: 1.20]), age at menopause (OR: 1.05 [1.03: 1.07]), and age at menarche (OR: 0.92 [0.86: 0.99], direct effect) influence breast cancer risk. However, multivariable Mendelian randomization analysis shows that the protective effect of childhood body size remains unaffected when accounting for these traits (ORs: 0.59-0.67). This suggests that none of the investigated potential mediators strongly contribute to the protective effect of childhood adiposity on breast cancer risk individually. It is plausible, however, that several related traits could collectively mediate the effect when analysed together, and this work provides a compelling foundation for investigating other mediating pathways in future studies.


Asunto(s)
Neoplasias de la Mama , Obesidad Infantil , Adiposidad/genética , Adulto , Índice de Masa Corporal , Neoplasias de la Mama/etiología , Neoplasias de la Mama/genética , Femenino , Humanos , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Factores de Riesgo
7.
Bioinformatics ; 37(9): 1304-1311, 2021 06 09.
Artículo en Inglés | MEDLINE | ID: mdl-33165574

RESUMEN

MOTIVATION: The wealth of data resources on human phenotypes, risk factors, molecular traits and therapeutic interventions presents new opportunities for population health sciences. These opportunities are paralleled by a growing need for data integration, curation and mining to increase research efficiency, reduce mis-inference and ensure reproducible research. RESULTS: We developed EpiGraphDB (https://epigraphdb.org/), a graph database containing an array of different biomedical and epidemiological relationships and an analytical platform to support their use in human population health data science. In addition, we present three case studies that illustrate the value of this platform. The first uses EpiGraphDB to evaluate potential pleiotropic relationships, addressing mis-inference in systematic causal analysis. In the second case study, we illustrate how protein-protein interaction data offer opportunities to identify new drug targets. The final case study integrates causal inference using Mendelian randomization with relationships mined from the biomedical literature to 'triangulate' evidence from different sources. AVAILABILITY AND IMPLEMENTATION: The EpiGraphDB platform is openly available at https://epigraphdb.org. Code for replicating case study results is available at https://github.com/MRCIEU/epigraphdb as Jupyter notebooks using the API, and https://mrcieu.github.io/epigraphdb-r using the R package. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Asunto(s)
Ciencia de los Datos , Programas Informáticos , Minería de Datos , Bases de Datos Factuales , Humanos , Fenotipo
8.
BMC Cancer ; 19(1): 824, 2019 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-31429720

RESUMEN

BACKGROUND: Genomic initiatives such as The Cancer Genome Atlas (TCGA) contain data from -omics profiling of thousands of tumor samples, which may be used to decipher cancer signaling, and related alterations. Managing and analyzing data from large-scale projects, such as TCGA, is a demanding task. It is difficult to dissect the high complexity hidden in genomic data and to account for inter-tumor heterogeneity adequately. METHODS: In this study, we used a robust statistical framework along with the integration of diverse bioinformatic tools to analyze next-generation sequencing data from more than 1000 patients from two different lung cancer subtypes, i.e., the lung adenocarcinoma (LUAD) and the squamous cell carcinoma (LUSC). RESULTS: We used the gene expression data to identify co-expression modules and differentially expressed genes to discriminate between LUAD and LUSC. We identified a group of genes which could act as specific oncogenes or tumor suppressor genes in one of the two lung cancer types, along with two dual role genes. Our results have been validated against other transcriptomics data of lung cancer patients. CONCLUSIONS: Our integrative approach allowed us to identify two key features: a substantial up-regulation of genes involved in O-glycosylation of mucins in LUAD, and a compromised immune response in LUSC. The immune-profile associated with LUSC might be linked to the activation of three oncogenic pathways, which promote the evasion of the antitumor immune response. Collectively, our results provide new future directions for the design of target therapies in lung cancer.


Asunto(s)
Adenocarcinoma del Pulmón/genética , Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/genética , Glicoproteínas de Membrana/genética , Mucina 5B/genética , Mucinas/genética , Adenocarcinoma del Pulmón/inmunología , Carcinoma de Células Escamosas/inmunología , Estudios de Cohortes , Bases de Datos de Ácidos Nucleicos , Regulación Neoplásica de la Expresión Génica , Glicosilación , Humanos , Interleucina-6/genética , Queratinas Tipo I/genética , Neoplasias Pulmonares/inmunología , Glicoproteínas de Membrana/metabolismo , Mucina 5B/metabolismo , Mucinas/metabolismo , Familia de Multigenes/genética , Modelos de Riesgos Proporcionales , RNA-Seq , Transcriptoma , Microambiente Tumoral/inmunología
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