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1.
Cell ; 187(10): 2502-2520.e17, 2024 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-38729110

RESUMEN

Human tissue, which is inherently three-dimensional (3D), is traditionally examined through standard-of-care histopathology as limited two-dimensional (2D) cross-sections that can insufficiently represent the tissue due to sampling bias. To holistically characterize histomorphology, 3D imaging modalities have been developed, but clinical translation is hampered by complex manual evaluation and lack of computational platforms to distill clinical insights from large, high-resolution datasets. We present TriPath, a deep-learning platform for processing tissue volumes and efficiently predicting clinical outcomes based on 3D morphological features. Recurrence risk-stratification models were trained on prostate cancer specimens imaged with open-top light-sheet microscopy or microcomputed tomography. By comprehensively capturing 3D morphologies, 3D volume-based prognostication achieves superior performance to traditional 2D slice-based approaches, including clinical/histopathological baselines from six certified genitourinary pathologists. Incorporating greater tissue volume improves prognostic performance and mitigates risk prediction variability from sampling bias, further emphasizing the value of capturing larger extents of heterogeneous morphology.


Asunto(s)
Imagenología Tridimensional , Neoplasias de la Próstata , Aprendizaje Automático Supervisado , Humanos , Masculino , Aprendizaje Profundo , Imagenología Tridimensional/métodos , Pronóstico , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/diagnóstico por imagen , Microtomografía por Rayos X/métodos
2.
Bioinformatics ; 39(10)2023 10 03.
Artículo en Inglés | MEDLINE | ID: mdl-37846039

RESUMEN

MOTIVATION: Coincidence of Convergent Amino Acid Substitutions (CAAS) with phenotypic convergences allow pinpointing genes and even individual mutations that are likely to be associated with trait variation within their phylogenetic context. Such findings can provide useful insights into the genetic architecture of complex phenotypes. RESULTS: Here we introduce CAAStools, a set of bioinformatics tools to identify and validate CAAS in orthologous protein alignments for predefined groups of species representing the phenotypic values targeted by the user. AVAILABILITY AND IMPLEMENTATION: CAAStools source code is available at http://github.com/linudz/caastools, along with documentation and examples.


Asunto(s)
Biología Computacional , Programas Informáticos , Filogenia , Sustitución de Aminoácidos , Documentación
3.
Nucleic Acids Res ; 50(5): 2464-2479, 2022 03 21.
Artículo en Inglés | MEDLINE | ID: mdl-35176773

RESUMEN

The combined analysis of haplotype panels with phenotype clinical cohorts is a common approach to explore the genetic architecture of human diseases. However, genetic studies are mainly based on single nucleotide variants (SNVs) and small insertions and deletions (indels). Here, we contribute to fill this gap by generating a dense haplotype map focused on the identification, characterization, and phasing of structural variants (SVs). By integrating multiple variant identification methods and Logistic Regression Models (LRMs), we present a catalogue of 35 431 441 variants, including 89 178 SVs (≥50 bp), 30 325 064 SNVs and 5 017 199 indels, across 785 Illumina high coverage (30x) whole-genomes from the Iberian GCAT Cohort, containing a median of 3.52M SNVs, 606 336 indels and 6393 SVs per individual. The haplotype panel is able to impute up to 14 360 728 SNVs/indels and 23 179 SVs, showing a 2.7-fold increase for SVs compared with available genetic variation panels. The value of this panel for SVs analysis is shown through an imputed rare Alu element located in a new locus associated with Mononeuritis of lower limb, a rare neuromuscular disease. This study represents the first deep characterization of genetic variation within the Iberian population and the first operational haplotype panel to systematically include the SVs into genome-wide genetic studies.


Asunto(s)
Genoma Humano , Haplotipos , Mutación INDEL , Aciltransferasas , Europa (Continente) , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lipasa , Polimorfismo de Nucleótido Simple , Secuenciación Completa del Genoma/métodos
4.
Int J Mol Sci ; 25(12)2024 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-38928144

