RESUMEN

Since their introduction, epigenetic clocks have been extensively used in aging, human disease, and rejuvenation studies. In this article, we report an intriguing pattern: epigenetic age predictions display a 24-h periodicity. We tested a circadian blood sample collection using 17 epigenetic clocks addressing different aspects of aging. Thirteen clocks exhibited significant oscillations with the youngest and oldest age estimates around midnight and noon, respectively. In addition, daily oscillations were consistent with the changes of epigenetic age across different times of day observed in an independant populational dataset. While these oscillations can in part be attributed to variations in white blood cell type composition, cell count correction methods might not fully resolve the issue. Furthermore, some epigenetic clocks exhibited 24-h periodicity even in the purified fraction of neutrophils pointing at plausible contributions of intracellular epigenomic oscillations. Evidence for circadian variation in epigenetic clocks emphasizes the importance of the time-of-day for obtaining accurate estimates of epigenetic age.

Asunto(s)

Envejecimiento , Ritmo Circadiano , Epigénesis Genética , Humanos , Envejecimiento/genética , Ritmo Circadiano/genética , Ritmo Circadiano/fisiología , Adulto , Masculino , Persona de Mediana Edad , Femenino , Anciano , Adulto Joven

RESUMEN

Higher proportions of early-onset and estrogen receptor (ER) negative cancers are observed in women of African ancestry than in women of European ancestry. Differences in risk factor distributions and associations by age at diagnosis and ER status may explain this disparity. We analyzed data from 1,126 cases (aged 18-74 years) with invasive breast cancer and 2,106 controls recruited from a population-based case-control study in Ghana. Odds ratios (OR) and 95% confidence intervals (CI) were estimated for menstrual and reproductive factors using polytomous logistic regression models adjusted for potential confounders. Among controls, medians for age at menarche, parity, age at first birth, and breastfeeding/pregnancy were 15 years, 4 births, 20 years and 18 months, respectively. For women ≥50 years, parity and extended breastfeeding were associated with decreased risks: >5 births vs. nulliparous, OR 0.40 (95% CI 0.20-0.83) and 0.71 (95% CI 0.51-0.98) for ≥19 vs. <13 breastfeeding months/pregnancy, which did not differ by ER. In contrast, for earlier onset cases (<50 years) parity was associated with increased risk for ER-negative tumors (p-heterogeneity by ER = 0.02), which was offset by extended breastfeeding. Similar associations were observed by intrinsic-like subtypes. Less consistent relationships were observed with ages at menarche and first birth. Reproductive risk factor distributions are different from European populations but exhibited etiologic heterogeneity by age at diagnosis and ER status similar to other populations. Differences in reproductive patterns and subtype heterogeneity are consistent with racial disparities in subtype distributions.

Asunto(s)

Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/epidemiología , Mama/patología , Historia Reproductiva , Adolescente , Adulto , Factores de Edad , Anciano , Biomarcadores de Tumor/análisis , Biopsia , Mama/fisiopatología , Lactancia Materna/estadística & datos numéricos , Neoplasias de la Mama/patología , Neoplasias de la Mama/fisiopatología , Estudios de Casos y Controles , Femenino , Ghana/epidemiología , Humanos , Menarquia/fisiología , Persona de Mediana Edad , Paridad/fisiología , Receptores de Estrógenos/análisis , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/análisis , Receptores de Progesterona/metabolismo , Factores de Riesgo , Adulto Joven

RESUMEN

Relapse in acute myeloid leukemia (AML) may result from variable genetic origins or convergence on common biological processes. Exploiting the specificity and sensitivity of regulatory DNA, we analyze patient samples of multiple clinical outcomes covering various AML molecular subtypes. We uncover regulatory variation among patients translating into a transcriptional signature that predicts relapse risk. In addition, we find clusters of coexpressed genes within this signature selectively link to relapse risk in distinct patient subgroups defined by molecular subtype or AML maturation. Analyzing these gene clusters and the AML subtypes separately enhances their prognostic value substantially and provides insight in the mechanisms underlying relapse risk across the distinct patient subgroups. We propose that prognostic gene expression signatures in AML are valid only within patient subgroups and do not transcend these subgroups.

Asunto(s)

Regulación Leucémica de la Expresión Génica/genética , Histonas/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Acetilación , Adolescente , Niño , Preescolar , Secuenciación de Inmunoprecipitación de Cromatina , Epigénesis Genética , Femenino , Perfilación de la Expresión Génica , Ontología de Genes , Histonas/química , Humanos , Lactante , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Masculino , Familia de Multigenes , Mutación , Pronóstico , Recurrencia , Secuencias Reguladoras de Ácidos Nucleicos , Factores de Riesgo , Transcriptoma

RESUMEN

Glioma diagnosis is based on histomorphology and grading; however, such classification does not have predictive clinical outcome after glioblastomas have developed. To date, no bona fide biomarkers that significantly translate into a survival benefit to glioblastoma patients have been identified. We previously reported that the IDH mutant G-CIMP-high subtype would be a predecessor to the G-CIMP-low subtype. Here, we performed a comprehensive DNA methylation longitudinal analysis of diffuse gliomas from 77 patients (200 tumors) to enlighten the epigenome-based malignant transformation of initially lower-grade gliomas. Intra-subtype heterogeneity among G-CIMP-high primary tumors allowed us to identify predictive biomarkers for assessing the risk of malignant recurrence at early stages of disease. G-CIMP-low recurrence appeared in 9.5% of all gliomas, and these resembled IDH-wild-type primary glioblastoma. G-CIMP-low recurrence can be characterized by distinct epigenetic changes at candidate functional tissue enhancers with AP-1/SOX binding elements, mesenchymal stem cell-like epigenomic phenotype, and genomic instability. Molecular abnormalities of longitudinal G-CIMP offer possibilities to defy glioblastoma progression.

Asunto(s)

Neoplasias Encefálicas/patología , Metilación de ADN , Glioma/patología , Recurrencia Local de Neoplasia/genética , Adulto , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/terapia , Islas de CpG , Femenino , Inestabilidad Genómica , Glioma/genética , Glioma/mortalidad , Glioma/terapia , Humanos , Isocitrato Deshidrogenasa/genética , Estimación de Kaplan-Meier , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Mutación , Clasificación del Tumor , Células Madre Neoplásicas/citología , Células Madre Neoplásicas/metabolismo , Fenotipo , Pronóstico

RESUMEN

Objective To investigate the clinical heterogeneity of Parkinson's disease in the early stages.Methods Clinical data of demographic,motor phenotype,disease progression,cognitive,mood,autonomic and hallucination variables were collected from 143 patients with PD in the early stages.The patients' subtypes were explored with statistical cluster analysis of the clinical data.Results The analysis indicated four main subtypes:1.the younger-onset subtype(n=40);2.The tremor dominant subtype(n=57);3.the non-tremor dominant subtype with fast progression(n=17);4.The non-tremor dominant subtype with mild depression(n=29).Age at onset,posture-instability scores,the ratio of tremor scores to non-tremor scores,rate of progression and apathy scores all differentiated patients of respective subgroups.Conclusion The patients with early Parkinson's disease have marked heterogeneity in the clinical phenotype.