RESUMEN

This study aimed to investigate obesity-related glomerulopathy (ORG) at cellular, structural, and transcriptomic levels. Thirty Wistar rats were randomized into two groups: 15 rats were fed with a standard diet (SD-rats), and 15 rats were fed with a high-fat diet (HFD-rats). After 10 weeks, the weight, kidney function, histological features, and transcriptomic changes were assessed. HFD-rats gained significantly more weight (55.8% vs. 29.2%; p < 0.001) and albuminuria (10,384.04 ng/mL vs. 5845.45 ng/mL; p < 0.001) compared to SD-rats. HFD-rats exhibited early stages of ORG, with predominant mesangial matrix increase and podocyte hypertrophy (PH). These lesions correlated with differentially expressed (DE) genes and miRNAs. Functional analysis showed that miR-205, which was DE in both the kidneys and urine of HFD-rats, negatively regulated the PTEN gene, promoting lipid endocytosis in podocytes. The downregulation of PTEN was proved through a higher PTEN/nephrin ratio in the SD-rats and the presence of lipid vacuoles in HFD-podocytes. This study has found a specific targetome of miRNAs and gene expression in early stages of ORG. Also, it emphasizes the potential value of miR-205 as a urinary biomarker for detecting podocyte injury in ORG, offering a tool for early diagnosis, and opening new avenues for future therapeutic research of obesity-related glomerulopathy.


Asunto(s)
Dieta Alta en Grasa , MicroARNs , Obesidad , Podocitos , ARN Mensajero , Ratas Wistar , Animales , MicroARNs/genética , Obesidad/complicaciones , Obesidad/genética , Obesidad/metabolismo , Ratas , Dieta Alta en Grasa/efectos adversos , Masculino , Podocitos/metabolismo , Podocitos/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Enfermedades Renales/etiología , Enfermedades Renales/genética , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica , Transcriptoma , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo
5.
Lab Invest ; 103(12): 100265, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37858679

RESUMEN

Prostate cancer prognostication largely relies on visual assessment of a few thinly sectioned biopsy specimens under a microscope to assign a Gleason grade group (GG). Unfortunately, the assigned GG is not always associated with a patient's outcome in part because of the limited sampling of spatially heterogeneous tumors achieved by 2-dimensional histopathology. In this study, open-top light-sheet microscopy was used to obtain 3-dimensional pathology data sets that were assessed by 4 human readers. Intrabiopsy variability was assessed by asking readers to perform Gleason grading of 5 different levels per biopsy for a total of 20 core needle biopsies (ie, 100 total images). Intrabiopsy variability (Cohen κ) was calculated as the worst pairwise agreement in GG between individual levels within each biopsy and found to be 0.34, 0.34, 0.38, and 0.43 for the 4 pathologists. These preliminary results reveal that even within a 1-mm-diameter needle core, GG based on 2-dimensional images can vary dramatically depending on the location within a biopsy being analyzed. We believe that morphologic assessment of whole biopsies in 3 dimension has the potential to enable more reliable and consistent tumor grading.


Asunto(s)
Próstata , Neoplasias de la Próstata , Masculino , Humanos , Próstata/patología , Biopsia , Neoplasias de la Próstata/patología , Biopsia con Aguja Gruesa , Clasificación del Tumor
6.
BMC Public Health ; 23(1): 2552, 2023 12 21.
Artículo en Inglés | MEDLINE | ID: mdl-38129873

RESUMEN

BACKGROUND: Prostate cancer (PCa) was the second most frequent cancer and the fifth leading cause of cancer death among men in 2020. The aim of this study was to analyze trends in the incidence, mortality and survival of PCa in Girona, Spain, over 25 years. METHODS: Population-based study of PCa collected in the Girona Cancer Registry, 1994-2018. Age-adjusted incidence and mortality rates were calculated per 100,000 men-year. Joinpoint regression models were used for trends, calculating the annual percentage changes (APC). Observed and net survival were analyzed using Kaplan-Meier and Pohar-Perme estimations, respectively. RESULTS: A total of 9,846 cases of PCa were registered between 1994-2018. The age-adjusted incidence and mortality rates were 154.7 (95%CI: 151.7 157.8) and 38.9 (95%CI: 37.3 -40.6), respectively. An increased incidence of 6.2% was observed from 1994 to 2003 (95%CI: 4.4 -8.1), and a decrease of -2.7% (95%CI: -3.5 -;-1.9) between 2003 and 2018. Mortality APC was -2.6% (95%CI: -3.3 --2.0). Five-year observed and net survival were 72.8% (95%CI: 71.8 - 73.7) and 87.2% (95%CI: 85.9 - 88.4), respectively. Five-year net survival increased over time from 72.9% (1994-1998) to 91.3% (2014-2018). CONCLUSIONS: The analyses show a clear reduction in PCa incidence rates from 2003 on, along with an increase in overall survival when comparing the earlier period with more recent years.


Asunto(s)
Neoplasias Primarias Secundarias , Neoplasias de la Próstata , Masculino , Humanos , Incidencia , Neoplasias de la Próstata/epidemiología , Sistema de Registros , España/epidemiología , Tasa de Supervivencia
7.
PLoS Genet ; 16(5): e1008742, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32392208

RESUMEN

The rhesus macaque is an abundant species of Old World monkeys and a valuable model organism for biomedical research due to its close phylogenetic relationship to humans. Copy number variation is one of the main sources of genomic diversity within and between species and a widely recognized cause of inter-individual differences in disease risk. However, copy number differences among rhesus macaques and between the human and macaque genomes, as well as the relevance of this diversity to research involving this nonhuman primate, remain understudied. Here we present a high-resolution map of sequence copy number for the rhesus macaque genome constructed from a dataset of 198 individuals. Our results show that about one-eighth of the rhesus macaque reference genome is composed of recently duplicated regions, either copy number variable regions or fixed duplications. Comparison with human genomic copy number maps based on previously published data shows that, despite overall similarities in the genome-wide distribution of these regions, there are specific differences at the chromosome level. Some of these create differences in the copy number profile between human disease genes and their rhesus macaque orthologs. Our results highlight the importance of addressing the number of copies of target genes in the design of experiments and cautions against human-centered assumptions in research conducted with model organisms. Overall, we present a genome-wide copy number map from a large sample of rhesus macaque individuals representing an important novel contribution concerning the evolution of copy number in primate genomes.


Asunto(s)
Mapeo Cromosómico , Variaciones en el Número de Copia de ADN/fisiología , Duplicación de Gen/fisiología , Macaca mulatta/genética , Animales , Mapeo Cromosómico/veterinaria , Femenino , Genética de Población , Genoma , Secuenciación de Nucleótidos de Alto Rendimiento/veterinaria , Humanos , Macaca mulatta/clasificación , Masculino , Sistemas de Lectura Abierta/genética , Filogenia , Análisis de Secuencia de ADN/veterinaria , Especificidad de la Especie
8.
Mol Biol Evol ; 38(11): 4948-4961, 2021 10 27.
Artículo en Inglés | MEDLINE | ID: mdl-34297086

RESUMEN

The enormous mammal's lifespan variation is the result of each species' adaptations to their own biological trade-offs and ecological conditions. Comparative genomics have demonstrated that genomic factors underlying both, species lifespans and longevity of individuals, are in part shared across the tree of life. Here, we compared protein-coding regions across the mammalian phylogeny to detect individual amino acid (AA) changes shared by the most long-lived mammals and genes whose rates of protein evolution correlate with longevity. We discovered a total of 2,737 AA in 2,004 genes that distinguish long- and short-lived mammals, significantly more than expected by chance (P = 0.003). These genes belong to pathways involved in regulating lifespan, such as inflammatory response and hemostasis. Among them, a total 1,157 AA showed a significant association with maximum lifespan in a phylogenetic test. Interestingly, most of the detected AA positions do not vary in extant human populations (81.2%) or have allele frequencies below 1% (99.78%). Consequently, almost none of these putatively important variants could have been detected by genome-wide association studies. Additionally, we identified four more genes whose rate of protein evolution correlated with longevity in mammals. Crucially, SNPs located in the detected genes explain a larger fraction of human lifespan heritability than expected, successfully demonstrating for the first time that comparative genomics can be used to enhance interpretation of human genome-wide association studies. Finally, we show that the human longevity-associated proteins are significantly more stable than the orthologous proteins from short-lived mammals, strongly suggesting that general protein stability is linked to increased lifespan.


Asunto(s)
Estudio de Asociación del Genoma Completo , Longevidad , Envejecimiento/genética , Animales , Genómica , Humanos , Longevidad/genética , Mamíferos/genética , Filogenia
9.
Hum Genet ; 140(3): 441-455, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32772156

RESUMEN

Psychiatric disorders such as Schizophrenia (SCZ) and Bipolar Disorder (BD) represent an evolutionary paradox, as they exhibit strong negative effects on fitness, such as decreased fecundity and early mortality, yet they persist at a worldwide prevalence of approximately 1%. Molecular mechanisms affecting lifespan, which may be widely common among complex diseases with fitness effects, can be studied by the integrated analysis of data from genome-wide association studies (GWAS) of human longevity together with any disease of interest. Here, we report the first of such studies, focusing on the genetic overlap-pleiotropy-between two psychiatric disorders with shortened lifespan, SCZ and BD, and human parental lifespan (PLS) as a surrogate of life expectancy. Our results are twofold: first, we demonstrate extensive polygenic overlap between SCZ and PLS and to a lesser extent between BD and PLS. Second, we identified novel loci shared between PLS and SCZ (n = 39), and BD (n = 8). Whereas most of the identified SCZ (66%) and BD (62%) pleiotropic risk alleles were associated with reduced lifespan, we also detected some antagonistic protective alleles associated to shorter lifespans. In fact, top-associated SNPs with SCZ seems to explain longevity variance explained (LVE) better than many other life-threatening diseases, including Type 2 diabetes and most cancers, probably due to a high overlap with smoking-related pathways. Overall, our study provides evidence of a genetic burden driven through premature mortality among people with SCZ, which can have profound implications for understanding, and potentially treating, the mortality gap associated with this psychiatric disorder.


Asunto(s)
Trastorno Bipolar/genética , Predisposición Genética a la Enfermedad , Longevidad/genética , Esquizofrenia/genética , Estudios de Casos y Controles , Evolución Molecular , Estudio de Asociación del Genoma Completo , Humanos , Desequilibrio de Ligamiento , Polimorfismo de Nucleótido Simple
10.
Mod Pathol ; 34(3): 660-671, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-32759979

RESUMEN

The Gleason score is the most important prognostic marker for prostate cancer patients, but it suffers from significant observer variability. Artificial intelligence (AI) systems based on deep learning can achieve pathologist-level performance at Gleason grading. However, the performance of such systems can degrade in the presence of artifacts, foreign tissue, or other anomalies. Pathologists integrating their expertise with feedback from an AI system could result in a synergy that outperforms both the individual pathologist and the system. Despite the hype around AI assistance, existing literature on this topic within the pathology domain is limited. We investigated the value of AI assistance for grading prostate biopsies. A panel of 14 observers graded 160 biopsies with and without AI assistance. Using AI, the agreement of the panel with an expert reference standard increased significantly (quadratically weighted Cohen's kappa, 0.799 vs. 0.872; p = 0.019). On an external validation set of 87 cases, the panel showed a significant increase in agreement with a panel of international experts in prostate pathology (quadratically weighted Cohen's kappa, 0.733 vs. 0.786; p = 0.003). In both experiments, on a group-level, AI-assisted pathologists outperformed the unassisted pathologists and the standalone AI system. Our results show the potential of AI systems for Gleason grading, but more importantly, show the benefits of pathologist-AI synergy.


Asunto(s)
Aprendizaje Profundo , Diagnóstico por Computador , Interpretación de Imagen Asistida por Computador , Microscopía , Patólogos , Neoplasias de la Próstata/patología , Biopsia , Humanos , Masculino , Clasificación del Tumor , Variaciones Dependientes del Observador , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados
11.
Bioinformatics ; 36(3): 890-896, 2020 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-31393550

RESUMEN

MOTIVATION: Association studies based on SNP arrays and Next Generation Sequencing technologies have enabled the discovery of thousands of genetic loci related to human diseases. Nevertheless, their biological interpretation is still elusive, and their medical applications limited. Recently, various tools have been developed to help bridging the gap between genomes and phenomes. To our knowledge, however none of these tools allows users to retrieve the phenotype-wide list of genetic variants that may be linked to a given disease or to visually explore the joint genetic architecture of different pathologies. RESULTS: We present the Genome-Phenome Explorer (GePhEx), a web-tool easing the visual exploration of phenotypic relationships supported by genetic evidences. GePhEx is primarily based on the thorough analysis of linkage disequilibrium between disease-associated variants and also considers relationships based on genes, pathways or drug-targets, leveraging on publicly available variant-disease associations to detect potential relationships between diseases. We demonstrate that GePhEx does retrieve well-known relationships as well as novel ones, and that, thus, it might help shedding light on the patho-physiological mechanisms underlying complex diseases. To this end, we investigate the potential relationship between schizophrenia and lung cancer, first detected using GePhEx and provide further evidence supporting a functional link between them. AVAILABILITY AND IMPLEMENTATION: GePhEx is available at: https://gephex.ega-archive.org/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Asunto(s)
Estudio de Asociación del Genoma Completo , Genoma , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Fenómica , Fenotipo , Programas Informáticos
12.
Eur Radiol ; 31(3): 1336-1346, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32876839

RESUMEN

OBJECTIVES: To explore the associations between T1 and T2 magnetic resonance fingerprinting (MRF) measurements and corresponding tissue compartment ratios (TCRs) on whole mount histopathology of prostate cancer (PCa) and prostatitis. MATERIALS AND METHODS: A retrospective, IRB-approved, HIPAA-compliant cohort consisting of 14 PCa patients who underwent 3 T multiparametric MRI along with T1 and T2 MRF maps prior to radical prostatectomy was used. Correspondences between whole mount specimens and MRI and MRF were manually established. Prostatitis, PCa, and normal peripheral zone (PZ) regions of interest (ROIs) on pathology were segmented for TCRs of epithelium, lumen, and stroma using two U-net deep learning models. Corresponding ROIs were mapped to T2-weighted MRI (T2w), apparent diffusion coefficient (ADC), and T1 and T2 MRF maps. Their correlations with TCRs were computed using Pearson's correlation coefficient (R). Statistically significant differences in means were assessed using one-way ANOVA. RESULTS: Statistically significant differences (p < 0.01) in means of TCRs and T1 and T2 MRF were observed between PCa, prostatitis, and normal PZ. A negative correlation was observed between T1 and T2 MRF and epithelium (R = - 0.38, - 0.44, p < 0.05) of PCa. T1 MRF was correlated in opposite directions with stroma of PCa and prostatitis (R = 0.35, - 0.44, p < 0.05). T2 MRF was positively correlated with lumen of PCa and prostatitis (R = 0.57, 0.46, p < 0.01). Mean T2 MRF showed significant differences (p < 0.01) between PCa and prostatitis across both transition zone (TZ) and PZ, while mean T1 MRF was significant (p = 0.02) in TZ. CONCLUSION: Significant associations between MRF (T1 in the TZ and T2 in the PZ) and tissue compartments on corresponding histopathology were observed. KEY POINTS: • Mean T2 MRF measurements and ADC within cancerous regions of interest dropped with increasing ISUP prognostic groups (IPG). • Mean T1 and T2 MRF measurements were significantly different (p < 0.001) across IPGs, prostatitis, and normal peripheral zone (NPZ). • T2 MRF showed stronger correlations in the peripheral zone, while T1 MRF showed stronger correlations in the transition zone with histopathology for prostate cancer.


Asunto(s)
Aprendizaje Profundo , Neoplasias de la Próstata , Prostatitis , Imagen de Difusión por Resonancia Magnética , Epitelio , Humanos , Imagen por Resonancia Magnética , Masculino , Neoplasias de la Próstata/diagnóstico por imagen , Prostatitis/diagnóstico por imagen , Estudios Retrospectivos
13.
Lancet Oncol ; 21(1): 33-43, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31838010

RESUMEN

BACKGROUND: In hormone receptor-positive, HER2-negative early stage breast cancer, cyclin-dependent kinases 4 and 6 (CDK4/6) inhibition in combination with endocrine therapy could represent an alternative to multiagent chemotherapy. We aimed to evaluate the biological and clinical activity of neoadjuvant ribociclib plus letrozole in the luminal B subtype of early stage breast cancer. METHODS: CORALLEEN is a parallel-arm, multicentre, randomised, open-label, phase 2 trial completed across 21 hospitals in Spain. We recruited postmenopausal women (≥18 years) with stage I-IIIA hormone receptor-positive, Eastern Cooperative Oncology Group Performance Status 0-1, HER2-negative breast cancer and luminal B by PAM50 with histologically confirmed, operable primary tumour size of at least 2 cm in diameter as measured by MRI. Patients were randomly assigned (1:1) using a web-based system and permuted blocks of 25 to receive either six 28-days cycles of ribociclib (oral 600 mg once daily for 3 weeks on, 1 week off) plus daily letrozole (oral 2·5 mg/day) or four cycles of doxorubicin (intravenous 60 mg/m2) and cyclophosphamide (intravenous 600 mg/m2) every 21 days followed by weekly paclitaxel (intravenous 80 mg/m2) for 12 weeks. The total duration of the neoadjuvant therapy was 24 weeks. Randomisation was stratified by tumour size and nodal involvement. Samples were prospectively collected at baseline (day 0), day 15, and surgery. The primary endpoint was to evaluate the proportion of patients with PAM50 low-risk-of-relapse (ROR) disease at surgery in the modified intention-to-treat population including all randomly assigned patients who received study drug and had a baseline and at least one post-baseline measurement of ROR score. The PAM50 ROR risk class integrated gene expression data, tumour size, and nodal status to define prognosis. This trial was registered at ClinicalTrials.gov, NCT03248427. FINDINGS: Between July 27, 2017 to Dec 7, 2018, 106 patients were enrolled. At baseline, of the 106 patients, 92 (87%) patients had high ROR disease (44 [85%] of 52 in the ribociclib and letrozole group and 48 [89%] of 54 in the chemotherapy group) and 14 (13%) patients had intermediate-ROR disease (eight [15%] and six [11%]). Median follow-up was 200·0 days (IQR 191·2-206·0). At surgery, 23 (46·9%; 95% CI 32·5-61·7) of 49 patients in the ribociclib plus letrozole group and 24 (46·1%; 32·9-61·5) of 52 patients in the chemotherapy group were low-ROR. The most common grade 3-4 adverse events in the ribociclib plus letrozole group were neutropenia (22 [43%] of 51 patients) and elevated alanine aminotransferase concentrations (ten [20%]). The most common grade 3-4 adverse events in the chemotherapy group were neutropenia (31 [60%] of 52 patients) and febrile neutropenia (seven [13%]). No deaths were observed during the study in either group. INTERPRETATION: Our results suggest that some patients with high-risk, early stage, hormone receptor-positive, HER2-negative breast cancer could achieve molecular downstaging of their disease with CDK4/6 inhibitor and endocrine therapy. FUNDING: Novartis, Nanostring, Breast Cancer Research Foundation-AACR Career Development Award.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Lobular/tratamiento farmacológico , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Anciano , Aminopiridinas/administración & dosificación , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patología , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patología , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Letrozol/administración & dosificación , Persona de Mediana Edad , Posmenopausia , Pronóstico , Purinas/administración & dosificación
14.
Mol Biol Evol ; 35(8): 1990-2004, 2018 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-29788292

RESUMEN

Aging is a complex process affecting different species and individuals in different ways. Comparing genetic variation across species with their aging phenotypes will help understanding the molecular basis of aging and longevity. Although most studies on aging have so far focused on short-lived model organisms, recent comparisons of genomic, transcriptomic, and metabolomic data across lineages with different lifespans are unveiling molecular signatures associated with longevity. Here, we examine the relationship between genomic variation and maximum lifespan across primate species. We used two different approaches. First, we searched for parallel amino-acid mutations that co-occur with increases in longevity across the primate linage. Twenty-five such amino-acid variants were identified, several of which have been previously reported by studies with different experimental setups and in different model organisms. The genes harboring these mutations are mainly enriched in functional categories such as wound healing, blood coagulation, and cardiovascular disorders. We demonstrate that these pathways are highly enriched for pleiotropic effects, as predicted by the antagonistic pleiotropy theory of aging. A second approach was focused on changes in rates of protein evolution across the primate phylogeny. Using the phylogenetic generalized least squares, we show that some genes exhibit strong correlations between their evolutionary rates and longevity-associated traits. These include genes in the Sphingosine 1-phosphate pathway, PI3K signaling, and the Thrombin/protease-activated receptor pathway, among other cardiovascular processes. Together, these results shed light into human senescence patterns and underscore the power of comparative genomics to identify pathways related to aging and longevity.


Asunto(s)
Evolución Biológica , Longevidad/genética , Primates/genética , Animales , Femenino , Pleiotropía Genética , Humanos , Mutación
16.
Sci Rep ; 14(1): 13562, 2024 06 12.
Artículo en Inglés | MEDLINE | ID: mdl-38866890

RESUMEN

Risk of depression increased in the general population after the COVID-19 pandemic outbreak. By examining the interplay between genetics and individual environmental exposures during the COVID-19 lockdown, we have been able to gain an insight as to why some individuals are more vulnerable to depression, while others are more resilient. This study, conducted on a Spanish cohort of 9218 individuals (COVICAT), includes a comprehensive non-genetic risk analysis, the exposome, complemented by a genomics analysis in a subset of 2442 participants. Depression levels were evaluated using the Hospital Anxiety and Depression Scale. Together with Polygenic Risk Scores (PRS), we introduced a novel score; Poly-Environmental Risk Scores (PERS) for non-genetic risks to estimate the effect of each cumulative score and gene-environment interaction. We found significant positive associations for PERSSoc (Social and Household), PERSLife (Lifestyle and Behaviour), and PERSEnv (Wider Environment and Health) scores across all levels of depression severity, and for PRSB (Broad depression) only for moderate depression (OR 1.2, 95% CI 1.03-1.40). On average OR increased 1.2-fold for PERSEnv and 1.6-fold for PERLife and PERSoc from mild to severe depression level. The complete adjusted model explained 16.9% of the variance. We further observed an interaction between PERSEnv and PRSB showing a potential mitigating effect. In summary, stressors within the social and behavioral domains emerged as the primary drivers of depression risk in this population, unveiling a mitigating interaction effect that should be interpreted with caution.


Asunto(s)
COVID-19 , Depresión , Exposoma , Interacción Gen-Ambiente , Humanos , COVID-19/epidemiología , COVID-19/psicología , COVID-19/virología , Depresión/epidemiología , Depresión/etiología , Masculino , Femenino , Persona de Mediana Edad , Adulto , España/epidemiología , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/genética , Anciano , Factores de Riesgo , Pandemias , Cuarentena/psicología , Estudios de Cohortes
17.
J Pathol Clin Res ; 10(1): e347, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37919231

RESUMEN

In recent years, technological advances in tissue preparation, high-throughput volumetric microscopy, and computational infrastructure have enabled rapid developments in nondestructive 3D pathology, in which high-resolution histologic datasets are obtained from thick tissue specimens, such as whole biopsies, without the need for physical sectioning onto glass slides. While 3D pathology generates massive datasets that are attractive for automated computational analysis, there is also a desire to use 3D pathology to improve the visual assessment of tissue histology. In this perspective, we discuss and provide examples of potential advantages of 3D pathology for the visual assessment of clinical specimens and the challenges of dealing with large 3D datasets (of individual or multiple specimens) that pathologists have not been trained to interpret. We discuss the need for artificial intelligence triaging algorithms and explainable analysis methods to assist pathologists or other domain experts in the interpretation of these novel, often complex, large datasets.


Asunto(s)
Inteligencia Artificial , Microscopía , Humanos , Microscopía/métodos , Biopsia
18.
Genome Med ; 16(1): 21, 2024 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-38308367

RESUMEN

BACKGROUND: The immune system has a central role in preventing carcinogenesis. Alteration of systemic immune cell levels may increase cancer risk. However, the extent to which common genetic variation influences blood traits and cancer risk remains largely undetermined. Here, we identify pleiotropic variants and predict their underlying molecular and cellular alterations. METHODS: Multivariate Cox regression was used to evaluate associations between blood traits and cancer diagnosis in cases in the UK Biobank. Shared genetic variants were identified from the summary statistics of the genome-wide association studies of 27 blood traits and 27 cancer types and subtypes, applying the conditional/conjunctional false-discovery rate approach. Analysis of genomic positions, expression quantitative trait loci, enhancers, regulatory marks, functionally defined gene sets, and bulk- and single-cell expression profiles predicted the biological impact of pleiotropic variants. Plasma small RNAs were sequenced to assess association with cancer diagnosis. RESULTS: The study identified 4093 common genetic variants, involving 1248 gene loci, that contributed to blood-cancer pleiotropism. Genomic hotspots of pleiotropism include chromosomal regions 5p15-TERT and 6p21-HLA. Genes whose products are involved in regulating telomere length are found to be enriched in pleiotropic variants. Pleiotropic gene candidates are frequently linked to transcriptional programs that regulate hematopoiesis and define progenitor cell states of immune system development. Perturbation of the myeloid lineage is indicated by pleiotropic associations with defined master regulators and cell alterations. Eosinophil count is inversely associated with cancer risk. A high frequency of pleiotropic associations is also centered on the regulation of small noncoding Y-RNAs. Predicted pleiotropic Y-RNAs show specific regulatory marks and are overabundant in the normal tissue and blood of cancer patients. Analysis of plasma small RNAs in women who developed breast cancer indicates there is an overabundance of Y-RNA preceding neoplasm diagnosis. CONCLUSIONS: This study reveals extensive pleiotropism between blood traits and cancer risk. Pleiotropism is linked to factors and processes involved in hematopoietic development and immune system function, including components of the major histocompatibility complexes, and regulators of telomere length and myeloid lineage. Deregulation of Y-RNAs is also associated with pleiotropism. Overexpression of these elements might indicate increased cancer risk.


Asunto(s)
Estudio de Asociación del Genoma Completo , Neoplasias , Humanos , Femenino , Fenotipo , Sitios de Carácter Cuantitativo , Pleiotropía Genética , Neoplasias/genética , Polimorfismo de Nucleótido Simple , Predisposición Genética a la Enfermedad
19.
NPJ Breast Cancer ; 10(1): 20, 2024 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-38448600

RESUMEN

In this study, we performed genomic analyses of cell cycle and tumor microenvironment changes during and after ribociclib and letrozole or chemotherapy in the CORALLEEN trial. 106 women with untreated PAM50-defined Luminal B early breast cancers were randomly assigned to receive neoadjuvant ribociclib and letrozole or standard-of-care chemotherapy. Ki67 immunohistochemistry, tumor-infiltrating lymphocytes quantification, and RNA sequencing were obtained from tissue biopsies pre-treatment, on day 14 of treatment, and tumor specimens from surgical resection. Results showed that at surgery, Ki67 and the PAM50 proliferation scores were lower after ribociclib compared to chemotherapy. However, consistent reactivation of tumor cell proliferation from day 14 to surgery was only observed in the ribociclib arm. In tumors with complete cell cycle arrest (CCCA) at surgery, PAM50 proliferation scores were lower in the ribociclib arm compared to chemotherapy (p < 0.001), whereas the opposite was observed with tumor cellularity (p = 0.002). Gene expression signatures (GES) associated with antigen-presenting cells (APCs) and innate immune system activity showed increased expression post-chemotherapy but decreased expression post-ribociclib. Interferon-associated GES had decreased expression with CCCA and increased expression with non-CCCA. Our findings suggest that while both treatment strategies decreased proliferation, the depth and the patterns over time differed by treatment arm. Immunologically, ribociclib was associated with downregulated GES associated with APCs and the innate immune system in Luminal B tumors, contrary to existing preclinical data. Further studies are needed to understand the effect of CDK4/6 inhibition on the tumor cells and microenvironment, an effect which may vary according to tumor subtypes.

20.
Histopathology ; 62(6): 954-61, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23672314

RESUMEN

AIMS: To evaluate epithelial cell adhesion molecule (Ep-CAM) and E48 expression, and their relationship with histological differentiation and nodal metastasis, in laryngeal squamous cell carcinomas (SCC). METHODS AND RESULTS: The expression of Ep-CAM and E48 was investigated using immunohistochemistry in a series of 66 SCC (stages 3 and 4) and their adjacent non-neoplastic epithelia. Ep-CAM expression increased with the progression from normal squamous epithelium to SCC. It was detected in 96% of carcinomas and high levels of Ep-CAM expression (50% or more positive cells) were associated with poorer differentiation (P = 0.003) and the presence of lymph node metastases (P = 0.001). E48 expression was characteristically strong and diffuse in non-neoplastic squamous epithelium, and decreased with progression to SCC. Poorly differentiated (grade 4) tumours had lower proportions of E48-positive cells than well- to moderately- differentiated cases (P < 0.001). CONCLUSIONS: Expression of both Ep-CAM and E48 correlated with cell differentiation, although in inverse fashion. In particular, the association between high levels of Ep-CAM expression and high frequency of nodal metastases suggests that Ep-CAM plays a role in the development of lymph node metastases in SCC of the larynx.


Asunto(s)
Antígenos de Neoplasias/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/metabolismo , Moléculas de Adhesión Celular/metabolismo , Neoplasias Laríngeas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/secundario , Diferenciación Celular , Progresión de la Enfermedad , Molécula de Adhesión Celular Epitelial , Proteínas Ligadas a GPI/metabolismo , Humanos , Inmunohistoquímica , Neoplasias Laríngeas/patología , Metástasis Linfática , Masculino , Persona de Mediana Edad
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